Alzheimer's & Cognition

 

Among older adults with low and intermediate genetic risk for dementia, favorable modifiable health and lifestyle factors are associated with lower likelihood of dementia. But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.

Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.

“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”

Grouped by APOE genotype

Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).

The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).

The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.

In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.

“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.

 

Lifestyle benefits tended to be greater in younger participants

“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.

“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.

“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”

The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.

“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”

The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.

Lifestyle factors may benefit only people with low genetic risk

“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.

The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.

Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.

“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.

The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.

Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.

[email protected]

SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.

 

Among older adults with low and intermediate genetic risk for dementia, favorable modifiable health and lifestyle factors are associated with lower likelihood of dementia. But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.

Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.

“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”

Grouped by APOE genotype

Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).

The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).

The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.

In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.

“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.

 

Lifestyle benefits tended to be greater in younger participants

“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.

“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.

“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”

The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.

“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”

The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.

Lifestyle factors may benefit only people with low genetic risk

“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.

The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.

Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.

“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.

The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.

Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.

[email protected]

SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.

 

Among older adults with low and intermediate genetic risk for dementia, favorable modifiable health and lifestyle factors are associated with lower likelihood of dementia. But among people at high genetic risk for dementia, these potentially modifiable factors – not smoking, not having depression or diabetes, getting regular physical activity, avoiding social isolation, and following a healthy diet – may not have protective associations, according to research published in Nature Medicine.

Recent analyses have indicated that eliminating known modifiable risk factors for dementia at a population level could prevent one-third of dementia cases, but prevention trials “have yielded inconsistent results so far,” wrote first author Silvan Licher, MD, of the department of epidemiology at Erasmus University Medical Center Rotterdam (the Netherlands) and his colleagues.

“Prior studies have mostly focused on the risk of dementia associated with an individual protective factor, yet the combination of multiple factors may yield more beneficial effects than the individual parts,” they wrote. “Combining data about a number of factors is also important because it takes into account the multifactorial nature of late-life dementia. We used data from the Rotterdam Study to determine to what extent a favorable profile based on modifiable risk factors is associated with a lower risk of dementia among individuals at low, intermediate, or high genetic risk.”

Grouped by APOE genotype

Patients who were apolipoprotein E epsilon-4 allele (APOE4) carriers (i.e., APOE2 and 4, APOE3 and 4, or two APOE4) were classified as having high genetic risk (n = 1,747). Other APOE genotypes were considered intermediate risk (n = 3,718 with two APOE3 alleles) or low risk (n = 887 with either two APOE2 alleles or APOE2 and 3).

The researchers measured six potentially modifiable lifestyle or health factors that “have been implicated in a lower risk of dementia.” Modifiable risk scores ranged from 0 to 6. Participants were classified as having an unfavorable profile (0-2 protective factors), an intermediate profile (3-4 protective factors), or a favorable profile (5-6 factors).

The researchers calculated the relative risk of developing dementia using a Cox proportional hazards model and the absolutely risk using competing risk models.

In all, 56.2% of the participants were women, the average age was about 69 years, and patient characteristics were similar across the categories of APOE risk. APOE4 carriers received dementia diagnoses at a younger age, more often had a parental history of dementia, and had higher total cholesterol levels, compared with noncarriers. In all, 915 people received a dementia diagnosis, of whom 739 received a diagnosis of Alzheimer’s disease. The other 2,644 participants died free from dementia. The median follow-up was 14.1 years.

“Dementia risk was significantly higher among participants at high or intermediate APOE risk, compared with those at low APOE risk,” the researchers said. In addition, the risk of dementia increased in participants who had fewer protective factors. Those with 0-2 protective factors had a 29% higher risk of dementia, compared with participants with 5 or 6 protective factors, after adjusting for age, sex, level of education, parental history of dementia, history of stroke, systolic blood pressure, and total and high-density lipoprotein cholesterol.

 

Lifestyle benefits tended to be greater in younger participants

“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.

“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.

“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”

The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.

“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”

The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.

