Alzheimer's & Cognition

Only a small fraction of older adults in the early stages of Alzheimer’s disease (AD) meet eligibility criteria to receive treatment with newly approved antiamyloid drugs, largely because of the presence of medical conditions or neuroimaging findings, new research shows. 

Applying the clinical trial criteria, only about 8%-17% of amyloid-positive individuals with early AD would be eligible for lecanemab (Leqembi), and even fewer, 5%-9%, would be eligible for aducanumab (Aduhelm), the researchers found.

This study highlights the “limited suitability” of most adults with mild cognitive impairment (MCI) or mild dementia with elevated brain amyloid for treatment with these anti–beta amyloid monoclonal antibodies, write Maria Vassilaki, MD, PhD, and colleagues with Mayo Clinic, Rochester, Minn.

The study was published online in Neurology 

The authors of an accompanying editorial write that this study “provides an important estimate of treatment eligibility for amyloid-lowering monoclonal antibodies for early AD to help health systems make realistic plans for providing these treatments.”
 

More real-world data needed

Dr. Vassilaki and colleagues applied eligibility criteria for lecanemab and aducanumab to 237 older adults with MCI or mild dementia and increased brain amyloid burden from the Mayo Clinic Study of Aging (MCSA). Their mean age was 80.9 years, 55% were men, and most were White. 

After applying lecanemab’s inclusion criteria, less than half of the study population was eligible to receive treatment (112 of 237, or 47%). 

A total of 21 people were excluded because of a body mass index less than 17 or greater than or equal to 35; 48 due to a Clinical Dementia Rating (CDR) global score other than 0.5 or 1.0; 46 because they did not meet WMS-R Logical Memory II scores for age; 8 because of a Mini Mental State Examination (MMSE) score outside the bounds of 22-30; and two because of a CDR memory score less than 0.5. 

Applying lecanemab’s exclusion criteria further narrowed the number of eligible participants from 112 to 19 (8% of 237). 

Notable exclusions included cardiopulmonary contraindications, central nervous system–related exclusions such as brain cancer, Parkinson’s disease, epilepsy or brain injury, imaging findings, and history of cancer. 

The results were similar for aducanumab, with 104 of the 237 participants (44%) meeting the trial’s inclusion criteria. Applying aducanumab’s exclusion criteria further reduced the number of eligible participants to 12 (5% of 237).

A sensitivity analysis including participants with MCI, without CDR global, MMSE, or WMS-R Logical Memory II score restrictions, resulted in a somewhat higher percentage of eligible participants (17.4% for lecanemab and 8.9% for aducanumab). 
 

Shared decision-making

“Clinicians and health systems should be aware that by applying the clinical trial criteria, a smaller percentage might be eligible for these treatments than originally anticipated,” Dr. Vassilaki told this news organization. To help clinicians, there are published recommendations for the appropriate use of these treatments, she noted. 

Given that clinical trial participants are typically healthier than the general population, Dr. Vassilaki said that research is needed to examine the safety and efficacy of antiamyloid therapies in larger, more diverse populations as well as in less healthy populations, before these therapies may be more widely available to people with AD. 

“We can take advantage of the postmarketing surveillance of side effects, and also enrollment of patients receiving these treatments to registries could provide us with data useful for any necessary adjustment to drug use,” Dr. Vassilaki told this news organization. 
 

‘Sharp focus’

This study “brings the issue of eligibility for amyloid-lowering antibody treatment into sharp focus,” Matthew Howe, MD, PhD, with Butler Hospital Memory & Aging Program, Providence, R.I., and colleagues note in their editorial. 

“The results underscore the importance of careful patient selection to help identify patients most likely to benefit from treatment and exclude those at risk for serious outcomes,” they write. 

They also write that appropriate use recommendations for lecanemab and aducanumab “will be revisited as more real-world data emerge, especially about safety.”

For now, clinicians “must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” they add. 

The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation and the Schuler Foundation. Dr. Vassilaki has consulted for F. Hoffmann-La Roche and has equity ownership in Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no conflicts of interest. 

A version of this article first appeared on Medscape.com.

Only a small fraction of older adults in the early stages of Alzheimer’s disease (AD) meet eligibility criteria to receive treatment with newly approved antiamyloid drugs, largely because of the presence of medical conditions or neuroimaging findings, new research shows. 

Applying the clinical trial criteria, only about 8%-17% of amyloid-positive individuals with early AD would be eligible for lecanemab (Leqembi), and even fewer, 5%-9%, would be eligible for aducanumab (Aduhelm), the researchers found.

This study highlights the “limited suitability” of most adults with mild cognitive impairment (MCI) or mild dementia with elevated brain amyloid for treatment with these anti–beta amyloid monoclonal antibodies, write Maria Vassilaki, MD, PhD, and colleagues with Mayo Clinic, Rochester, Minn.

The study was published online in Neurology 

The authors of an accompanying editorial write that this study “provides an important estimate of treatment eligibility for amyloid-lowering monoclonal antibodies for early AD to help health systems make realistic plans for providing these treatments.”
 

More real-world data needed

Dr. Vassilaki and colleagues applied eligibility criteria for lecanemab and aducanumab to 237 older adults with MCI or mild dementia and increased brain amyloid burden from the Mayo Clinic Study of Aging (MCSA). Their mean age was 80.9 years, 55% were men, and most were White. 

After applying lecanemab’s inclusion criteria, less than half of the study population was eligible to receive treatment (112 of 237, or 47%). 

A total of 21 people were excluded because of a body mass index less than 17 or greater than or equal to 35; 48 due to a Clinical Dementia Rating (CDR) global score other than 0.5 or 1.0; 46 because they did not meet WMS-R Logical Memory II scores for age; 8 because of a Mini Mental State Examination (MMSE) score outside the bounds of 22-30; and two because of a CDR memory score less than 0.5. 

Applying lecanemab’s exclusion criteria further narrowed the number of eligible participants from 112 to 19 (8% of 237). 

Notable exclusions included cardiopulmonary contraindications, central nervous system–related exclusions such as brain cancer, Parkinson’s disease, epilepsy or brain injury, imaging findings, and history of cancer. 

The results were similar for aducanumab, with 104 of the 237 participants (44%) meeting the trial’s inclusion criteria. Applying aducanumab’s exclusion criteria further reduced the number of eligible participants to 12 (5% of 237).

A sensitivity analysis including participants with MCI, without CDR global, MMSE, or WMS-R Logical Memory II score restrictions, resulted in a somewhat higher percentage of eligible participants (17.4% for lecanemab and 8.9% for aducanumab). 
 

Shared decision-making

“Clinicians and health systems should be aware that by applying the clinical trial criteria, a smaller percentage might be eligible for these treatments than originally anticipated,” Dr. Vassilaki told this news organization. To help clinicians, there are published recommendations for the appropriate use of these treatments, she noted. 

Given that clinical trial participants are typically healthier than the general population, Dr. Vassilaki said that research is needed to examine the safety and efficacy of antiamyloid therapies in larger, more diverse populations as well as in less healthy populations, before these therapies may be more widely available to people with AD. 

“We can take advantage of the postmarketing surveillance of side effects, and also enrollment of patients receiving these treatments to registries could provide us with data useful for any necessary adjustment to drug use,” Dr. Vassilaki told this news organization. 
 

‘Sharp focus’

This study “brings the issue of eligibility for amyloid-lowering antibody treatment into sharp focus,” Matthew Howe, MD, PhD, with Butler Hospital Memory & Aging Program, Providence, R.I., and colleagues note in their editorial. 

“The results underscore the importance of careful patient selection to help identify patients most likely to benefit from treatment and exclude those at risk for serious outcomes,” they write. 

They also write that appropriate use recommendations for lecanemab and aducanumab “will be revisited as more real-world data emerge, especially about safety.”

For now, clinicians “must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” they add. 

The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation and the Schuler Foundation. Dr. Vassilaki has consulted for F. Hoffmann-La Roche and has equity ownership in Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no conflicts of interest. 

A version of this article first appeared on Medscape.com.

Only a small fraction of older adults in the early stages of Alzheimer’s disease (AD) meet eligibility criteria to receive treatment with newly approved antiamyloid drugs, largely because of the presence of medical conditions or neuroimaging findings, new research shows. 

Applying the clinical trial criteria, only about 8%-17% of amyloid-positive individuals with early AD would be eligible for lecanemab (Leqembi), and even fewer, 5%-9%, would be eligible for aducanumab (Aduhelm), the researchers found.

This study highlights the “limited suitability” of most adults with mild cognitive impairment (MCI) or mild dementia with elevated brain amyloid for treatment with these anti–beta amyloid monoclonal antibodies, write Maria Vassilaki, MD, PhD, and colleagues with Mayo Clinic, Rochester, Minn.

The study was published online in Neurology 

The authors of an accompanying editorial write that this study “provides an important estimate of treatment eligibility for amyloid-lowering monoclonal antibodies for early AD to help health systems make realistic plans for providing these treatments.”
 

More real-world data needed

Dr. Vassilaki and colleagues applied eligibility criteria for lecanemab and aducanumab to 237 older adults with MCI or mild dementia and increased brain amyloid burden from the Mayo Clinic Study of Aging (MCSA). Their mean age was 80.9 years, 55% were men, and most were White. 

After applying lecanemab’s inclusion criteria, less than half of the study population was eligible to receive treatment (112 of 237, or 47%). 

A total of 21 people were excluded because of a body mass index less than 17 or greater than or equal to 35; 48 due to a Clinical Dementia Rating (CDR) global score other than 0.5 or 1.0; 46 because they did not meet WMS-R Logical Memory II scores for age; 8 because of a Mini Mental State Examination (MMSE) score outside the bounds of 22-30; and two because of a CDR memory score less than 0.5. 

Applying lecanemab’s exclusion criteria further narrowed the number of eligible participants from 112 to 19 (8% of 237). 

Notable exclusions included cardiopulmonary contraindications, central nervous system–related exclusions such as brain cancer, Parkinson’s disease, epilepsy or brain injury, imaging findings, and history of cancer. 

The results were similar for aducanumab, with 104 of the 237 participants (44%) meeting the trial’s inclusion criteria. Applying aducanumab’s exclusion criteria further reduced the number of eligible participants to 12 (5% of 237).

A sensitivity analysis including participants with MCI, without CDR global, MMSE, or WMS-R Logical Memory II score restrictions, resulted in a somewhat higher percentage of eligible participants (17.4% for lecanemab and 8.9% for aducanumab). 
 

Shared decision-making

“Clinicians and health systems should be aware that by applying the clinical trial criteria, a smaller percentage might be eligible for these treatments than originally anticipated,” Dr. Vassilaki told this news organization. To help clinicians, there are published recommendations for the appropriate use of these treatments, she noted. 

Given that clinical trial participants are typically healthier than the general population, Dr. Vassilaki said that research is needed to examine the safety and efficacy of antiamyloid therapies in larger, more diverse populations as well as in less healthy populations, before these therapies may be more widely available to people with AD. 

“We can take advantage of the postmarketing surveillance of side effects, and also enrollment of patients receiving these treatments to registries could provide us with data useful for any necessary adjustment to drug use,” Dr. Vassilaki told this news organization. 
 

‘Sharp focus’

This study “brings the issue of eligibility for amyloid-lowering antibody treatment into sharp focus,” Matthew Howe, MD, PhD, with Butler Hospital Memory & Aging Program, Providence, R.I., and colleagues note in their editorial. 

“The results underscore the importance of careful patient selection to help identify patients most likely to benefit from treatment and exclude those at risk for serious outcomes,” they write. 

They also write that appropriate use recommendations for lecanemab and aducanumab “will be revisited as more real-world data emerge, especially about safety.”

For now, clinicians “must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” they add. 

The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation and the Schuler Foundation. Dr. Vassilaki has consulted for F. Hoffmann-La Roche and has equity ownership in Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no conflicts of interest. 

A version of this article first appeared on Medscape.com.

The anti–amyloid-beta monoclonal antibodies lecanemab and aducanumab have introduced a new class of drugs for targeting early stage Alzheimer’s disease, but fewer than 10% of older adults with early signs of the disease would meet eligibility requirements to receive either treatment, a cross sectional study has found.

Reporting in the journal Neurology, researchers from the Mayo Clinic in Rochester, Minn., and the University of Chicago found that only a small percentage of patients in the Mayo Clinic Study of Aging (MCSA) with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease would meet the clinical trial eligibility requirements of either agent.

Mayo Clinic

“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” said lead researcher Maria Vassilaki, MD, PhD, an epidemiologist at Mayo Clinic in Rochester, Minn.
 

Applying clinical trial exclusion criteria to a broader population

The study included 237 people aged 50-90, 222 who had MCI and 15 with mild dementia, and whose brain scans showed increased amounts of amyloid-beta plaques. Average age of the participants was 80.9 years and 97.5% were White (99.6% not Hispanic or Latino).

The researchers then looked at the eligibility criteria for the pivotal clinical trials for lecanemab, which the U.S. Food and Drug Administration approved in January this year, and aducanumab, which the FDA cleared in 2021. Both drugs received FDA accelerated approval.

For lecanemab, clinical trial inclusion required specific scores for the Clinical Dementia Rating (CDR) (other than 0.5 or 1.0), Wechsler Memory Scale (WMS-R) Logical Memory II (which varied with age group), or Mini-Mental State Examination (MMSE) (22 to 30). A body mass index between 17 and 35 kg/m² was also an inclusion criteria. Only 112 people, or 47%, met the inclusion criteria. Exclusion criteria included a history of cardiovascular disease or cancer, Parkinson’s disease, or brain injury, or a positive brain scan. When the exclusion criteria were applied, only 19 people, or 8%, qualified for the lecanemab trial.

When the researchers modified the exclusion criteria to include all study participants with MCI but not applying results from additional cognitive tests, 17.4% of MCSA patients would have been eligible for the lecanemab trial.

Aducanumab clinical trial inclusion criteria were a CDR global score other than 0.5 and an MMSE below 24, with an age cutoff of 85 years. Only 104 of the MCSA population, or 44%, met the clinical trial criteria. When the researchers applied the exclusion criteria for cardiovascular disease, central nervous system-related exclusions (such as brain cancer or epilepsy), a history of cancer, or brain scan abnormalities, they found that only 12 people, or 5%, would have been eligible for an aducanumab trial.

“Clinical trials often have strict eligibility criteria and could exclude those with other conditions that could be common in older adults,” Dr. Vassilaki said in emailed comments. “Thus, we wanted to examine if we apply these criteria to a study that recruits participants from the community, how many of the individuals in the early symptomatic stages, mild cognitive impairment or mild dementia due to Alzheimer’s disease, would be eligible for the treatment.”

Dr. Vassilaki said these drugs need to be studied in larger, more diverse populations, as well as in less healthy populations, before they’re more widely available to people with Alzheimer’s disease. “In addition,” she said, “we can learn more from the postmarketing surveillance of side effects and also from registries of patients receiving these treatments.”

One limitation of the study Dr. Vassilaki pointed out is the overwhelmingly White population. Evaluating the clinical trial eligibility criteria in more diverse populations is crucial, she said.
 

Estimating the number of patients who would qualify for treatment

In an accompanying commentary, Matthew Howes, MD, of Butler Hospital and Brown University in Providence, R.I., and colleagues wrote that the study findings provide health systems planning to offer amyloid-lowering antibodies for Alzheimer’s disease an estimate of how many patients would be eligible for the treatments. “Providers must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” the commentators wrote.

The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation, and the Schuler Foundation. Dr. Vassilaki disclosed relationships with F. Hoffmann-La Roche, Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no relevant disclosures.
 

The anti–amyloid-beta monoclonal antibodies lecanemab and aducanumab have introduced a new class of drugs for targeting early stage Alzheimer’s disease, but fewer than 10% of older adults with early signs of the disease would meet eligibility requirements to receive either treatment, a cross sectional study has found.

Reporting in the journal Neurology, researchers from the Mayo Clinic in Rochester, Minn., and the University of Chicago found that only a small percentage of patients in the Mayo Clinic Study of Aging (MCSA) with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease would meet the clinical trial eligibility requirements of either agent.

Mayo Clinic

“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” said lead researcher Maria Vassilaki, MD, PhD, an epidemiologist at Mayo Clinic in Rochester, Minn.
 

Applying clinical trial exclusion criteria to a broader population

The study included 237 people aged 50-90, 222 who had MCI and 15 with mild dementia, and whose brain scans showed increased amounts of amyloid-beta plaques. Average age of the participants was 80.9 years and 97.5% were White (99.6% not Hispanic or Latino).

The researchers then looked at the eligibility criteria for the pivotal clinical trials for lecanemab, which the U.S. Food and Drug Administration approved in January this year, and aducanumab, which the FDA cleared in 2021. Both drugs received FDA accelerated approval.

For lecanemab, clinical trial inclusion required specific scores for the Clinical Dementia Rating (CDR) (other than 0.5 or 1.0), Wechsler Memory Scale (WMS-R) Logical Memory II (which varied with age group), or Mini-Mental State Examination (MMSE) (22 to 30). A body mass index between 17 and 35 kg/m² was also an inclusion criteria. Only 112 people, or 47%, met the inclusion criteria. Exclusion criteria included a history of cardiovascular disease or cancer, Parkinson’s disease, or brain injury, or a positive brain scan. When the exclusion criteria were applied, only 19 people, or 8%, qualified for the lecanemab trial.

When the researchers modified the exclusion criteria to include all study participants with MCI but not applying results from additional cognitive tests, 17.4% of MCSA patients would have been eligible for the lecanemab trial.

Aducanumab clinical trial inclusion criteria were a CDR global score other than 0.5 and an MMSE below 24, with an age cutoff of 85 years. Only 104 of the MCSA population, or 44%, met the clinical trial criteria. When the researchers applied the exclusion criteria for cardiovascular disease, central nervous system-related exclusions (such as brain cancer or epilepsy), a history of cancer, or brain scan abnormalities, they found that only 12 people, or 5%, would have been eligible for an aducanumab trial.

“Clinical trials often have strict eligibility criteria and could exclude those with other conditions that could be common in older adults,” Dr. Vassilaki said in emailed comments. “Thus, we wanted to examine if we apply these criteria to a study that recruits participants from the community, how many of the individuals in the early symptomatic stages, mild cognitive impairment or mild dementia due to Alzheimer’s disease, would be eligible for the treatment.”

Dr. Vassilaki said these drugs need to be studied in larger, more diverse populations, as well as in less healthy populations, before they’re more widely available to people with Alzheimer’s disease. “In addition,” she said, “we can learn more from the postmarketing surveillance of side effects and also from registries of patients receiving these treatments.”

One limitation of the study Dr. Vassilaki pointed out is the overwhelmingly White population. Evaluating the clinical trial eligibility criteria in more diverse populations is crucial, she said.
 

Estimating the number of patients who would qualify for treatment

In an accompanying commentary, Matthew Howes, MD, of Butler Hospital and Brown University in Providence, R.I., and colleagues wrote that the study findings provide health systems planning to offer amyloid-lowering antibodies for Alzheimer’s disease an estimate of how many patients would be eligible for the treatments. “Providers must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” the commentators wrote.

The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation, and the Schuler Foundation. Dr. Vassilaki disclosed relationships with F. Hoffmann-La Roche, Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no relevant disclosures.
 

The anti–amyloid-beta monoclonal antibodies lecanemab and aducanumab have introduced a new class of drugs for targeting early stage Alzheimer’s disease, but fewer than 10% of older adults with early signs of the disease would meet eligibility requirements to receive either treatment, a cross sectional study has found.

Reporting in the journal Neurology, researchers from the Mayo Clinic in Rochester, Minn., and the University of Chicago found that only a small percentage of patients in the Mayo Clinic Study of Aging (MCSA) with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease would meet the clinical trial eligibility requirements of either agent.

Mayo Clinic

“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” said lead researcher Maria Vassilaki, MD, PhD, an epidemiologist at Mayo Clinic in Rochester, Minn.
 

Applying clinical trial exclusion criteria to a broader population

The study included 237 people aged 50-90, 222 who had MCI and 15 with mild dementia, and whose brain scans showed increased amounts of amyloid-beta plaques. Average age of the participants was 80.9 years and 97.5% were White (99.6% not Hispanic or Latino).

The researchers then looked at the eligibility criteria for the pivotal clinical trials for lecanemab, which the U.S. Food and Drug Administration approved in January this year, and aducanumab, which the FDA cleared in 2021. Both drugs received FDA accelerated approval.

For lecanemab, clinical trial inclusion required specific scores for the Clinical Dementia Rating (CDR) (other than 0.5 or 1.0), Wechsler Memory Scale (WMS-R) Logical Memory II (which varied with age group), or Mini-Mental State Examination (MMSE) (22 to 30). A body mass index between 17 and 35 kg/m² was also an inclusion criteria. Only 112 people, or 47%, met the inclusion criteria. Exclusion criteria included a history of cardiovascular disease or cancer, Parkinson’s disease, or brain injury, or a positive brain scan. When the exclusion criteria were applied, only 19 people, or 8%, qualified for the lecanemab trial.

When the researchers modified the exclusion criteria to include all study participants with MCI but not applying results from additional cognitive tests, 17.4% of MCSA patients would have been eligible for the lecanemab trial.

Aducanumab clinical trial inclusion criteria were a CDR global score other than 0.5 and an MMSE below 24, with an age cutoff of 85 years. Only 104 of the MCSA population, or 44%, met the clinical trial criteria. When the researchers applied the exclusion criteria for cardiovascular disease, central nervous system-related exclusions (such as brain cancer or epilepsy), a history of cancer, or brain scan abnormalities, they found that only 12 people, or 5%, would have been eligible for an aducanumab trial.

“Clinical trials often have strict eligibility criteria and could exclude those with other conditions that could be common in older adults,” Dr. Vassilaki said in emailed comments. “Thus, we wanted to examine if we apply these criteria to a study that recruits participants from the community, how many of the individuals in the early symptomatic stages, mild cognitive impairment or mild dementia due to Alzheimer’s disease, would be eligible for the treatment.”

Dr. Vassilaki said these drugs need to be studied in larger, more diverse populations, as well as in less healthy populations, before they’re more widely available to people with Alzheimer’s disease. “In addition,” she said, “we can learn more from the postmarketing surveillance of side effects and also from registries of patients receiving these treatments.”

One limitation of the study Dr. Vassilaki pointed out is the overwhelmingly White population. Evaluating the clinical trial eligibility criteria in more diverse populations is crucial, she said.
 

Estimating the number of patients who would qualify for treatment

In an accompanying commentary, Matthew Howes, MD, of Butler Hospital and Brown University in Providence, R.I., and colleagues wrote that the study findings provide health systems planning to offer amyloid-lowering antibodies for Alzheimer’s disease an estimate of how many patients would be eligible for the treatments. “Providers must exercise clinical judgment in selecting patients for treatment with shared decision-making with patients and families,” the commentators wrote.

The study was supported by the National Institutes of Health, the National Institute on Aging, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Mayo Foundation for Medical Education and Research, the Liston Award, the GHR Foundation, and the Schuler Foundation. Dr. Vassilaki disclosed relationships with F. Hoffmann-La Roche, Abbott Laboratories, Johnson & Johnson, Medtronic, Merck, and Amgen. Dr. Howe has no relevant disclosures.
 

Even at an advanced age, superagers have the memory of someone 20 or 30 years their junior. But why is that? A new study shows that, in superagers, age-related atrophy of the gray matter, especially in the areas responsible for memory, develops much more slowly than in normal older adults. However, the study also emphasizes the importance of physical and mental fitness for a healthy aging process.

“One of the most important unanswered questions with regard to superagers is: ‘Are they resistant to age-related memory loss, or do they have coping mechanisms that allow them to better offset this memory loss?’ ” wrote Marta Garo-Pascual, a PhD candidate at the Autonomous University of Madrid, Spain, and colleagues in the Lancet Healthy Longevity. “Our results indicate that superagers are resistant to these processes.”
 

Six years’ monitoring

From a cohort of older adults who had participated in a study aiming to identify early indicators of Alzheimer’s disease, the research group chose 64 superagers and 55 normal senior citizens. The latter served as the control group. While the superagers performed just as well in a memory test as people 30 years their junior, the control group’s performance was in line with their age and level of education.

All study participants were over age 79 years. Both the group of superagers and the control group included more females than males. On average, they were monitored for 6 years. During this period, a checkup was scheduled annually with an MRI examination, clinical tests, blood tests, and documentation of lifestyle factors.

For Alessandro Cellerino, PhD, of the Leibniz Institute on Aging–Fritz Lipmann Institute in Jena, Germany, this is the most crucial aspect of the study. “Even before this study, we knew that superagers demonstrated less atrophy in certain areas of the brain, but this was always only ever based on a single measurement.”
 

Memory centers protected

The MRI examinations confirmed that in superagers, gray matter atrophy in the regions responsible for memory (such as the medial temporal lobe and cholinergic forebrain), as well in regions important for movement (such as the motor thalamus), was less pronounced. In addition, the volume of gray matter in these regions, especially in the medial temporal lobe, decreased much more slowly in the superagers than in the control subjects over the study period.

Ms. Garo-Pascual and associates used a machine-learning algorithm to differentiate between superagers and normal older adults. From the 89 demographic, lifestyle, and clinical factors entered into the algorithm, two were the most important for the classification: the ability to move and mental health.
 

Mobility and mental health

Clinical tests such as the Timed Up-and-Go Test and the Finger Tapping Test revealed that superagers can be distinguished from the normally aging control subjects with regard to their mobility and fine motor skills. Their physical condition was better, although they, by their own admission, did not move any more than the control subjects in day-to-day life. According to Dr. Cellerino, this finding confirms that physical activity is paramount for cognitive function. “These people were over 80 years old – the fact that there was not much difference between their levels of activity is not surprising. Much more relevant is the question of how you get there – i.e., how active you are at the ages of 40, 50 or even 60 years old.”

Remaining active is important

As a matter of fact, the superagers indicated that generally they had been more active than the control subjects during their middle years. “Attempting to stay physically fit is essential; even if it just means going for a walk or taking the stairs,” said Dr. Cellerino.

On average, the superagers also fared much better in tests on physical health than the control subjects. They suffered significantly less from depression or anxiety disorders. “Earlier studies suggest that depression and anxiety disorders may influence performance in memory tests across all ages and that they are risk factors for developing dementia,” said Dr. Cellerino.

To avoid mental health issues in later life, gerontologist Dr. Cellerino recommended remaining socially engaged and involved. “Depression and anxiety are commonly also a consequence of social isolation,” he said.
 

Potential genetic differences

Blood sample analyses demonstrated that the superagers exhibited lower concentrations of biomarkers for neurodegenerative diseases than the control group did. In contrast, there was no difference between the two groups in the prevalence of the apo e4 allele, one of the most important genetic risk factors for Alzheimer’s disease. Nevertheless, Ms. Garo-Pascual and associates assume that genetics also play a role. They found that, despite 89 variables employed, the algorithm used could only distinguish superagers from normal older adults 66% of the time. This suggests that additional factors must be in play, such as genetic differences.

Body and mind

Since this is an observational study, whether the determined factors have a direct effect on superaging cannot be ascertained, the authors wrote. However, the results are consistent with earlier findings.

“Regarding the management of old age, we actually haven’t learned anything more than what we already knew. But it does confirm that physical and mental function are closely entwined and that we must maintain both to age healthily,” Dr. Cellerino concluded.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Even at an advanced age, superagers have the memory of someone 20 or 30 years their junior. But why is that? A new study shows that, in superagers, age-related atrophy of the gray matter, especially in the areas responsible for memory, develops much more slowly than in normal older adults. However, the study also emphasizes the importance of physical and mental fitness for a healthy aging process.

“One of the most important unanswered questions with regard to superagers is: ‘Are they resistant to age-related memory loss, or do they have coping mechanisms that allow them to better offset this memory loss?’ ” wrote Marta Garo-Pascual, a PhD candidate at the Autonomous University of Madrid, Spain, and colleagues in the Lancet Healthy Longevity. “Our results indicate that superagers are resistant to these processes.”
 

Six years’ monitoring

From a cohort of older adults who had participated in a study aiming to identify early indicators of Alzheimer’s disease, the research group chose 64 superagers and 55 normal senior citizens. The latter served as the control group. While the superagers performed just as well in a memory test as people 30 years their junior, the control group’s performance was in line with their age and level of education.

All study participants were over age 79 years. Both the group of superagers and the control group included more females than males. On average, they were monitored for 6 years. During this period, a checkup was scheduled annually with an MRI examination, clinical tests, blood tests, and documentation of lifestyle factors.

For Alessandro Cellerino, PhD, of the Leibniz Institute on Aging–Fritz Lipmann Institute in Jena, Germany, this is the most crucial aspect of the study. “Even before this study, we knew that superagers demonstrated less atrophy in certain areas of the brain, but this was always only ever based on a single measurement.”
 

Memory centers protected

The MRI examinations confirmed that in superagers, gray matter atrophy in the regions responsible for memory (such as the medial temporal lobe and cholinergic forebrain), as well in regions important for movement (such as the motor thalamus), was less pronounced. In addition, the volume of gray matter in these regions, especially in the medial temporal lobe, decreased much more slowly in the superagers than in the control subjects over the study period.

Ms. Garo-Pascual and associates used a machine-learning algorithm to differentiate between superagers and normal older adults. From the 89 demographic, lifestyle, and clinical factors entered into the algorithm, two were the most important for the classification: the ability to move and mental health.
 

Mobility and mental health

Clinical tests such as the Timed Up-and-Go Test and the Finger Tapping Test revealed that superagers can be distinguished from the normally aging control subjects with regard to their mobility and fine motor skills. Their physical condition was better, although they, by their own admission, did not move any more than the control subjects in day-to-day life. According to Dr. Cellerino, this finding confirms that physical activity is paramount for cognitive function. “These people were over 80 years old – the fact that there was not much difference between their levels of activity is not surprising. Much more relevant is the question of how you get there – i.e., how active you are at the ages of 40, 50 or even 60 years old.”

Remaining active is important

As a matter of fact, the superagers indicated that generally they had been more active than the control subjects during their middle years. “Attempting to stay physically fit is essential; even if it just means going for a walk or taking the stairs,” said Dr. Cellerino.

On average, the superagers also fared much better in tests on physical health than the control subjects. They suffered significantly less from depression or anxiety disorders. “Earlier studies suggest that depression and anxiety disorders may influence performance in memory tests across all ages and that they are risk factors for developing dementia,” said Dr. Cellerino.

To avoid mental health issues in later life, gerontologist Dr. Cellerino recommended remaining socially engaged and involved. “Depression and anxiety are commonly also a consequence of social isolation,” he said.
 

Potential genetic differences

Blood sample analyses demonstrated that the superagers exhibited lower concentrations of biomarkers for neurodegenerative diseases than the control group did. In contrast, there was no difference between the two groups in the prevalence of the apo e4 allele, one of the most important genetic risk factors for Alzheimer’s disease. Nevertheless, Ms. Garo-Pascual and associates assume that genetics also play a role. They found that, despite 89 variables employed, the algorithm used could only distinguish superagers from normal older adults 66% of the time. This suggests that additional factors must be in play, such as genetic differences.

Body and mind

Since this is an observational study, whether the determined factors have a direct effect on superaging cannot be ascertained, the authors wrote. However, the results are consistent with earlier findings.