Lifestyle factors may benefit only people with low genetic risk

“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.

The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.

Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.

“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.

The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.

Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.

[email protected]

SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.

 

Two variants of MS4A are associated with the risk of Alzheimer’s disease, according to research published online August 14 in Science Translational Medicine. The variants affect cerebrospinal fluid (CSF) concentrations of a soluble form of the TREM2 protein (sTREM2), which may be involved in Alzheimer’s disease pathology. “Increasing TREM2 or activating the TREM2 signaling pathway could offer a new therapeutic approach for treating Alzheimer’s disease,” wrote the researchers.

Previous investigations have indicated that CSF levels of sTREM2 are increased in patients with Alzheimer’s disease. Changes in these levels appear to follow amyloid accumulation at approximately 5 years before the onset of clinical symptoms in autosomal dominant forms of the disease.

Yuetiva Deming, PhD, of the University of Wisconsin–Madison and colleagues conducted a genome-wide association study to identify genetic modifiers of CSF sTREM2. They analyzed CSF sTREM2 levels in 813 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Of this population, 172 participants had Alzheimer’s disease, 169 were cognitively normal, 183 had early mild cognitive impairment (MCI), 221 had late MCI, and 68 had significant memory concerns.

The rs1582763 single-nucleotide polymorphism (SNP) on chromosome 11 within the MS4A gene region was significantly associated with increased CSF levels of sTREM2. Conditional analyses of the MS4A locus indicated that rs6591561, a missense variant within MS4A4A, was associated with reduced CSF sTREM2. Analyzing 580 additional CSF sTREM2 samples, along with associated genetic data, from six other studies replicated these findings in an independent dataset.

Furthermore, Dr. Deming and colleagues found that rs1582763 was associated with reduced risk for Alzheimer’s disease and older age at Alzheimer’s disease onset. In addition, rs6591561 was associated with increased risk of Alzheimer’s disease and earlier onset of Alzheimer’s disease.

Subsequent analyses showed that rs1582763 modified the expression of the MS4A4A and MS4A6A genes in various tissues. This finding suggests that one or both of these genes are important for influencing the production of sTREM2, wrote Dr. Deming and colleagues. Using human macrophages as a proxy for microglia, the investigators observed that the MS4A4A and TREM2 proteins colocalized on lipid rafts at the plasma membrane. In addition, sTREM2 concentrations increased with MS4A4A overexpression, and silencing of MS4A4A reduced sTREM2 production.

These findings “provide a putative biological connection between the MS4A family, TREM2, and Alzheimer’s disease risk,” wrote the researchers. The data also suggest that MS4A4A is a potential therapeutic target in Alzheimer’s disease. Understanding the role of sTREM2 in Alzheimer’s disease will require additional research, but it may be involved in pathogenesis, wrote Dr. Deming and colleagues.

One of the study’s limitations is that the investigators included only common variants and thus could not determine the effect of genes that only harbor low-frequency or rare functional variants. Another limitation is that the data cannot support conclusions about whether other genes in the MS4A locus also modulate sTREM2, wrote Dr. Deming and colleagues.

Grants from the National Institutes of Health supported this study. The investigators disclosed consulting and other relationships with various pharmaceutical companies.
 

 

[email protected]

SOURCE: Deming Y et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aau2291.

 

Two variants of MS4A are associated with the risk of Alzheimer’s disease, according to research published online August 14 in Science Translational Medicine. The variants affect cerebrospinal fluid (CSF) concentrations of a soluble form of the TREM2 protein (sTREM2), which may be involved in Alzheimer’s disease pathology. “Increasing TREM2 or activating the TREM2 signaling pathway could offer a new therapeutic approach for treating Alzheimer’s disease,” wrote the researchers.

Previous investigations have indicated that CSF levels of sTREM2 are increased in patients with Alzheimer’s disease. Changes in these levels appear to follow amyloid accumulation at approximately 5 years before the onset of clinical symptoms in autosomal dominant forms of the disease.

Yuetiva Deming, PhD, of the University of Wisconsin–Madison and colleagues conducted a genome-wide association study to identify genetic modifiers of CSF sTREM2. They analyzed CSF sTREM2 levels in 813 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Of this population, 172 participants had Alzheimer’s disease, 169 were cognitively normal, 183 had early mild cognitive impairment (MCI), 221 had late MCI, and 68 had significant memory concerns.

The rs1582763 single-nucleotide polymorphism (SNP) on chromosome 11 within the MS4A gene region was significantly associated with increased CSF levels of sTREM2. Conditional analyses of the MS4A locus indicated that rs6591561, a missense variant within MS4A4A, was associated with reduced CSF sTREM2. Analyzing 580 additional CSF sTREM2 samples, along with associated genetic data, from six other studies replicated these findings in an independent dataset.

Furthermore, Dr. Deming and colleagues found that rs1582763 was associated with reduced risk for Alzheimer’s disease and older age at Alzheimer’s disease onset. In addition, rs6591561 was associated with increased risk of Alzheimer’s disease and earlier onset of Alzheimer’s disease.

Subsequent analyses showed that rs1582763 modified the expression of the MS4A4A and MS4A6A genes in various tissues. This finding suggests that one or both of these genes are important for influencing the production of sTREM2, wrote Dr. Deming and colleagues. Using human macrophages as a proxy for microglia, the investigators observed that the MS4A4A and TREM2 proteins colocalized on lipid rafts at the plasma membrane. In addition, sTREM2 concentrations increased with MS4A4A overexpression, and silencing of MS4A4A reduced sTREM2 production.

These findings “provide a putative biological connection between the MS4A family, TREM2, and Alzheimer’s disease risk,” wrote the researchers. The data also suggest that MS4A4A is a potential therapeutic target in Alzheimer’s disease. Understanding the role of sTREM2 in Alzheimer’s disease will require additional research, but it may be involved in pathogenesis, wrote Dr. Deming and colleagues.

One of the study’s limitations is that the investigators included only common variants and thus could not determine the effect of genes that only harbor low-frequency or rare functional variants. Another limitation is that the data cannot support conclusions about whether other genes in the MS4A locus also modulate sTREM2, wrote Dr. Deming and colleagues.

Grants from the National Institutes of Health supported this study. The investigators disclosed consulting and other relationships with various pharmaceutical companies.
 

 

[email protected]

SOURCE: Deming Y et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aau2291.

 

Two variants of MS4A are associated with the risk of Alzheimer’s disease, according to research published online August 14 in Science Translational Medicine. The variants affect cerebrospinal fluid (CSF) concentrations of a soluble form of the TREM2 protein (sTREM2), which may be involved in Alzheimer’s disease pathology. “Increasing TREM2 or activating the TREM2 signaling pathway could offer a new therapeutic approach for treating Alzheimer’s disease,” wrote the researchers.

Previous investigations have indicated that CSF levels of sTREM2 are increased in patients with Alzheimer’s disease. Changes in these levels appear to follow amyloid accumulation at approximately 5 years before the onset of clinical symptoms in autosomal dominant forms of the disease.

Yuetiva Deming, PhD, of the University of Wisconsin–Madison and colleagues conducted a genome-wide association study to identify genetic modifiers of CSF sTREM2. They analyzed CSF sTREM2 levels in 813 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Of this population, 172 participants had Alzheimer’s disease, 169 were cognitively normal, 183 had early mild cognitive impairment (MCI), 221 had late MCI, and 68 had significant memory concerns.

The rs1582763 single-nucleotide polymorphism (SNP) on chromosome 11 within the MS4A gene region was significantly associated with increased CSF levels of sTREM2. Conditional analyses of the MS4A locus indicated that rs6591561, a missense variant within MS4A4A, was associated with reduced CSF sTREM2. Analyzing 580 additional CSF sTREM2 samples, along with associated genetic data, from six other studies replicated these findings in an independent dataset.