“Regarding the management of old age, we actually haven’t learned anything more than what we already knew. But it does confirm that physical and mental function are closely entwined and that we must maintain both to age healthily,” Dr. Cellerino concluded.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Even at an advanced age, superagers have the memory of someone 20 or 30 years their junior. But why is that? A new study shows that, in superagers, age-related atrophy of the gray matter, especially in the areas responsible for memory, develops much more slowly than in normal older adults. However, the study also emphasizes the importance of physical and mental fitness for a healthy aging process.

“One of the most important unanswered questions with regard to superagers is: ‘Are they resistant to age-related memory loss, or do they have coping mechanisms that allow them to better offset this memory loss?’ ” wrote Marta Garo-Pascual, a PhD candidate at the Autonomous University of Madrid, Spain, and colleagues in the Lancet Healthy Longevity. “Our results indicate that superagers are resistant to these processes.”
 

Six years’ monitoring

From a cohort of older adults who had participated in a study aiming to identify early indicators of Alzheimer’s disease, the research group chose 64 superagers and 55 normal senior citizens. The latter served as the control group. While the superagers performed just as well in a memory test as people 30 years their junior, the control group’s performance was in line with their age and level of education.

All study participants were over age 79 years. Both the group of superagers and the control group included more females than males. On average, they were monitored for 6 years. During this period, a checkup was scheduled annually with an MRI examination, clinical tests, blood tests, and documentation of lifestyle factors.

For Alessandro Cellerino, PhD, of the Leibniz Institute on Aging–Fritz Lipmann Institute in Jena, Germany, this is the most crucial aspect of the study. “Even before this study, we knew that superagers demonstrated less atrophy in certain areas of the brain, but this was always only ever based on a single measurement.”
 

Memory centers protected

The MRI examinations confirmed that in superagers, gray matter atrophy in the regions responsible for memory (such as the medial temporal lobe and cholinergic forebrain), as well in regions important for movement (such as the motor thalamus), was less pronounced. In addition, the volume of gray matter in these regions, especially in the medial temporal lobe, decreased much more slowly in the superagers than in the control subjects over the study period.

Ms. Garo-Pascual and associates used a machine-learning algorithm to differentiate between superagers and normal older adults. From the 89 demographic, lifestyle, and clinical factors entered into the algorithm, two were the most important for the classification: the ability to move and mental health.
 

Mobility and mental health

Clinical tests such as the Timed Up-and-Go Test and the Finger Tapping Test revealed that superagers can be distinguished from the normally aging control subjects with regard to their mobility and fine motor skills. Their physical condition was better, although they, by their own admission, did not move any more than the control subjects in day-to-day life. According to Dr. Cellerino, this finding confirms that physical activity is paramount for cognitive function. “These people were over 80 years old – the fact that there was not much difference between their levels of activity is not surprising. Much more relevant is the question of how you get there – i.e., how active you are at the ages of 40, 50 or even 60 years old.”

Remaining active is important

As a matter of fact, the superagers indicated that generally they had been more active than the control subjects during their middle years. “Attempting to stay physically fit is essential; even if it just means going for a walk or taking the stairs,” said Dr. Cellerino.

On average, the superagers also fared much better in tests on physical health than the control subjects. They suffered significantly less from depression or anxiety disorders. “Earlier studies suggest that depression and anxiety disorders may influence performance in memory tests across all ages and that they are risk factors for developing dementia,” said Dr. Cellerino.

To avoid mental health issues in later life, gerontologist Dr. Cellerino recommended remaining socially engaged and involved. “Depression and anxiety are commonly also a consequence of social isolation,” he said.
 

Potential genetic differences

Blood sample analyses demonstrated that the superagers exhibited lower concentrations of biomarkers for neurodegenerative diseases than the control group did. In contrast, there was no difference between the two groups in the prevalence of the apo e4 allele, one of the most important genetic risk factors for Alzheimer’s disease. Nevertheless, Ms. Garo-Pascual and associates assume that genetics also play a role. They found that, despite 89 variables employed, the algorithm used could only distinguish superagers from normal older adults 66% of the time. This suggests that additional factors must be in play, such as genetic differences.

Body and mind

Since this is an observational study, whether the determined factors have a direct effect on superaging cannot be ascertained, the authors wrote. However, the results are consistent with earlier findings.

“Regarding the management of old age, we actually haven’t learned anything more than what we already knew. But it does confirm that physical and mental function are closely entwined and that we must maintain both to age healthily,” Dr. Cellerino concluded.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Measuring levels of the synaptic protein NPTX2 in cerebrospinal fluid (CSF) may serve as an early predictor of mild cognitive impairment (MCI) years before symptoms appear, new research indicates.

“Our study shows that low NPTX2 levels are predictive of MCI symptom onset more than 7 years in advance, including among individuals who are in late middle age,” said study investigator Anja Soldan, PhD, associate professor of neurology, Johns Hopkins University School of Medicine, Baltimore.

NPTX2 is still considered an “emerging biomarker” because knowledge about this protein is limited, Dr. Soldan noted.

Prior studies have shown that levels of NPTX2 are lower in people with MCI and dementia than in those with normal cognition and that low levels of this protein in people with MCI are associated with an increased risk of developing dementia.

“Our study extends these prior findings by showing that low protein levels are also associated with the onset of MCI symptoms,” Dr. Soldan said.

The study was published online in Annals of Neurology.
 

New therapeutic target?

The researchers measured NPTX2, as well as amyloid beta 42/40, phosphorylated (p)-tau181, and total (t)-tau in CSF collected longitudinally from 269 cognitively normal adults from the BIOCARD study.

The average age at baseline was 57.7 years. Nearly all were White, 59% were women, most were college educated, and three-quarters had a close relative with Alzheimer’s disease.

During a mean follow-up average of 16 years, 77 participants progressed to MCI or dementia within or after 7 years of baseline measurements.

In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio, 0.76; P = .023). This association was significant for progression within 7 years (P = .036) and after 7 years from baseline (P = .001), the investigators reported.

Adults who progressed to MCI had, on average, about 15% lower levels of NPTX2 at baseline, compared with adults who remained cognitively normal.

Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline Alzheimer’s disease biomarker levels (P < .01), and NPTX2 did not interact with the CSF Alzheimer’s disease biomarkers or APOE-ε4 genetic status.

Higher baseline levels of p-tau181 and t-tau were associated with higher baseline NPTX2 levels (both P < .001) and with greater declines in NPTX2 over time, suggesting that NPTX2 may decline in response to tau pathology, the investigators suggested.

Dr. Soldan said NPTX2 may be “a novel target” for developing new therapeutics for Alzheimer’s disease and other dementing and neurodegenerative disorders, as it is not an Alzheimer’s disease–specific protein.

“Efforts are underway for developing a sensitive way to measure NPTX2 brain levels in blood, which could then help clinicians identify individuals at greatest risk for cognitive decline,” she explained.

“Other next steps are to examine how changes in NPTX2 over time relate to changes in brain structure and function and to identify factors that alter levels of NPTX2, including genetic factors and potentially modifiable lifestyle factors,” Dr. Soldan said.

“If having higher levels of NPTX2 in the brain provides some resilience against developing symptoms of Alzheimer’s disease, it would be great if we could somehow increase levels of the protein,” she noted.
 

Caveats, cautionary notes

Commenting on this research, Christopher Weber, PhD, Alzheimer’s Association director of global science initiatives, said, “Research has shown that when NPTX2 levels are low, it may lead to weaker connections between neurons and could potentially affect cognitive functions, including memory and learning.”

“This new study found an association between lower levels of NPTX2 in CSF and earlier time to MCI symptom onset, and when combined with other established Alzheimer’s biomarkers, they found that NPTX2 improved the prediction of Alzheimer’s symptom onset,” Dr. Weber said.

“This is in line with previous research that suggests NPTX2 levels are associated with an increased risk of progression from MCI to Alzheimer’s dementia,” Dr. Weber said.

However, he noted some limitations of the study. “Participants were primarily White [and] highly educated, and therefore findings may not be generalizable to a real-world population,” he cautioned.

Dr. Weber said it’s also important to note that NPTX2 is not considered an Alzheimer’s-specific biomarker but rather a marker of synaptic activity and neurodegeneration. “The exact role of NPTX2 in predicting dementia is unknown,” Dr. Weber said.

He said that more studies with larger, more diverse cohorts are needed to fully understand its significance as a biomarker or therapeutic target for neurodegenerative diseases, as well as to develop a blood test for NPTX2.  

The study was supported by the National Institutes of Health. Dr. Soldan and Dr. Weber report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Measuring levels of the synaptic protein NPTX2 in cerebrospinal fluid (CSF) may serve as an early predictor of mild cognitive impairment (MCI) years before symptoms appear, new research indicates.

“Our study shows that low NPTX2 levels are predictive of MCI symptom onset more than 7 years in advance, including among individuals who are in late middle age,” said study investigator Anja Soldan, PhD, associate professor of neurology, Johns Hopkins University School of Medicine, Baltimore.

NPTX2 is still considered an “emerging biomarker” because knowledge about this protein is limited, Dr. Soldan noted.

Prior studies have shown that levels of NPTX2 are lower in people with MCI and dementia than in those with normal cognition and that low levels of this protein in people with MCI are associated with an increased risk of developing dementia.

“Our study extends these prior findings by showing that low protein levels are also associated with the onset of MCI symptoms,” Dr. Soldan said.

The study was published online in Annals of Neurology.
 

New therapeutic target?

The researchers measured NPTX2, as well as amyloid beta 42/40, phosphorylated (p)-tau181, and total (t)-tau in CSF collected longitudinally from 269 cognitively normal adults from the BIOCARD study.

The average age at baseline was 57.7 years. Nearly all were White, 59% were women, most were college educated, and three-quarters had a close relative with Alzheimer’s disease.

During a mean follow-up average of 16 years, 77 participants progressed to MCI or dementia within or after 7 years of baseline measurements.

In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio, 0.76; P = .023). This association was significant for progression within 7 years (P = .036) and after 7 years from baseline (P = .001), the investigators reported.

Adults who progressed to MCI had, on average, about 15% lower levels of NPTX2 at baseline, compared with adults who remained cognitively normal.

Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline Alzheimer’s disease biomarker levels (P < .01), and NPTX2 did not interact with the CSF Alzheimer’s disease biomarkers or APOE-ε4 genetic status.

Higher baseline levels of p-tau181 and t-tau were associated with higher baseline NPTX2 levels (both P < .001) and with greater declines in NPTX2 over time, suggesting that NPTX2 may decline in response to tau pathology, the investigators suggested.

Dr. Soldan said NPTX2 may be “a novel target” for developing new therapeutics for Alzheimer’s disease and other dementing and neurodegenerative disorders, as it is not an Alzheimer’s disease–specific protein.

“Efforts are underway for developing a sensitive way to measure NPTX2 brain levels in blood, which could then help clinicians identify individuals at greatest risk for cognitive decline,” she explained.

“Other next steps are to examine how changes in NPTX2 over time relate to changes in brain structure and function and to identify factors that alter levels of NPTX2, including genetic factors and potentially modifiable lifestyle factors,” Dr. Soldan said.

“If having higher levels of NPTX2 in the brain provides some resilience against developing symptoms of Alzheimer’s disease, it would be great if we could somehow increase levels of the protein,” she noted.
 

Caveats, cautionary notes

Commenting on this research, Christopher Weber, PhD, Alzheimer’s Association director of global science initiatives, said, “Research has shown that when NPTX2 levels are low, it may lead to weaker connections between neurons and could potentially affect cognitive functions, including memory and learning.”

“This new study found an association between lower levels of NPTX2 in CSF and earlier time to MCI symptom onset, and when combined with other established Alzheimer’s biomarkers, they found that NPTX2 improved the prediction of Alzheimer’s symptom onset,” Dr. Weber said.

“This is in line with previous research that suggests NPTX2 levels are associated with an increased risk of progression from MCI to Alzheimer’s dementia,” Dr. Weber said.

However, he noted some limitations of the study. “Participants were primarily White [and] highly educated, and therefore findings may not be generalizable to a real-world population,” he cautioned.

Dr. Weber said it’s also important to note that NPTX2 is not considered an Alzheimer’s-specific biomarker but rather a marker of synaptic activity and neurodegeneration. “The exact role of NPTX2 in predicting dementia is unknown,” Dr. Weber said.

He said that more studies with larger, more diverse cohorts are needed to fully understand its significance as a biomarker or therapeutic target for neurodegenerative diseases, as well as to develop a blood test for NPTX2.  

The study was supported by the National Institutes of Health. Dr. Soldan and Dr. Weber report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Measuring levels of the synaptic protein NPTX2 in cerebrospinal fluid (CSF) may serve as an early predictor of mild cognitive impairment (MCI) years before symptoms appear, new research indicates.

“Our study shows that low NPTX2 levels are predictive of MCI symptom onset more than 7 years in advance, including among individuals who are in late middle age,” said study investigator Anja Soldan, PhD, associate professor of neurology, Johns Hopkins University School of Medicine, Baltimore.

NPTX2 is still considered an “emerging biomarker” because knowledge about this protein is limited, Dr. Soldan noted.

Prior studies have shown that levels of NPTX2 are lower in people with MCI and dementia than in those with normal cognition and that low levels of this protein in people with MCI are associated with an increased risk of developing dementia.

“Our study extends these prior findings by showing that low protein levels are also associated with the onset of MCI symptoms,” Dr. Soldan said.

The study was published online in Annals of Neurology.
 

New therapeutic target?

The researchers measured NPTX2, as well as amyloid beta 42/40, phosphorylated (p)-tau181, and total (t)-tau in CSF collected longitudinally from 269 cognitively normal adults from the BIOCARD study.

The average age at baseline was 57.7 years. Nearly all were White, 59% were women, most were college educated, and three-quarters had a close relative with Alzheimer’s disease.

During a mean follow-up average of 16 years, 77 participants progressed to MCI or dementia within or after 7 years of baseline measurements.

In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio, 0.76; P = .023). This association was significant for progression within 7 years (P = .036) and after 7 years from baseline (P = .001), the investigators reported.

Adults who progressed to MCI had, on average, about 15% lower levels of NPTX2 at baseline, compared with adults who remained cognitively normal.

Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline Alzheimer’s disease biomarker levels (P < .01), and NPTX2 did not interact with the CSF Alzheimer’s disease biomarkers or APOE-ε4 genetic status.

Higher baseline levels of p-tau181 and t-tau were associated with higher baseline NPTX2 levels (both P < .001) and with greater declines in NPTX2 over time, suggesting that NPTX2 may decline in response to tau pathology, the investigators suggested.

Dr. Soldan said NPTX2 may be “a novel target” for developing new therapeutics for Alzheimer’s disease and other dementing and neurodegenerative disorders, as it is not an Alzheimer’s disease–specific protein.

“Efforts are underway for developing a sensitive way to measure NPTX2 brain levels in blood, which could then help clinicians identify individuals at greatest risk for cognitive decline,” she explained.

“Other next steps are to examine how changes in NPTX2 over time relate to changes in brain structure and function and to identify factors that alter levels of NPTX2, including genetic factors and potentially modifiable lifestyle factors,” Dr. Soldan said.

“If having higher levels of NPTX2 in the brain provides some resilience against developing symptoms of Alzheimer’s disease, it would be great if we could somehow increase levels of the protein,” she noted.
 

Caveats, cautionary notes

Commenting on this research, Christopher Weber, PhD, Alzheimer’s Association director of global science initiatives, said, “Research has shown that when NPTX2 levels are low, it may lead to weaker connections between neurons and could potentially affect cognitive functions, including memory and learning.”

“This new study found an association between lower levels of NPTX2 in CSF and earlier time to MCI symptom onset, and when combined with other established Alzheimer’s biomarkers, they found that NPTX2 improved the prediction of Alzheimer’s symptom onset,” Dr. Weber said.

“This is in line with previous research that suggests NPTX2 levels are associated with an increased risk of progression from MCI to Alzheimer’s dementia,” Dr. Weber said.

However, he noted some limitations of the study. “Participants were primarily White [and] highly educated, and therefore findings may not be generalizable to a real-world population,” he cautioned.

Dr. Weber said it’s also important to note that NPTX2 is not considered an Alzheimer’s-specific biomarker but rather a marker of synaptic activity and neurodegeneration. “The exact role of NPTX2 in predicting dementia is unknown,” Dr. Weber said.

He said that more studies with larger, more diverse cohorts are needed to fully understand its significance as a biomarker or therapeutic target for neurodegenerative diseases, as well as to develop a blood test for NPTX2.  

The study was supported by the National Institutes of Health. Dr. Soldan and Dr. Weber report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Inhaling a pleasant aroma during sleep has been linked to a “dramatic” improvement in memory, early research suggests.

In a small, randomized controlled trial researchers found that when cognitively normal individuals were exposed to the scent of an essential oil for 2 hours every night over 6 months, they experienced a 226% improvement in memory compared with a control group who received only a trace amount of the diffused scent.

In addition, functional magnetic resonance imaging (fMRI) showed that those in the enriched group had improved functioning of the left uncinate fasciculus, an area of the brain linked to memory and cognition, which typically declines with age.

“To my knowledge, that level of [memory] improvement is far greater than anything that has been reported for healthy older adults and we also found a critical memory pathway in their brains improved to a similar extent relative to unenriched older adults,” senior investigator Michael Leon, PhD, professor emeritus, University of California, Irvine, said in an interview.

The study was published online in Frontiers of Neuroscience.
 

The brain’s “superhighway”

Olfactory enrichment “involves the daily exposure of individuals to multiple odorants” and has been shown in mouse models to improve memory and neurogenesis, the investigators noted.

A previous study showed that exposure to individual essential oils for 30 minutes a day over 3 months induced neurogenesis in the olfactory bulb and the hippocampus.

“The olfactory system is the only sense that has a direct ‘superhighway’ input to the memory centers areas of the brain; all the other senses have to reach those brain areas through what you might call the ‘side streets’ of the brain, and so consequently, they have much less impact on maintaining the health of those memory centers.”

When olfaction is compromised, “the memory centers of the brain start to deteriorate and, conversely, when people are given olfactory enrichment, their memory areas become larger and more functional,” he added.

Olfactory dysfunction is the first symptom of Alzheimer’s disease (AD) and is also found in virtually all neurological and psychiatric disorders.

“I’ve counted 68 of them – including anorexia, anxiety, [attention-deficit/hyperactivity disorder], depression, epilepsy, and stroke. In fact, by mid-life, your all-cause mortality can be predicted by your ability to smell things,” Dr. Leon said.

Dr. Leon and colleagues previously developed an effective treatment for autism using environmental enrichment that focused on odor stimulation, along with stimulating other senses. “We then considered the possibility that olfactory enrichment alone might improve brain function.”
 

Rose, orange, eucalyptus …

For the study, the researchers randomly assigned 43 older adults, aged 60-85 years, to receive either nightly exposure to essential oil scents delivered via a diffuser (n = 20; mean [SD] age, 70.1 [6.6] years) or to a sham control with only trace amounts of odorants (n = 23; mean age, 69.2 [7.1] years) for a period of 6 months.

The intervention group was exposed to a single odorant, delivered through a diffuser, for 2 hours nightly, rotating through seven pleasant aromas each week. They included rose, orange, eucalyptus, lemon, peppermint, rosemary, and lavender scents.

All participants completed a battery of tests at baseline, including the Mini-Mental State Examination (MMSE), which confirmed normal cognitive functioning. At baseline and after a 6-month follow-up, participants completed the Rey Auditory Verbal Learning Test (RAVLT) as well as three subsets of the Wechsler Adult Intelligence Scale–Third Edition (WAIS-III).

Olfactory system function was assessed using “Sniffin Sticks,” allowing the researchers to determine if olfactory enrichment enhanced olfactory performance.

Participants underwent fMRI at baseline and again at 6 months.

Brain imaging results showed a “clear, statistically significant 226% difference between enriched and control older adults in performance on the RAVLT, which evaluates learning and memory (timepoint × group interaction; F = 6.63; P = .02; Cohen’s d = 1.08; a “large effect size”).

They also found a significant change in the mean diffusivity of the left uncinate fasciculus in the enriched group compared with the controls (timepoint × group interaction; F = 4.39; P = .043; h 2 p = .101; a “medium-size effect”).

The uncinate fasciculus is a “major pathway” connecting the basolateral amygdala and the entorhinal cortex to the prefrontal cortex. This pathway deteriorates in aging and in AD and “has been suggested to play a role in mediating episodic memory, language, socio-emotional processing, and selecting among competing memories during retrieval.”

No significant differences were found between the groups in olfactory ability.

Limitations of the study include its small sample size. The investigators hope the findings will “stimulate larger scale clinical trials systematically testing the therapeutic efficacy of olfactory enrichment in treating memory loss in older adults.”
 

Exciting but preliminary

Commenting for this article, Donald Wilson, PhD, professor of child and adolescent psychiatry and of neuroscience and physiology, the Child Study Center, NYU Langone Medical Center, New York, said that multiple studies have “demonstrated that problems with sense of smell are associated with and sometimes can precede other symptoms for many disorders, including AD, Parkinson’s disease, and depression.”

Recent work has suggested that this relationship can be “bidirectional” – for example, losing one’s sense of smell might promote depression, while depressive disorder might lead to impaired smell, according to Dr. Wilson, also director and senior research scientist, the Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research. He was not involved with the study.

This “two-way interaction” may raise the possibility that “improving olfaction could impact nonolfactory disorders.”

This paper “brings together” previous research findings to show that odors during bedtime can improve some aspects of cognitive function and circuits that are known to be important for memory and cognition – which Dr. Wilson called “a very exciting, though relatively preliminary, finding.”

A caveat is that several measures of cognitive function were assessed and only one (verbal memory) showed clear improvement.

Nevertheless, there’s “very strong interest now in the olfactory and nonolfactory aspects of odor training and this training expands the training possibilities to sleep. This could be a powerful tool for cognitive improvement and/or rescue if follow-up studies support these findings,” Dr. Wilson said.

A version of this article appeared on Medscape.com.

Inhaling a pleasant aroma during sleep has been linked to a “dramatic” improvement in memory, early research suggests.

In a small, randomized controlled trial researchers found that when cognitively normal individuals were exposed to the scent of an essential oil for 2 hours every night over 6 months, they experienced a 226% improvement in memory compared with a control group who received only a trace amount of the diffused scent.

In addition, functional magnetic resonance imaging (fMRI) showed that those in the enriched group had improved functioning of the left uncinate fasciculus, an area of the brain linked to memory and cognition, which typically declines with age.

“To my knowledge, that level of [memory] improvement is far greater than anything that has been reported for healthy older adults and we also found a critical memory pathway in their brains improved to a similar extent relative to unenriched older adults,” senior investigator Michael Leon, PhD, professor emeritus, University of California, Irvine, said in an interview.

The study was published online in Frontiers of Neuroscience.
 

The brain’s “superhighway”

Olfactory enrichment “involves the daily exposure of individuals to multiple odorants” and has been shown in mouse models to improve memory and neurogenesis, the investigators noted.

A previous study showed that exposure to individual essential oils for 30 minutes a day over 3 months induced neurogenesis in the olfactory bulb and the hippocampus.

“The olfactory system is the only sense that has a direct ‘superhighway’ input to the memory centers areas of the brain; all the other senses have to reach those brain areas through what you might call the ‘side streets’ of the brain, and so consequently, they have much less impact on maintaining the health of those memory centers.”

When olfaction is compromised, “the memory centers of the brain start to deteriorate and, conversely, when people are given olfactory enrichment, their memory areas become larger and more functional,” he added.

Olfactory dysfunction is the first symptom of Alzheimer’s disease (AD) and is also found in virtually all neurological and psychiatric disorders.

“I’ve counted 68 of them – including anorexia, anxiety, [attention-deficit/hyperactivity disorder], depression, epilepsy, and stroke. In fact, by mid-life, your all-cause mortality can be predicted by your ability to smell things,” Dr. Leon said.

Dr. Leon and colleagues previously developed an effective treatment for autism using environmental enrichment that focused on odor stimulation, along with stimulating other senses. “We then considered the possibility that olfactory enrichment alone might improve brain function.”
 

Rose, orange, eucalyptus …

For the study, the researchers randomly assigned 43 older adults, aged 60-85 years, to receive either nightly exposure to essential oil scents delivered via a diffuser (n = 20; mean [SD] age, 70.1 [6.6] years) or to a sham control with only trace amounts of odorants (n = 23; mean age, 69.2 [7.1] years) for a period of 6 months.

The intervention group was exposed to a single odorant, delivered through a diffuser, for 2 hours nightly, rotating through seven pleasant aromas each week. They included rose, orange, eucalyptus, lemon, peppermint, rosemary, and lavender scents.

All participants completed a battery of tests at baseline, including the Mini-Mental State Examination (MMSE), which confirmed normal cognitive functioning. At baseline and after a 6-month follow-up, participants completed the Rey Auditory Verbal Learning Test (RAVLT) as well as three subsets of the Wechsler Adult Intelligence Scale–Third Edition (WAIS-III).

Olfactory system function was assessed using “Sniffin Sticks,” allowing the researchers to determine if olfactory enrichment enhanced olfactory performance.

Participants underwent fMRI at baseline and again at 6 months.

Brain imaging results showed a “clear, statistically significant 226% difference between enriched and control older adults in performance on the RAVLT, which evaluates learning and memory (timepoint × group interaction; F = 6.63; P = .02; Cohen’s d = 1.08; a “large effect size”).

They also found a significant change in the mean diffusivity of the left uncinate fasciculus in the enriched group compared with the controls (timepoint × group interaction; F = 4.39; P = .043; h 2 p = .101; a “medium-size effect”).

The uncinate fasciculus is a “major pathway” connecting the basolateral amygdala and the entorhinal cortex to the prefrontal cortex. This pathway deteriorates in aging and in AD and “has been suggested to play a role in mediating episodic memory, language, socio-emotional processing, and selecting among competing memories during retrieval.”

No significant differences were found between the groups in olfactory ability.

Limitations of the study include its small sample size. The investigators hope the findings will “stimulate larger scale clinical trials systematically testing the therapeutic efficacy of olfactory enrichment in treating memory loss in older adults.”
 

Exciting but preliminary

Commenting for this article, Donald Wilson, PhD, professor of child and adolescent psychiatry and of neuroscience and physiology, the Child Study Center, NYU Langone Medical Center, New York, said that multiple studies have “demonstrated that problems with sense of smell are associated with and sometimes can precede other symptoms for many disorders, including AD, Parkinson’s disease, and depression.”

Recent work has suggested that this relationship can be “bidirectional” – for example, losing one’s sense of smell might promote depression, while depressive disorder might lead to impaired smell, according to Dr. Wilson, also director and senior research scientist, the Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research. He was not involved with the study.

This “two-way interaction” may raise the possibility that “improving olfaction could impact nonolfactory disorders.”

This paper “brings together” previous research findings to show that odors during bedtime can improve some aspects of cognitive function and circuits that are known to be important for memory and cognition – which Dr. Wilson called “a very exciting, though relatively preliminary, finding.”

A caveat is that several measures of cognitive function were assessed and only one (verbal memory) showed clear improvement.

Nevertheless, there’s “very strong interest now in the olfactory and nonolfactory aspects of odor training and this training expands the training possibilities to sleep. This could be a powerful tool for cognitive improvement and/or rescue if follow-up studies support these findings,” Dr. Wilson said.

A version of this article appeared on Medscape.com.

Inhaling a pleasant aroma during sleep has been linked to a “dramatic” improvement in memory, early research suggests.

In a small, randomized controlled trial researchers found that when cognitively normal individuals were exposed to the scent of an essential oil for 2 hours every night over 6 months, they experienced a 226% improvement in memory compared with a control group who received only a trace amount of the diffused scent.

In addition, functional magnetic resonance imaging (fMRI) showed that those in the enriched group had improved functioning of the left uncinate fasciculus, an area of the brain linked to memory and cognition, which typically declines with age.

“To my knowledge, that level of [memory] improvement is far greater than anything that has been reported for healthy older adults and we also found a critical memory pathway in their brains improved to a similar extent relative to unenriched older adults,” senior investigator Michael Leon, PhD, professor emeritus, University of California, Irvine, said in an interview.

The study was published online in Frontiers of Neuroscience.
 

The brain’s “superhighway”

Olfactory enrichment “involves the daily exposure of individuals to multiple odorants” and has been shown in mouse models to improve memory and neurogenesis, the investigators noted.

A previous study showed that exposure to individual essential oils for 30 minutes a day over 3 months induced neurogenesis in the olfactory bulb and the hippocampus.

“The olfactory system is the only sense that has a direct ‘superhighway’ input to the memory centers areas of the brain; all the other senses have to reach those brain areas through what you might call the ‘side streets’ of the brain, and so consequently, they have much less impact on maintaining the health of those memory centers.”

When olfaction is compromised, “the memory centers of the brain start to deteriorate and, conversely, when people are given olfactory enrichment, their memory areas become larger and more functional,” he added.

Olfactory dysfunction is the first symptom of Alzheimer’s disease (AD) and is also found in virtually all neurological and psychiatric disorders.

“I’ve counted 68 of them – including anorexia, anxiety, [attention-deficit/hyperactivity disorder], depression, epilepsy, and stroke. In fact, by mid-life, your all-cause mortality can be predicted by your ability to smell things,” Dr. Leon said.

Dr. Leon and colleagues previously developed an effective treatment for autism using environmental enrichment that focused on odor stimulation, along with stimulating other senses. “We then considered the possibility that olfactory enrichment alone might improve brain function.”
 

Rose, orange, eucalyptus …

For the study, the researchers randomly assigned 43 older adults, aged 60-85 years, to receive either nightly exposure to essential oil scents delivered via a diffuser (n = 20; mean [SD] age, 70.1 [6.6] years) or to a sham control with only trace amounts of odorants (n = 23; mean age, 69.2 [7.1] years) for a period of 6 months.

The intervention group was exposed to a single odorant, delivered through a diffuser, for 2 hours nightly, rotating through seven pleasant aromas each week. They included rose, orange, eucalyptus, lemon, peppermint, rosemary, and lavender scents.

All participants completed a battery of tests at baseline, including the Mini-Mental State Examination (MMSE), which confirmed normal cognitive functioning. At baseline and after a 6-month follow-up, participants completed the Rey Auditory Verbal Learning Test (RAVLT) as well as three subsets of the Wechsler Adult Intelligence Scale–Third Edition (WAIS-III).

Olfactory system function was assessed using “Sniffin Sticks,” allowing the researchers to determine if olfactory enrichment enhanced olfactory performance.

Participants underwent fMRI at baseline and again at 6 months.

Brain imaging results showed a “clear, statistically significant 226% difference between enriched and control older adults in performance on the RAVLT, which evaluates learning and memory (timepoint × group interaction; F = 6.63; P = .02; Cohen’s d = 1.08; a “large effect size”).

They also found a significant change in the mean diffusivity of the left uncinate fasciculus in the enriched group compared with the controls (timepoint × group interaction; F = 4.39; P = .043; h 2 p = .101; a “medium-size effect”).

The uncinate fasciculus is a “major pathway” connecting the basolateral amygdala and the entorhinal cortex to the prefrontal cortex. This pathway deteriorates in aging and in AD and “has been suggested to play a role in mediating episodic memory, language, socio-emotional processing, and selecting among competing memories during retrieval.”

No significant differences were found between the groups in olfactory ability.

Limitations of the study include its small sample size. The investigators hope the findings will “stimulate larger scale clinical trials systematically testing the therapeutic efficacy of olfactory enrichment in treating memory loss in older adults.”
 

Exciting but preliminary

Commenting for this article, Donald Wilson, PhD, professor of child and adolescent psychiatry and of neuroscience and physiology, the Child Study Center, NYU Langone Medical Center, New York, said that multiple studies have “demonstrated that problems with sense of smell are associated with and sometimes can precede other symptoms for many disorders, including AD, Parkinson’s disease, and depression.”

Recent work has suggested that this relationship can be “bidirectional” – for example, losing one’s sense of smell might promote depression, while depressive disorder might lead to impaired smell, according to Dr. Wilson, also director and senior research scientist, the Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research. He was not involved with the study.

This “two-way interaction” may raise the possibility that “improving olfaction could impact nonolfactory disorders.”

This paper “brings together” previous research findings to show that odors during bedtime can improve some aspects of cognitive function and circuits that are known to be important for memory and cognition – which Dr. Wilson called “a very exciting, though relatively preliminary, finding.”

A caveat is that several measures of cognitive function were assessed and only one (verbal memory) showed clear improvement.

Nevertheless, there’s “very strong interest now in the olfactory and nonolfactory aspects of odor training and this training expands the training possibilities to sleep. This could be a powerful tool for cognitive improvement and/or rescue if follow-up studies support these findings,” Dr. Wilson said.

A version of this article appeared on Medscape.com.

Adults with depression have more than double the risk of developing dementia and the risk persists regardless of when in life depression is diagnosed, a large population-based study shows.

That the association between depression and dementia persisted even among individuals first diagnosed with depression in early or mid-life provides “strong evidence that depression is not only an early symptom of dementia, but also that depression increases dementia risk,” study investigator Holly Elser, MD, PhD, epidemiologist and resident physician, University of Pennsylvania, Philadelphia, told this news organization.

The study was published online in JAMA Neurology.
 

Double the risk

Several prior studies that have examined the relationship between depression and dementia over the life course have consistently shown depression later in life is associated with subsequent dementia.

“Late-life depression is generally thought to be an early symptom of dementia or a reaction to subclinical cognitive decline,” said Dr. Elser.

The investigators wanted to examine whether the association between depression and dementia persists even when depression is diagnosed earlier in life, which may suggest it increases the risk of dementia.

“To my knowledge, ours is the largest study on this topic to date, leveraging routinely and prospectively collected data from more than 1.4 million Danish citizens followed from 1977 to 2018,” Dr. Elser noted.

The cohort included 246,499 individuals diagnosed with depression and 1,190,302 individuals without depression. 

In both groups, the median age was 50 years and 65% were women. Roughly two-thirds (68%) of those diagnosed with depression were diagnosed before age 60 years.

In Cox proportional hazards regression models, the overall hazard of dementia was more than doubled in those diagnosed with depression (hazard ratio [HR] 2.41). The risk of dementia with depression was more pronounced for men (HR, 2.98) than in women (HR, 2.21).

This association persisted even when the time elapsed from depression diagnosis was between 20 and 39 years (HR, 1.79) and whether depression was diagnosed in early life (18-44 years: HR, 3.08), mid-life (45-59 years: HR, 2.95), or late life (≥ 60 years: HR, 2.31).

It remains unclear whether effective treatment of depression modifies the risk of dementia, as the current study explored the role of antidepressants in a “very limited fashion,” Dr. Elser said.

Specifically, the researchers considered whether an individual was treated with an antidepressant within 6 months of the initial depression diagnosis and found no evidence of a difference in dementia risk between the treated and untreated groups.

“Research that explores implications of the timing and duration of treatment with antidepressants for dementia, treatment with cognitive behavioral therapy, and is able to evaluate the effectiveness of those treatments will be extremely important,” Dr. Elser said.
 

‘An assault on the brain’

Reached for comment, John Showalter, MD, chief product officer at Linus Health, said one of the most “intriguing” findings of the study is that a depression diagnosis earlier in adulthood conferred a greater risk of developing vascular dementia (HR, 3.28) than did dementia due to Alzheimer’s disease (HR, 1.73).

“The difference in risk for subtypes of dementia is a meaningful addition to our understanding of depression’s connection to dementia,” said Dr. Showalter, who was not involved in the study.

Also weighing in, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said the findings from this “far-reaching investigation leave little room for doubt – depression unleashes a devastating storm within the brain, wreaking havoc on the lives of those ensnared by its grip.

“This massive, multi-decade, and high-data quality registry study adds another brick to the growing edifice of evidence attesting to the profound connection between psychiatric health and the very essence of brain health,” said Dr. Lakhan, who was not involved in the study.

“In a resounding declaration, this research underscores that psychiatric health should be perceived as an integral component of overall health – a paradigm shift that challenges long-standing misconceptions and stigmas surrounding mental disorders. Depression, once marginalized, now claims its rightful place on the pedestal of health concerns that must be addressed with unwavering resolve,” said Dr. Lakhan.

He noted that depression is “not just a mental battle, it’s a profound assault on the very fabric of the brain, leaving lives in turmoil and hearts in search of hope. No longer shrouded in silence, depression demands society’s attention.”

The study had no specific funding. Dr. Elser, Dr. Showalter, and Dr. Lakhan have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Adults with depression have more than double the risk of developing dementia and the risk persists regardless of when in life depression is diagnosed, a large population-based study shows.

That the association between depression and dementia persisted even among individuals first diagnosed with depression in early or mid-life provides “strong evidence that depression is not only an early symptom of dementia, but also that depression increases dementia risk,” study investigator Holly Elser, MD, PhD, epidemiologist and resident physician, University of Pennsylvania, Philadelphia, told this news organization.

The study was published online in JAMA Neurology.
 

Double the risk

Several prior studies that have examined the relationship between depression and dementia over the life course have consistently shown depression later in life is associated with subsequent dementia.

“Late-life depression is generally thought to be an early symptom of dementia or a reaction to subclinical cognitive decline,” said Dr. Elser.

The investigators wanted to examine whether the association between depression and dementia persists even when depression is diagnosed earlier in life, which may suggest it increases the risk of dementia.

“To my knowledge, ours is the largest study on this topic to date, leveraging routinely and prospectively collected data from more than 1.4 million Danish citizens followed from 1977 to 2018,” Dr. Elser noted.

The cohort included 246,499 individuals diagnosed with depression and 1,190,302 individuals without depression. 

In both groups, the median age was 50 years and 65% were women. Roughly two-thirds (68%) of those diagnosed with depression were diagnosed before age 60 years.

In Cox proportional hazards regression models, the overall hazard of dementia was more than doubled in those diagnosed with depression (hazard ratio [HR] 2.41). The risk of dementia with depression was more pronounced for men (HR, 2.98) than in women (HR, 2.21).

This association persisted even when the time elapsed from depression diagnosis was between 20 and 39 years (HR, 1.79) and whether depression was diagnosed in early life (18-44 years: HR, 3.08), mid-life (45-59 years: HR, 2.95), or late life (≥ 60 years: HR, 2.31).

It remains unclear whether effective treatment of depression modifies the risk of dementia, as the current study explored the role of antidepressants in a “very limited fashion,” Dr. Elser said.

Specifically, the researchers considered whether an individual was treated with an antidepressant within 6 months of the initial depression diagnosis and found no evidence of a difference in dementia risk between the treated and untreated groups.

“Research that explores implications of the timing and duration of treatment with antidepressants for dementia, treatment with cognitive behavioral therapy, and is able to evaluate the effectiveness of those treatments will be extremely important,” Dr. Elser said.
 

‘An assault on the brain’

Reached for comment, John Showalter, MD, chief product officer at Linus Health, said one of the most “intriguing” findings of the study is that a depression diagnosis earlier in adulthood conferred a greater risk of developing vascular dementia (HR, 3.28) than did dementia due to Alzheimer’s disease (HR, 1.73).

“The difference in risk for subtypes of dementia is a meaningful addition to our understanding of depression’s connection to dementia,” said Dr. Showalter, who was not involved in the study.

Also weighing in, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said the findings from this “far-reaching investigation leave little room for doubt – depression unleashes a devastating storm within the brain, wreaking havoc on the lives of those ensnared by its grip.

“This massive, multi-decade, and high-data quality registry study adds another brick to the growing edifice of evidence attesting to the profound connection between psychiatric health and the very essence of brain health,” said Dr. Lakhan, who was not involved in the study.

“In a resounding declaration, this research underscores that psychiatric health should be perceived as an integral component of overall health – a paradigm shift that challenges long-standing misconceptions and stigmas surrounding mental disorders. Depression, once marginalized, now claims its rightful place on the pedestal of health concerns that must be addressed with unwavering resolve,” said Dr. Lakhan.

He noted that depression is “not just a mental battle, it’s a profound assault on the very fabric of the brain, leaving lives in turmoil and hearts in search of hope. No longer shrouded in silence, depression demands society’s attention.”

The study had no specific funding. Dr. Elser, Dr. Showalter, and Dr. Lakhan have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Adults with depression have more than double the risk of developing dementia and the risk persists regardless of when in life depression is diagnosed, a large population-based study shows.

That the association between depression and dementia persisted even among individuals first diagnosed with depression in early or mid-life provides “strong evidence that depression is not only an early symptom of dementia, but also that depression increases dementia risk,” study investigator Holly Elser, MD, PhD, epidemiologist and resident physician, University of Pennsylvania, Philadelphia, told this news organization.

The study was published online in JAMA Neurology.
 

Double the risk

Several prior studies that have examined the relationship between depression and dementia over the life course have consistently shown depression later in life is associated with subsequent dementia.

“Late-life depression is generally thought to be an early symptom of dementia or a reaction to subclinical cognitive decline,” said Dr. Elser.

The investigators wanted to examine whether the association between depression and dementia persists even when depression is diagnosed earlier in life, which may suggest it increases the risk of dementia.

“To my knowledge, ours is the largest study on this topic to date, leveraging routinely and prospectively collected data from more than 1.4 million Danish citizens followed from 1977 to 2018,” Dr. Elser noted.

The cohort included 246,499 individuals diagnosed with depression and 1,190,302 individuals without depression. 

In both groups, the median age was 50 years and 65% were women. Roughly two-thirds (68%) of those diagnosed with depression were diagnosed before age 60 years.

In Cox proportional hazards regression models, the overall hazard of dementia was more than doubled in those diagnosed with depression (hazard ratio [HR] 2.41). The risk of dementia with depression was more pronounced for men (HR, 2.98) than in women (HR, 2.21).

This association persisted even when the time elapsed from depression diagnosis was between 20 and 39 years (HR, 1.79) and whether depression was diagnosed in early life (18-44 years: HR, 3.08), mid-life (45-59 years: HR, 2.95), or late life (≥ 60 years: HR, 2.31).

It remains unclear whether effective treatment of depression modifies the risk of dementia, as the current study explored the role of antidepressants in a “very limited fashion,” Dr. Elser said.

Specifically, the researchers considered whether an individual was treated with an antidepressant within 6 months of the initial depression diagnosis and found no evidence of a difference in dementia risk between the treated and untreated groups.

“Research that explores implications of the timing and duration of treatment with antidepressants for dementia, treatment with cognitive behavioral therapy, and is able to evaluate the effectiveness of those treatments will be extremely important,” Dr. Elser said.
 

‘An assault on the brain’

Reached for comment, John Showalter, MD, chief product officer at Linus Health, said one of the most “intriguing” findings of the study is that a depression diagnosis earlier in adulthood conferred a greater risk of developing vascular dementia (HR, 3.28) than did dementia due to Alzheimer’s disease (HR, 1.73).

“The difference in risk for subtypes of dementia is a meaningful addition to our understanding of depression’s connection to dementia,” said Dr. Showalter, who was not involved in the study.

Also weighing in, Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, said the findings from this “far-reaching investigation leave little room for doubt – depression unleashes a devastating storm within the brain, wreaking havoc on the lives of those ensnared by its grip.

“This massive, multi-decade, and high-data quality registry study adds another brick to the growing edifice of evidence attesting to the profound connection between psychiatric health and the very essence of brain health,” said Dr. Lakhan, who was not involved in the study.

“In a resounding declaration, this research underscores that psychiatric health should be perceived as an integral component of overall health – a paradigm shift that challenges long-standing misconceptions and stigmas surrounding mental disorders. Depression, once marginalized, now claims its rightful place on the pedestal of health concerns that must be addressed with unwavering resolve,” said Dr. Lakhan.

He noted that depression is “not just a mental battle, it’s a profound assault on the very fabric of the brain, leaving lives in turmoil and hearts in search of hope. No longer shrouded in silence, depression demands society’s attention.”

The study had no specific funding. Dr. Elser, Dr. Showalter, and Dr. Lakhan have reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Under a new Medicare pilot program that will begin in 2024, the federal government will pay clinicians to coordinate at-home dementia support services, including respite care for family members.

A Department of Health & Human Services initiative, part of the aim of the Guiding an Improved Dementia Experience (GUIDE) program is to help Medicare beneficiaries with dementia stay in the community for as long as possible. It is estimated that there are 6.7 million Americans living with Alzheimer’s disease or some other form of dementia, said HHS.

The program is voluntary and will be open to Medicare-enrolled clinicians and other providers who can assemble an interdisciplinary care team and meet the program’s participation criteria.

“Our new GUIDE Model has the potential to improve the quality of life for people with dementia and alleviate the significant strain on our families,” said HHS Secretary Xavier Becerra, in a statement.

“Not only is dementia care management a proven way to improve the quality of care and quality of life for those living with Alzheimer’s and other dementia, but now we know that it would also save the federal government billions of dollars,” Robert Egge, Alzheimer’s Association chief public policy officer and Alzheimer’s Impact Movement (AIM) executive director, said in a statement.

Mr. Egge cited a recent analysis commissioned by AIM that found that dementia care management would save the federal government nearly $21 billion over 10 years.

“People living with dementia and their caregivers too often struggle to manage their health care and connect with key supports that can allow them to remain in their homes and communities,” said Centers for Medicare & Medicaid Services Administrator Chiquita Brooks-LaSure, in the HHS statement.

“Fragmented care contributes to the mental and physical health strain of caring for someone with dementia, as well as the substantial financial burden,” she said, adding that Black, Hispanic, Asian American, Native Hawaiian, and Pacific Islander populations have been especially disadvantaged.

The GUIDE Model will provide new resources and greater access to specialty care to those communities, said Ms. Brooks-LaSure.

Care teams that seek to participate in the GUIDE model must have a care navigator who has received required training in dementia, assessment, and care planning.

The teams also must have a clinician with dementia proficiency as recognized by experience caring for adults with cognitive impairment; experience caring for patients aged 65 years old or older; or specialty designation in neurology, psychiatry, geriatrics, geriatric psychiatry, behavioral neurology, or geriatric neurology.

Medicare beneficiaries will be eligible if they are not residing in a nursing home; are not enrolled in hospice; and have a confirmed dementia diagnosis.

Beneficiaries who receive care from GUIDE participants will be placed in one of five “tiers,” based on a combination of disease stage and caregiver status. Beneficiary needs, and care intensity and payment, increase by tier.

GUIDE teams will receive a monthly, per-beneficiary amount for providing care management and coordination and caregiver education and support services. They can also bill for respite services – up to an annual cap – for Medicare beneficiaries who have an unpaid caregiver.

Clinicians seeking to participate in GUIDE can apply beginning in the fall. The program will run for 8 years beginning July 1, 2024.

Alzheimer’s Association President and CEO Joanne Pike, DrPH, said in a statement that the organization had “advocated for this approach for years, believing it [to be] the key to addressing systemic challenges faced by those with dementia, their families and those who provide them with care and support.”

The John A. Hartford Foundation noted that it also had long pushed for a comprehensive dementia care program. “Comprehensive dementia care supports both the medical and nonmedical needs of patients and their family caregivers,” said Foundation President Terry Fulmer, PhD, RN, FAAN, in a statement.

“Notably and necessarily, the model will help improve equity in access to care for underserved communities by addressing unpaid caregiver needs, including respite services and screening for health-related social needs,” added Dr. Fulmer.

A version of this article first appeared on Medscape.com.

Under a new Medicare pilot program that will begin in 2024, the federal government will pay clinicians to coordinate at-home dementia support services, including respite care for family members.

A Department of Health & Human Services initiative, part of the aim of the Guiding an Improved Dementia Experience (GUIDE) program is to help Medicare beneficiaries with dementia stay in the community for as long as possible. It is estimated that there are 6.7 million Americans living with Alzheimer’s disease or some other form of dementia, said HHS.

The program is voluntary and will be open to Medicare-enrolled clinicians and other providers who can assemble an interdisciplinary care team and meet the program’s participation criteria.

“Our new GUIDE Model has the potential to improve the quality of life for people with dementia and alleviate the significant strain on our families,” said HHS Secretary Xavier Becerra, in a statement.

“Not only is dementia care management a proven way to improve the quality of care and quality of life for those living with Alzheimer’s and other dementia, but now we know that it would also save the federal government billions of dollars,” Robert Egge, Alzheimer’s Association chief public policy officer and Alzheimer’s Impact Movement (AIM) executive director, said in a statement.

Mr. Egge cited a recent analysis commissioned by AIM that found that dementia care management would save the federal government nearly $21 billion over 10 years.

“People living with dementia and their caregivers too often struggle to manage their health care and connect with key supports that can allow them to remain in their homes and communities,” said Centers for Medicare & Medicaid Services Administrator Chiquita Brooks-LaSure, in the HHS statement.

“Fragmented care contributes to the mental and physical health strain of caring for someone with dementia, as well as the substantial financial burden,” she said, adding that Black, Hispanic, Asian American, Native Hawaiian, and Pacific Islander populations have been especially disadvantaged.

The GUIDE Model will provide new resources and greater access to specialty care to those communities, said Ms. Brooks-LaSure.

Care teams that seek to participate in the GUIDE model must have a care navigator who has received required training in dementia, assessment, and care planning.

The teams also must have a clinician with dementia proficiency as recognized by experience caring for adults with cognitive impairment; experience caring for patients aged 65 years old or older; or specialty designation in neurology, psychiatry, geriatrics, geriatric psychiatry, behavioral neurology, or geriatric neurology.

Medicare beneficiaries will be eligible if they are not residing in a nursing home; are not enrolled in hospice; and have a confirmed dementia diagnosis.

Beneficiaries who receive care from GUIDE participants will be placed in one of five “tiers,” based on a combination of disease stage and caregiver status. Beneficiary needs, and care intensity and payment, increase by tier.

GUIDE teams will receive a monthly, per-beneficiary amount for providing care management and coordination and caregiver education and support services. They can also bill for respite services – up to an annual cap – for Medicare beneficiaries who have an unpaid caregiver.

Clinicians seeking to participate in GUIDE can apply beginning in the fall. The program will run for 8 years beginning July 1, 2024.

Alzheimer’s Association President and CEO Joanne Pike, DrPH, said in a statement that the organization had “advocated for this approach for years, believing it [to be] the key to addressing systemic challenges faced by those with dementia, their families and those who provide them with care and support.”

The John A. Hartford Foundation noted that it also had long pushed for a comprehensive dementia care program. “Comprehensive dementia care supports both the medical and nonmedical needs of patients and their family caregivers,” said Foundation President Terry Fulmer, PhD, RN, FAAN, in a statement.

“Notably and necessarily, the model will help improve equity in access to care for underserved communities by addressing unpaid caregiver needs, including respite services and screening for health-related social needs,” added Dr. Fulmer.

A version of this article first appeared on Medscape.com.

Under a new Medicare pilot program that will begin in 2024, the federal government will pay clinicians to coordinate at-home dementia support services, including respite care for family members.

A Department of Health & Human Services initiative, part of the aim of the Guiding an Improved Dementia Experience (GUIDE) program is to help Medicare beneficiaries with dementia stay in the community for as long as possible. It is estimated that there are 6.7 million Americans living with Alzheimer’s disease or some other form of dementia, said HHS.

The program is voluntary and will be open to Medicare-enrolled clinicians and other providers who can assemble an interdisciplinary care team and meet the program’s participation criteria.

“Our new GUIDE Model has the potential to improve the quality of life for people with dementia and alleviate the significant strain on our families,” said HHS Secretary Xavier Becerra, in a statement.

“Not only is dementia care management a proven way to improve the quality of care and quality of life for those living with Alzheimer’s and other dementia, but now we know that it would also save the federal government billions of dollars,” Robert Egge, Alzheimer’s Association chief public policy officer and Alzheimer’s Impact Movement (AIM) executive director, said in a statement.

Mr. Egge cited a recent analysis commissioned by AIM that found that dementia care management would save the federal government nearly $21 billion over 10 years.

“People living with dementia and their caregivers too often struggle to manage their health care and connect with key supports that can allow them to remain in their homes and communities,” said Centers for Medicare & Medicaid Services Administrator Chiquita Brooks-LaSure, in the HHS statement.

“Fragmented care contributes to the mental and physical health strain of caring for someone with dementia, as well as the substantial financial burden,” she said, adding that Black, Hispanic, Asian American, Native Hawaiian, and Pacific Islander populations have been especially disadvantaged.

The GUIDE Model will provide new resources and greater access to specialty care to those communities, said Ms. Brooks-LaSure.

Care teams that seek to participate in the GUIDE model must have a care navigator who has received required training in dementia, assessment, and care planning.

The teams also must have a clinician with dementia proficiency as recognized by experience caring for adults with cognitive impairment; experience caring for patients aged 65 years old or older; or specialty designation in neurology, psychiatry, geriatrics, geriatric psychiatry, behavioral neurology, or geriatric neurology.

Medicare beneficiaries will be eligible if they are not residing in a nursing home; are not enrolled in hospice; and have a confirmed dementia diagnosis.

Beneficiaries who receive care from GUIDE participants will be placed in one of five “tiers,” based on a combination of disease stage and caregiver status. Beneficiary needs, and care intensity and payment, increase by tier.

GUIDE teams will receive a monthly, per-beneficiary amount for providing care management and coordination and caregiver education and support services. They can also bill for respite services – up to an annual cap – for Medicare beneficiaries who have an unpaid caregiver.

Clinicians seeking to participate in GUIDE can apply beginning in the fall. The program will run for 8 years beginning July 1, 2024.

Alzheimer’s Association President and CEO Joanne Pike, DrPH, said in a statement that the organization had “advocated for this approach for years, believing it [to be] the key to addressing systemic challenges faced by those with dementia, their families and those who provide them with care and support.”

The John A. Hartford Foundation noted that it also had long pushed for a comprehensive dementia care program. “Comprehensive dementia care supports both the medical and nonmedical needs of patients and their family caregivers,” said Foundation President Terry Fulmer, PhD, RN, FAAN, in a statement.

“Notably and necessarily, the model will help improve equity in access to care for underserved communities by addressing unpaid caregiver needs, including respite services and screening for health-related social needs,” added Dr. Fulmer.

A version of this article first appeared on Medscape.com.

Gum disease and tooth loss are linked to hippocampal atrophy and may have a more negative impact on the brain than aging, new research suggests.

Investigators found that in a late middle-aged and older cohort, among patients with mild periodontitis, having fewer teeth was linked to a faster rate of left hippocampal atrophy. For those with severe gum disease, each additional lost tooth was associated with a faster rate of brain shrinkage, equivalent to 1.3 years of brain aging.

“Tooth loss and gum disease, which is inflammation of the tissue around the teeth that can cause shrinkage of the gums and loosening of the teeth, are very common, so evaluating a potential link with dementia is incredibly important,” study investigator Satoshi Yamaguchi, PhD, DDS, of Tohoku University, in Sendai, Japan, said in a release.

“Our study found that these conditions may play a role in the health of the brain area that controls thinking and memory, giving people another reason to take better care of their teeth,” Dr. Yamaguchi noted.

The findings were published online in Neurology.
 

Greater effect than aging

Although previous research suggests that tooth loss and periodontitis are risk factors for Alzheimer’s disease, longitudinal research has not shown a significant correlation between these conditions and hippocampal atrophy.

To clarify this association, the investigators followed 172 men and women (average age, 67 years) who had undergone two MRI brain scans 4 years apart and had had a dental examination. None of the participants had any signs of cognitive decline at baseline.

At study outset, information on cerebrovascular and cardiovascular disease, alcohol consumption, smoking, depression history, and cognitive function was gathered. The Mini Mental State Exam and dental exams were administered at baseline and at 4-year follow-up.

For each participant, the number of teeth was counted, and all participants were assessed for gum disease via periodontal probing depth (PD).

Healthy gums typically measure between 1 and 3 mm in depth. Mild gum disease is signified by measurements of 3-4 mm in several areas. Severe gum disease involves measurements of 5-6 mm and is accompanied by greater bone loss, leading to potential tooth loss.

Multiple regression analysis was performed, with the annual symmetric percentage change (SPC) of hippocampal volume as the dependent variable. The analysis included an interaction term between the number of teeth present (NTP) and mean PD.

Over the 4-year study period, the investigators found that the qualitative interaction between NTP and mean PD was significant for the annual SPC in the left hippocampus.

Among those with mild periodontitis, having fewer teeth correlated with more rapid atrophy of the left hippocampus, such that every tooth lost was equivalent to nearly 1 year of brain aging.

In contrast, having more teeth was associated with a faster rate of left hippocampal atrophy among those with severe periodontitis and was equivalent to 1.3 years of brain aging.

For those with severe gum disease, each additional lost tooth corresponded to a faster rate of brain shrinkage, equivalent to 1.3 years of brain aging.

“This finding indicates that periodontitis may have a greater association with left hippocampal atrophy than the association exhibited by age. Furthermore, in cases of mild periodontitis, fewer teeth may be associated with a subsequent decline in cognitive function,” the investigators write.

The study’s results, they add, highlight the importance of preserving oral health, not just the retaining of teeth. “These findings suggest that retaining teeth with severe gum disease is associated with brain atrophy,” said Dr. Yamaguchi.

“Controlling the progression of gum disease through regular dental visits is crucial, and teeth with severe gum disease may need to be extracted and replaced with appropriate prosthetic devices,” he added.

The researchers note that further studies are needed to confirm these findings.

The study was supported the Japanese Ministry of Education, Culture, Sports, Science, and Technology; Kelo University; Japan Arteriosclerosis Prevention Fund; Japanese Ministry of Health, Labor, and Welfare; Teiko University; Pfizer Japan; Bayer Yakuhin; Chugai Pharmaceutical; Daiichi Sankyo; Astrellas Pharma; Takeda Pharmaceutical; the Health Care Science Institute; the Health Science Center; and the Takeda Science Foundation. The investigators reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Gum disease and tooth loss are linked to hippocampal atrophy and may have a more negative impact on the brain than aging, new research suggests.

Investigators found that in a late middle-aged and older cohort, among patients with mild periodontitis, having fewer teeth was linked to a faster rate of left hippocampal atrophy. For those with severe gum disease, each additional lost tooth was associated with a faster rate of brain shrinkage, equivalent to 1.3 years of brain aging.

“Tooth loss and gum disease, which is inflammation of the tissue around the teeth that can cause shrinkage of the gums and loosening of the teeth, are very common, so evaluating a potential link with dementia is incredibly important,” study investigator Satoshi Yamaguchi, PhD, DDS, of Tohoku University, in Sendai, Japan, said in a release.

“Our study found that these conditions may play a role in the health of the brain area that controls thinking and memory, giving people another reason to take better care of their teeth,” Dr. Yamaguchi noted.

The findings were published online in Neurology.
 

Greater effect than aging

Although previous research suggests that tooth loss and periodontitis are risk factors for Alzheimer’s disease, longitudinal research has not shown a significant correlation between these conditions and hippocampal atrophy.

To clarify this association, the investigators followed 172 men and women (average age, 67 years) who had undergone two MRI brain scans 4 years apart and had had a dental examination. None of the participants had any signs of cognitive decline at baseline.

At study outset, information on cerebrovascular and cardiovascular disease, alcohol consumption, smoking, depression history, and cognitive function was gathered. The Mini Mental State Exam and dental exams were administered at baseline and at 4-year follow-up.

For each participant, the number of teeth was counted, and all participants were assessed for gum disease via periodontal probing depth (PD).

Healthy gums typically measure between 1 and 3 mm in depth. Mild gum disease is signified by measurements of 3-4 mm in several areas. Severe gum disease involves measurements of 5-6 mm and is accompanied by greater bone loss, leading to potential tooth loss.

Multiple regression analysis was performed, with the annual symmetric percentage change (SPC) of hippocampal volume as the dependent variable. The analysis included an interaction term between the number of teeth present (NTP) and mean PD.

Over the 4-year study period, the investigators found that the qualitative interaction between NTP and mean PD was significant for the annual SPC in the left hippocampus.

Among those with mild periodontitis, having fewer teeth correlated with more rapid atrophy of the left hippocampus, such that every tooth lost was equivalent to nearly 1 year of brain aging.

In contrast, having more teeth was associated with a faster rate of left hippocampal atrophy among those with severe periodontitis and was equivalent to 1.3 years of brain aging.

For those with severe gum disease, each additional lost tooth corresponded to a faster rate of brain shrinkage, equivalent to 1.3 years of brain aging.

“This finding indicates that periodontitis may have a greater association with left hippocampal atrophy than the association exhibited by age. Furthermore, in cases of mild periodontitis, fewer teeth may be associated with a subsequent decline in cognitive function,” the investigators write.

The study’s results, they add, highlight the importance of preserving oral health, not just the retaining of teeth. “These findings suggest that retaining teeth with severe gum disease is associated with brain atrophy,” said Dr. Yamaguchi.

“Controlling the progression of gum disease through regular dental visits is crucial, and teeth with severe gum disease may need to be extracted and replaced with appropriate prosthetic devices,” he added.

The researchers note that further studies are needed to confirm these findings.

The study was supported the Japanese Ministry of Education, Culture, Sports, Science, and Technology; Kelo University; Japan Arteriosclerosis Prevention Fund; Japanese Ministry of Health, Labor, and Welfare; Teiko University; Pfizer Japan; Bayer Yakuhin; Chugai Pharmaceutical; Daiichi Sankyo; Astrellas Pharma; Takeda Pharmaceutical; the Health Care Science Institute; the Health Science Center; and the Takeda Science Foundation. The investigators reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Gum disease and tooth loss are linked to hippocampal atrophy and may have a more negative impact on the brain than aging, new research suggests.

Investigators found that in a late middle-aged and older cohort, among patients with mild periodontitis, having fewer teeth was linked to a faster rate of left hippocampal atrophy. For those with severe gum disease, each additional lost tooth was associated with a faster rate of brain shrinkage, equivalent to 1.3 years of brain aging.

“Tooth loss and gum disease, which is inflammation of the tissue around the teeth that can cause shrinkage of the gums and loosening of the teeth, are very common, so evaluating a potential link with dementia is incredibly important,” study investigator Satoshi Yamaguchi, PhD, DDS, of Tohoku University, in Sendai, Japan, said in a release.

“Our study found that these conditions may play a role in the health of the brain area that controls thinking and memory, giving people another reason to take better care of their teeth,” Dr. Yamaguchi noted.

The findings were published online in Neurology.
 

Greater effect than aging

Although previous research suggests that tooth loss and periodontitis are risk factors for Alzheimer’s disease, longitudinal research has not shown a significant correlation between these conditions and hippocampal atrophy.

To clarify this association, the investigators followed 172 men and women (average age, 67 years) who had undergone two MRI brain scans 4 years apart and had had a dental examination. None of the participants had any signs of cognitive decline at baseline.

At study outset, information on cerebrovascular and cardiovascular disease, alcohol consumption, smoking, depression history, and cognitive function was gathered. The Mini Mental State Exam and dental exams were administered at baseline and at 4-year follow-up.

For each participant, the number of teeth was counted, and all participants were assessed for gum disease via periodontal probing depth (PD).

Healthy gums typically measure between 1 and 3 mm in depth. Mild gum disease is signified by measurements of 3-4 mm in several areas. Severe gum disease involves measurements of 5-6 mm and is accompanied by greater bone loss, leading to potential tooth loss.

Multiple regression analysis was performed, with the annual symmetric percentage change (SPC) of hippocampal volume as the dependent variable. The analysis included an interaction term between the number of teeth present (NTP) and mean PD.

Over the 4-year study period, the investigators found that the qualitative interaction between NTP and mean PD was significant for the annual SPC in the left hippocampus.

Among those with mild periodontitis, having fewer teeth correlated with more rapid atrophy of the left hippocampus, such that every tooth lost was equivalent to nearly 1 year of brain aging.

In contrast, having more teeth was associated with a faster rate of left hippocampal atrophy among those with severe periodontitis and was equivalent to 1.3 years of brain aging.

For those with severe gum disease, each additional lost tooth corresponded to a faster rate of brain shrinkage, equivalent to 1.3 years of brain aging.

“This finding indicates that periodontitis may have a greater association with left hippocampal atrophy than the association exhibited by age. Furthermore, in cases of mild periodontitis, fewer teeth may be associated with a subsequent decline in cognitive function,” the investigators write.

The study’s results, they add, highlight the importance of preserving oral health, not just the retaining of teeth. “These findings suggest that retaining teeth with severe gum disease is associated with brain atrophy,” said Dr. Yamaguchi.

“Controlling the progression of gum disease through regular dental visits is crucial, and teeth with severe gum disease may need to be extracted and replaced with appropriate prosthetic devices,” he added.

The researchers note that further studies are needed to confirm these findings.

The study was supported the Japanese Ministry of Education, Culture, Sports, Science, and Technology; Kelo University; Japan Arteriosclerosis Prevention Fund; Japanese Ministry of Health, Labor, and Welfare; Teiko University; Pfizer Japan; Bayer Yakuhin; Chugai Pharmaceutical; Daiichi Sankyo; Astrellas Pharma; Takeda Pharmaceutical; the Health Care Science Institute; the Health Science Center; and the Takeda Science Foundation. The investigators reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Social isolation in older individuals has been linked to reduced brain volume in regions associated with memory, a new study shows.

Further, the association between social isolation and reduced brain volume appears to be at least partly mediated by depressive symptoms.

“We believe that efforts should be made to reduce social isolation among the elderly as much as possible,” investigator Toshiharu Ninomiya, MD, PhD, professor of epidemiology and public health at Kyushu University in Fukuoka, Japan, said in an interview.

The study was published online in Neurology.
 

A dementia prevention strategy

Dr. Ninomiya noted there have been several studies suggesting that social interaction is beneficial in preventing cognitive decline and the onset of dementia.

In addition, recent epidemiological studies have shown social isolation is associated with a risk for cognitive decline and dementia.

Although the investigators note that very little is known about the link between the two, some studies have shown that social isolation is linked with depressive symptoms in older adults, and late-life depression has been associated with brain atrophy.

To explore the potential link between social isolation and brain atrophy, as well as the role of depression as a potential mediator, the investigators studied nearly 9,000 citizens aged 65 and older as part of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), an ongoing, community-based nationwide cohort study of dementia in Japan.

Participants were recruited from eight research sites across Japan, and each had a baseline MRI scan between 2016 and 2018. The investigators excluded those with a dementia diagnosis at baseline. Self-reported frequency of social contact was categorized as every day, several times a week, several times a month, or seldom.

Participants also answered questions about medical history and treatment, antihypertensive or antidiabetic medications, exercise, current alcohol intake, and smoking habits. Depressive symptoms were assessed with the Geriatric Depression Scale. Of the participants, 57% were women, and the mean age was 73 years.
 

Lower brain volume

Total brain volume was lower in those with the lowest frequency of social contact vs. those with the highest frequency (67.3% vs. 67.8%). Less social contact was also linked to smaller temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala volumes.

White matter lesion volume increased with fewer social interactions, from 0.26% in the most social group to 0.30% in the least.

Cognitive function was higher in participants who had daily social contact, compared with those who had the least contact (28 vs. 27 on the Mini-Mental State Examination; P < .001). Scores between 25 and 30 are considered normal.

Depressive symptoms were lower in the daily contact group, compared with the seldom-contact group (P < .001).

The team also found that lower frequency of social contact was significantly associated with the smaller superior, middle, or inferior temporal gyrus; and a smaller fusiform gyrus, transverse temporal gyrus, temporal pole, and entorhinal cortex, among other subregions.

Mediation analyses indicated that depressive symptoms accounted for only 15%-29% of the associations of lower frequency of social contact with each regional volume.
 

Worse physical health

The results also showed that socially isolated participants were more likely to have diabetes, to have hypertension, to smoke, and to be physically inactive.

“Cardiovascular risk factors have been reported to cause endothelial dysfunction in the brain, which could in turn lead to problems in maintaining microcirculation and blood-brain barrier function,” the investigators write.

Some epidemiological studies have associated cardiovascular risk factors with brain atrophy, they noted, which could have been one of the underlying mechanisms.

Another possibility is that reduced cognitive stimulation due to social isolation may cause brain atrophy, they add.

“Ultimately,” Dr. Ninomiya said, “the detailed mechanism of the relationship between social isolation and brain volume is not yet clear.”

He also said more research is needed to know whether the findings would apply to people in other countries.

In an accompanying editorial, Alexa Walter, PhD, and Danielle Sandsmark, MD, PhD, from the University of Pennsylvania, Philadelphia, note that  isolation has been associated with many adverse health outcomes, including increased risk of heart disease, stroke, and premature death.

“Given these findings, future work considering social health factors in the context of neurological disease is an important area of research to consider. Additionally, leveraging other existing longitudinal studies could provide us with an opportunity to better understand these relationships within populations and inform public policy to address these issues,” Dr. Walter and Dr. Sandsmark write.

The study was funded by the Japan Agency for Medical Research and Development and Suntory Holdings Limited. Dr. Ninomiya reports receiving grants from Suntory Holdings Limited.

A version of this article first appeared on Medscape.com.

Social isolation in older individuals has been linked to reduced brain volume in regions associated with memory, a new study shows.

Further, the association between social isolation and reduced brain volume appears to be at least partly mediated by depressive symptoms.

“We believe that efforts should be made to reduce social isolation among the elderly as much as possible,” investigator Toshiharu Ninomiya, MD, PhD, professor of epidemiology and public health at Kyushu University in Fukuoka, Japan, said in an interview.

The study was published online in Neurology.
 

A dementia prevention strategy

Dr. Ninomiya noted there have been several studies suggesting that social interaction is beneficial in preventing cognitive decline and the onset of dementia.

In addition, recent epidemiological studies have shown social isolation is associated with a risk for cognitive decline and dementia.

Although the investigators note that very little is known about the link between the two, some studies have shown that social isolation is linked with depressive symptoms in older adults, and late-life depression has been associated with brain atrophy.

To explore the potential link between social isolation and brain atrophy, as well as the role of depression as a potential mediator, the investigators studied nearly 9,000 citizens aged 65 and older as part of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), an ongoing, community-based nationwide cohort study of dementia in Japan.

Participants were recruited from eight research sites across Japan, and each had a baseline MRI scan between 2016 and 2018. The investigators excluded those with a dementia diagnosis at baseline. Self-reported frequency of social contact was categorized as every day, several times a week, several times a month, or seldom.

Participants also answered questions about medical history and treatment, antihypertensive or antidiabetic medications, exercise, current alcohol intake, and smoking habits. Depressive symptoms were assessed with the Geriatric Depression Scale. Of the participants, 57% were women, and the mean age was 73 years.
 

Lower brain volume

Total brain volume was lower in those with the lowest frequency of social contact vs. those with the highest frequency (67.3% vs. 67.8%). Less social contact was also linked to smaller temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala volumes.

White matter lesion volume increased with fewer social interactions, from 0.26% in the most social group to 0.30% in the least.

Cognitive function was higher in participants who had daily social contact, compared with those who had the least contact (28 vs. 27 on the Mini-Mental State Examination; P < .001). Scores between 25 and 30 are considered normal.

Depressive symptoms were lower in the daily contact group, compared with the seldom-contact group (P < .001).

The team also found that lower frequency of social contact was significantly associated with the smaller superior, middle, or inferior temporal gyrus; and a smaller fusiform gyrus, transverse temporal gyrus, temporal pole, and entorhinal cortex, among other subregions.

Mediation analyses indicated that depressive symptoms accounted for only 15%-29% of the associations of lower frequency of social contact with each regional volume.
 

Worse physical health

The results also showed that socially isolated participants were more likely to have diabetes, to have hypertension, to smoke, and to be physically inactive.

“Cardiovascular risk factors have been reported to cause endothelial dysfunction in the brain, which could in turn lead to problems in maintaining microcirculation and blood-brain barrier function,” the investigators write.

Some epidemiological studies have associated cardiovascular risk factors with brain atrophy, they noted, which could have been one of the underlying mechanisms.

Another possibility is that reduced cognitive stimulation due to social isolation may cause brain atrophy, they add.

“Ultimately,” Dr. Ninomiya said, “the detailed mechanism of the relationship between social isolation and brain volume is not yet clear.”

He also said more research is needed to know whether the findings would apply to people in other countries.

In an accompanying editorial, Alexa Walter, PhD, and Danielle Sandsmark, MD, PhD, from the University of Pennsylvania, Philadelphia, note that  isolation has been associated with many adverse health outcomes, including increased risk of heart disease, stroke, and premature death.

“Given these findings, future work considering social health factors in the context of neurological disease is an important area of research to consider. Additionally, leveraging other existing longitudinal studies could provide us with an opportunity to better understand these relationships within populations and inform public policy to address these issues,” Dr. Walter and Dr. Sandsmark write.

The study was funded by the Japan Agency for Medical Research and Development and Suntory Holdings Limited. Dr. Ninomiya reports receiving grants from Suntory Holdings Limited.

A version of this article first appeared on Medscape.com.

Social isolation in older individuals has been linked to reduced brain volume in regions associated with memory, a new study shows.

Further, the association between social isolation and reduced brain volume appears to be at least partly mediated by depressive symptoms.

“We believe that efforts should be made to reduce social isolation among the elderly as much as possible,” investigator Toshiharu Ninomiya, MD, PhD, professor of epidemiology and public health at Kyushu University in Fukuoka, Japan, said in an interview.

The study was published online in Neurology.
 

A dementia prevention strategy

Dr. Ninomiya noted there have been several studies suggesting that social interaction is beneficial in preventing cognitive decline and the onset of dementia.

In addition, recent epidemiological studies have shown social isolation is associated with a risk for cognitive decline and dementia.

Although the investigators note that very little is known about the link between the two, some studies have shown that social isolation is linked with depressive symptoms in older adults, and late-life depression has been associated with brain atrophy.

To explore the potential link between social isolation and brain atrophy, as well as the role of depression as a potential mediator, the investigators studied nearly 9,000 citizens aged 65 and older as part of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), an ongoing, community-based nationwide cohort study of dementia in Japan.

Participants were recruited from eight research sites across Japan, and each had a baseline MRI scan between 2016 and 2018. The investigators excluded those with a dementia diagnosis at baseline. Self-reported frequency of social contact was categorized as every day, several times a week, several times a month, or seldom.

Participants also answered questions about medical history and treatment, antihypertensive or antidiabetic medications, exercise, current alcohol intake, and smoking habits. Depressive symptoms were assessed with the Geriatric Depression Scale. Of the participants, 57% were women, and the mean age was 73 years.
 

Lower brain volume

Total brain volume was lower in those with the lowest frequency of social contact vs. those with the highest frequency (67.3% vs. 67.8%). Less social contact was also linked to smaller temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala volumes.

White matter lesion volume increased with fewer social interactions, from 0.26% in the most social group to 0.30% in the least.

Cognitive function was higher in participants who had daily social contact, compared with those who had the least contact (28 vs. 27 on the Mini-Mental State Examination; P < .001). Scores between 25 and 30 are considered normal.

Depressive symptoms were lower in the daily contact group, compared with the seldom-contact group (P < .001).

The team also found that lower frequency of social contact was significantly associated with the smaller superior, middle, or inferior temporal gyrus; and a smaller fusiform gyrus, transverse temporal gyrus, temporal pole, and entorhinal cortex, among other subregions.

Mediation analyses indicated that depressive symptoms accounted for only 15%-29% of the associations of lower frequency of social contact with each regional volume.
 

Worse physical health

The results also showed that socially isolated participants were more likely to have diabetes, to have hypertension, to smoke, and to be physically inactive.

“Cardiovascular risk factors have been reported to cause endothelial dysfunction in the brain, which could in turn lead to problems in maintaining microcirculation and blood-brain barrier function,” the investigators write.

Some epidemiological studies have associated cardiovascular risk factors with brain atrophy, they noted, which could have been one of the underlying mechanisms.

Another possibility is that reduced cognitive stimulation due to social isolation may cause brain atrophy, they add.

“Ultimately,” Dr. Ninomiya said, “the detailed mechanism of the relationship between social isolation and brain volume is not yet clear.”

He also said more research is needed to know whether the findings would apply to people in other countries.

In an accompanying editorial, Alexa Walter, PhD, and Danielle Sandsmark, MD, PhD, from the University of Pennsylvania, Philadelphia, note that  isolation has been associated with many adverse health outcomes, including increased risk of heart disease, stroke, and premature death.

“Given these findings, future work considering social health factors in the context of neurological disease is an important area of research to consider. Additionally, leveraging other existing longitudinal studies could provide us with an opportunity to better understand these relationships within populations and inform public policy to address these issues,” Dr. Walter and Dr. Sandsmark write.

The study was funded by the Japan Agency for Medical Research and Development and Suntory Holdings Limited. Dr. Ninomiya reports receiving grants from Suntory Holdings Limited.

A version of this article first appeared on Medscape.com.

With the Food and Drug Administration’s full stamp of approval in hand, Leqembi (lecanemab) is poised to catapult us into a new era of treatment for Alzheimer’s disease. And now that the donanemab trial data are out, there’s another antiamyloid drug waiting in the wings.

To finally have true disease-modifying therapies for Alzheimer’s disease is a massive step forward for a field that’s been plagued with disappointment. But these drugs come with serious concerns and unknowns. They will require complex decision-making, putting doctors, patients, and their families in a medical quandary.

Striking the right balance between cautious optimism and realistic expectations will be a formidable challenge.
 

Managing patient and family expectations

These drugs are no magic bullet. They slow down the dementia’s progression, buying patients more time (on the order of months) before they begin to experience significant worsening. We’ll need a lot more information from research and clinical experience before we can understand how meaningful that treatment effect is. Right now, it is unclear whether eligible patients and their families will even perceive tangible differences.

In the CLARITY-AD trial, participants on lecanemab experienced a 27% slowing in the rate of cognitive decline over 18 months. Donanemab was shown to slow decline in memory and cognition by about 35% over the same time frame in the TRAILBLAZER-ALZ 2 trial. That translates to more time for patients and their families to enjoy independence, maintain normal life, and stave off the most distressing parts of the disease.

But what happens after 18 months of treatment – will the treatment effect magnify or dissipate? How much time are we really buying in the long run? Counseling patients and their families is made all the more difficult when the answers to important questions like these remain to be seen.
 

Only a sliver of Alzheimer’s patients are current candidates

The fact is that most patients living with Alzheimer’s disease will not qualify for treatment with these drugs. Lecanemab is approved for people with early-stage disease, meaning their dementia is mild or they have mild cognitive impairment, which is a precursor to full-blown Alzheimer’s disease. Of the 6 million people in the United States living with Alzheimer’s, about 1.5 million are estimated to fall into that category. We can expect to see a similar qualifier for donanemab if it receives FDA approval, especially because that trial suggested a more pronounced treatment effect for patients in the earliest stages of the disease.

Even if a patient hits the sweet spot where they have just enough cognitive impairment, but not too much, they aren’t technically therapeutic candidates until prerequisite testing confirms amyloid protein accumulation in the brain via PET scan or cerebrospinal fluid analysis.

Even then, the FDA’s boxed warning for lecanemab recommends that patients undergo genetic testing for the apo E4 mutation to identify those at a particularly high risk for severe adverse effects including brain bleeding and swelling. This recommendation is not unreasonable considering that 15% of the Alzheimer’s population has two copies of the apo E4 mutation and fall into that high-risk group.
 

Significant risks

Antiamyloid drugs are well-known to cause serious side effects. In the lecanemab trial, 13% of participants receiving Leqembi experienced brain swelling (vs. 2% of participants receiving placebo) and 17% of participants had brain bleeding (vs. 9% of participants on placebo). In the donanemab trial, brain bleeding occurred in 31.4% of participants on the drug (vs. 13.6% on placebo) and swelling occurred in 24% (vs. 2.1% receiving placebo). Thankfully, in both trials, most of these adverse events did not produce significant symptoms, but in rare cases these events caused severe or catastrophic neurologic injury, including death.

How can we best guide patients and their families to weigh the uncertain benefits against potentially serious risks? We can start by considering the patient characteristics most likely to portend increased risk for serious side effects: apo E4 mutations, blood thinner use, and the presence of microhemorrhages on brain imaging. But after that, we’re left with a lot of uncertainty in terms of which patients are most likely to see meaningful clinical improvements from the drug and unknown factors that may increase the risks of treatment.
 

A costly therapy

Medicare plans to cover 80% of lecanemab’s steep cost of $26,500 per year. Still, that will leave many patients with a hefty copay, potentially over $6,000 per year. But that only scratches the surface. Consider the frequent medical visits, repeated brain scans, laboratory tests, and infusion center appointments. It’s been estimated that all-in, the treatment will actually cost about $90,000 per year.

Yes, Medicare will reimburse a large portion of that cost, but it adds up to an estimated $2 billion per year for about 85,000 patients. This will probably spur increases to Medicare premiums, among other economic consequences for the health care system.

We’ll probably have to wait for an FDA approval decision before we know where donanemab will be priced.
 

Logistical challenges could be a rate-limiting step

Ask anyone who’s tried to see a neurologist recently, and they’ll tell you that the wait for a new patient appointment is months long. The shortage of neurologists in the United States is already a crisis, and there are even fewer cognitive neurologists. How long will patients be forced to wait for their diagnosis?

Many geriatricians will get comfortable prescribing these drugs, but will our already overburdened primary care providers have the bandwidth to do the same? It’s a tall order.

A new world of Alzheimer’s treatments also means that the infrastructure of our health care systems will need to be ramped up. Lecanemab infusions are administered every 2 weeks and donanemab every 4 weeks. Infusion centers will need to accommodate a lot more patients. And those patients will need frequent brain scans, so neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.
 

Antiamyloid drugs: An exciting first step

The bottom line is that these drugs aren’t the Alzheimer’s holy grail: An accessible treatment that could stop the disease in its tracks or reverse cognitive impairment. They are, however, a very promising breakthrough.

Yes, there are a ton of kinks to work out here, but this is an exciting start. Alzheimer’s research is entering a renaissance era that will hopefully bring more groundbreaking developments. Better biomarkers to facilitate faster, easier diagnosis. More drugs that go beyond amyloid proteins for their therapeutic targets. Treatments for later-stage disease. Drugs that prevent dementia altogether.

Ultimately, these new antiamyloid beta drugs are an exciting indication that we will eventually have a toolkit of Alzheimer’s drugs to choose from. For now, we’ve taken a solid step forward and there is ample reason to be hopeful for the future.

Dr. Croll is assistant professor of neurology at Temple University, Philadelphia. She reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

With the Food and Drug Administration’s full stamp of approval in hand, Leqembi (lecanemab) is poised to catapult us into a new era of treatment for Alzheimer’s disease. And now that the donanemab trial data are out, there’s another antiamyloid drug waiting in the wings.

To finally have true disease-modifying therapies for Alzheimer’s disease is a massive step forward for a field that’s been plagued with disappointment. But these drugs come with serious concerns and unknowns. They will require complex decision-making, putting doctors, patients, and their families in a medical quandary.

Striking the right balance between cautious optimism and realistic expectations will be a formidable challenge.
 

Managing patient and family expectations

These drugs are no magic bullet. They slow down the dementia’s progression, buying patients more time (on the order of months) before they begin to experience significant worsening. We’ll need a lot more information from research and clinical experience before we can understand how meaningful that treatment effect is. Right now, it is unclear whether eligible patients and their families will even perceive tangible differences.

In the CLARITY-AD trial, participants on lecanemab experienced a 27% slowing in the rate of cognitive decline over 18 months. Donanemab was shown to slow decline in memory and cognition by about 35% over the same time frame in the TRAILBLAZER-ALZ 2 trial. That translates to more time for patients and their families to enjoy independence, maintain normal life, and stave off the most distressing parts of the disease.

But what happens after 18 months of treatment – will the treatment effect magnify or dissipate? How much time are we really buying in the long run? Counseling patients and their families is made all the more difficult when the answers to important questions like these remain to be seen.
 

Only a sliver of Alzheimer’s patients are current candidates

The fact is that most patients living with Alzheimer’s disease will not qualify for treatment with these drugs. Lecanemab is approved for people with early-stage disease, meaning their dementia is mild or they have mild cognitive impairment, which is a precursor to full-blown Alzheimer’s disease. Of the 6 million people in the United States living with Alzheimer’s, about 1.5 million are estimated to fall into that category. We can expect to see a similar qualifier for donanemab if it receives FDA approval, especially because that trial suggested a more pronounced treatment effect for patients in the earliest stages of the disease.

Even if a patient hits the sweet spot where they have just enough cognitive impairment, but not too much, they aren’t technically therapeutic candidates until prerequisite testing confirms amyloid protein accumulation in the brain via PET scan or cerebrospinal fluid analysis.

Even then, the FDA’s boxed warning for lecanemab recommends that patients undergo genetic testing for the apo E4 mutation to identify those at a particularly high risk for severe adverse effects including brain bleeding and swelling. This recommendation is not unreasonable considering that 15% of the Alzheimer’s population has two copies of the apo E4 mutation and fall into that high-risk group.
 

Significant risks

Antiamyloid drugs are well-known to cause serious side effects. In the lecanemab trial, 13% of participants receiving Leqembi experienced brain swelling (vs. 2% of participants receiving placebo) and 17% of participants had brain bleeding (vs. 9% of participants on placebo). In the donanemab trial, brain bleeding occurred in 31.4% of participants on the drug (vs. 13.6% on placebo) and swelling occurred in 24% (vs. 2.1% receiving placebo). Thankfully, in both trials, most of these adverse events did not produce significant symptoms, but in rare cases these events caused severe or catastrophic neurologic injury, including death.

How can we best guide patients and their families to weigh the uncertain benefits against potentially serious risks? We can start by considering the patient characteristics most likely to portend increased risk for serious side effects: apo E4 mutations, blood thinner use, and the presence of microhemorrhages on brain imaging. But after that, we’re left with a lot of uncertainty in terms of which patients are most likely to see meaningful clinical improvements from the drug and unknown factors that may increase the risks of treatment.
 

A costly therapy

Medicare plans to cover 80% of lecanemab’s steep cost of $26,500 per year. Still, that will leave many patients with a hefty copay, potentially over $6,000 per year. But that only scratches the surface. Consider the frequent medical visits, repeated brain scans, laboratory tests, and infusion center appointments. It’s been estimated that all-in, the treatment will actually cost about $90,000 per year.

Yes, Medicare will reimburse a large portion of that cost, but it adds up to an estimated $2 billion per year for about 85,000 patients. This will probably spur increases to Medicare premiums, among other economic consequences for the health care system.

We’ll probably have to wait for an FDA approval decision before we know where donanemab will be priced.
 

Logistical challenges could be a rate-limiting step

Ask anyone who’s tried to see a neurologist recently, and they’ll tell you that the wait for a new patient appointment is months long. The shortage of neurologists in the United States is already a crisis, and there are even fewer cognitive neurologists. How long will patients be forced to wait for their diagnosis?

Many geriatricians will get comfortable prescribing these drugs, but will our already overburdened primary care providers have the bandwidth to do the same? It’s a tall order.

A new world of Alzheimer’s treatments also means that the infrastructure of our health care systems will need to be ramped up. Lecanemab infusions are administered every 2 weeks and donanemab every 4 weeks. Infusion centers will need to accommodate a lot more patients. And those patients will need frequent brain scans, so neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.
 

Antiamyloid drugs: An exciting first step

The bottom line is that these drugs aren’t the Alzheimer’s holy grail: An accessible treatment that could stop the disease in its tracks or reverse cognitive impairment. They are, however, a very promising breakthrough.

Yes, there are a ton of kinks to work out here, but this is an exciting start. Alzheimer’s research is entering a renaissance era that will hopefully bring more groundbreaking developments. Better biomarkers to facilitate faster, easier diagnosis. More drugs that go beyond amyloid proteins for their therapeutic targets. Treatments for later-stage disease. Drugs that prevent dementia altogether.

Ultimately, these new antiamyloid beta drugs are an exciting indication that we will eventually have a toolkit of Alzheimer’s drugs to choose from. For now, we’ve taken a solid step forward and there is ample reason to be hopeful for the future.

Dr. Croll is assistant professor of neurology at Temple University, Philadelphia. She reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

With the Food and Drug Administration’s full stamp of approval in hand, Leqembi (lecanemab) is poised to catapult us into a new era of treatment for Alzheimer’s disease. And now that the donanemab trial data are out, there’s another antiamyloid drug waiting in the wings.

To finally have true disease-modifying therapies for Alzheimer’s disease is a massive step forward for a field that’s been plagued with disappointment. But these drugs come with serious concerns and unknowns. They will require complex decision-making, putting doctors, patients, and their families in a medical quandary.

Striking the right balance between cautious optimism and realistic expectations will be a formidable challenge.
 

Managing patient and family expectations

These drugs are no magic bullet. They slow down the dementia’s progression, buying patients more time (on the order of months) before they begin to experience significant worsening. We’ll need a lot more information from research and clinical experience before we can understand how meaningful that treatment effect is. Right now, it is unclear whether eligible patients and their families will even perceive tangible differences.

In the CLARITY-AD trial, participants on lecanemab experienced a 27% slowing in the rate of cognitive decline over 18 months. Donanemab was shown to slow decline in memory and cognition by about 35% over the same time frame in the TRAILBLAZER-ALZ 2 trial. That translates to more time for patients and their families to enjoy independence, maintain normal life, and stave off the most distressing parts of the disease.

But what happens after 18 months of treatment – will the treatment effect magnify or dissipate? How much time are we really buying in the long run? Counseling patients and their families is made all the more difficult when the answers to important questions like these remain to be seen.
 

Only a sliver of Alzheimer’s patients are current candidates

The fact is that most patients living with Alzheimer’s disease will not qualify for treatment with these drugs. Lecanemab is approved for people with early-stage disease, meaning their dementia is mild or they have mild cognitive impairment, which is a precursor to full-blown Alzheimer’s disease. Of the 6 million people in the United States living with Alzheimer’s, about 1.5 million are estimated to fall into that category. We can expect to see a similar qualifier for donanemab if it receives FDA approval, especially because that trial suggested a more pronounced treatment effect for patients in the earliest stages of the disease.

Even if a patient hits the sweet spot where they have just enough cognitive impairment, but not too much, they aren’t technically therapeutic candidates until prerequisite testing confirms amyloid protein accumulation in the brain via PET scan or cerebrospinal fluid analysis.

Even then, the FDA’s boxed warning for lecanemab recommends that patients undergo genetic testing for the apo E4 mutation to identify those at a particularly high risk for severe adverse effects including brain bleeding and swelling. This recommendation is not unreasonable considering that 15% of the Alzheimer’s population has two copies of the apo E4 mutation and fall into that high-risk group.
 

Significant risks

Antiamyloid drugs are well-known to cause serious side effects. In the lecanemab trial, 13% of participants receiving Leqembi experienced brain swelling (vs. 2% of participants receiving placebo) and 17% of participants had brain bleeding (vs. 9% of participants on placebo). In the donanemab trial, brain bleeding occurred in 31.4% of participants on the drug (vs. 13.6% on placebo) and swelling occurred in 24% (vs. 2.1% receiving placebo). Thankfully, in both trials, most of these adverse events did not produce significant symptoms, but in rare cases these events caused severe or catastrophic neurologic injury, including death.

How can we best guide patients and their families to weigh the uncertain benefits against potentially serious risks? We can start by considering the patient characteristics most likely to portend increased risk for serious side effects: apo E4 mutations, blood thinner use, and the presence of microhemorrhages on brain imaging. But after that, we’re left with a lot of uncertainty in terms of which patients are most likely to see meaningful clinical improvements from the drug and unknown factors that may increase the risks of treatment.
 

A costly therapy

Medicare plans to cover 80% of lecanemab’s steep cost of $26,500 per year. Still, that will leave many patients with a hefty copay, potentially over $6,000 per year. But that only scratches the surface. Consider the frequent medical visits, repeated brain scans, laboratory tests, and infusion center appointments. It’s been estimated that all-in, the treatment will actually cost about $90,000 per year.

Yes, Medicare will reimburse a large portion of that cost, but it adds up to an estimated $2 billion per year for about 85,000 patients. This will probably spur increases to Medicare premiums, among other economic consequences for the health care system.

We’ll probably have to wait for an FDA approval decision before we know where donanemab will be priced.
 

Logistical challenges could be a rate-limiting step

Ask anyone who’s tried to see a neurologist recently, and they’ll tell you that the wait for a new patient appointment is months long. The shortage of neurologists in the United States is already a crisis, and there are even fewer cognitive neurologists. How long will patients be forced to wait for their diagnosis?

Many geriatricians will get comfortable prescribing these drugs, but will our already overburdened primary care providers have the bandwidth to do the same? It’s a tall order.

A new world of Alzheimer’s treatments also means that the infrastructure of our health care systems will need to be ramped up. Lecanemab infusions are administered every 2 weeks and donanemab every 4 weeks. Infusion centers will need to accommodate a lot more patients. And those patients will need frequent brain scans, so neuroimaging centers will need to increase their capacity to perform many more brain MRI and PET scans.
 

Antiamyloid drugs: An exciting first step

The bottom line is that these drugs aren’t the Alzheimer’s holy grail: An accessible treatment that could stop the disease in its tracks or reverse cognitive impairment. They are, however, a very promising breakthrough.

Yes, there are a ton of kinks to work out here, but this is an exciting start. Alzheimer’s research is entering a renaissance era that will hopefully bring more groundbreaking developments. Better biomarkers to facilitate faster, easier diagnosis. More drugs that go beyond amyloid proteins for their therapeutic targets. Treatments for later-stage disease. Drugs that prevent dementia altogether.

Ultimately, these new antiamyloid beta drugs are an exciting indication that we will eventually have a toolkit of Alzheimer’s drugs to choose from. For now, we’ve taken a solid step forward and there is ample reason to be hopeful for the future.

Dr. Croll is assistant professor of neurology at Temple University, Philadelphia. She reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.