Furthermore, Dr. Deming and colleagues found that rs1582763 was associated with reduced risk for Alzheimer’s disease and older age at Alzheimer’s disease onset. In addition, rs6591561 was associated with increased risk of Alzheimer’s disease and earlier onset of Alzheimer’s disease.

Subsequent analyses showed that rs1582763 modified the expression of the MS4A4A and MS4A6A genes in various tissues. This finding suggests that one or both of these genes are important for influencing the production of sTREM2, wrote Dr. Deming and colleagues. Using human macrophages as a proxy for microglia, the investigators observed that the MS4A4A and TREM2 proteins colocalized on lipid rafts at the plasma membrane. In addition, sTREM2 concentrations increased with MS4A4A overexpression, and silencing of MS4A4A reduced sTREM2 production.

These findings “provide a putative biological connection between the MS4A family, TREM2, and Alzheimer’s disease risk,” wrote the researchers. The data also suggest that MS4A4A is a potential therapeutic target in Alzheimer’s disease. Understanding the role of sTREM2 in Alzheimer’s disease will require additional research, but it may be involved in pathogenesis, wrote Dr. Deming and colleagues.

One of the study’s limitations is that the investigators included only common variants and thus could not determine the effect of genes that only harbor low-frequency or rare functional variants. Another limitation is that the data cannot support conclusions about whether other genes in the MS4A locus also modulate sTREM2, wrote Dr. Deming and colleagues.

Grants from the National Institutes of Health supported this study. The investigators disclosed consulting and other relationships with various pharmaceutical companies.
 

 

[email protected]

SOURCE: Deming Y et al. Sci Transl Med. 2019 Aug 14. doi: 10.1126/scitranslmed.aau2291.

 

Uncontrolled hypertension among individuals aged 45-65 years of age is associated with an increased risk of subsequent dementia, according to a relatively large prospective population-based cohort study that followed patients for almost 30 years.

Ingram Publishing/ThinkStock

Even though previously published studies have not conclusively linked blood pressure control with a reduction in dementia risk, a second study, published simultaneously, did link blood pressure control with a smaller increase in white matter lesions, which are a marker of dementia risk. However, a reduction in total brain volume that accompanied this protection raised concern.

In the first of the two reports published Aug. 13 in JAMA, individuals 45-65 years of age participating in the Atherosclerosis Risk in Communities (ARIC) study were followed for cognitive function in relation to blood pressure. The baseline visit took place in 1987-1989. Cognitive function was also evaluated at the fifth visit, which took place in 2011-2013, and the sixth visit, which took place in 2016-2017.

At the sixth visit, the incidence of dementia among patients who were normotensive at baseline and also normotensive at the fifth visit was 1.31 per 100 person-years. For those with hypertension (greater than 140/90 mm Hg) at the fifth visit but normotensive at baseline, the incidence was 1.99 per 100 patient-years. For those with hypertension at both time points, the incidence was 4.26 per 100 patient-years.

When translated into hazard ratios, those with midlife and late-life hypertension were nearly 50% more likely to develop dementia (HR, 1.49) relative to those who remained normotensive. For those who had only midlife hypertension, the risk was also significantly increased (HR, 1.41) relative to those who remained normotensive at both time points.

Those with midlife hypertension but late-life hypotension were also found to be at greater risk of dementia (HR, 1.62) relative to those who remained normotensive.

These data support the premise that uncontrolled midlife hypertension increases risk of dementia but do not touch on whether blood pressure reductions reduce this risk. However, a second study published simultaneously provided at least some evidence that blood pressure control might offer some protection.

In this report, which is a substudy of the previously published Systolic Blood Pressure Intervention Trial (SPRINT) MIND trial, brain volume changes were evaluated via MRI in 449 of the more than 2,000 patients included in the previously published trial (Williamson JD et al. JAMA. 2019;321[6]:553-61).

After a median 3.4 years of follow-up, mean white matter lesion volume increased only 0.92 cm³ in patients receiving intensive systolic blood pressure control, defined as less than 120 mm Hg, versus 1.45 cm³ in those with higher systolic blood pressures.

These substudy data are encouraging, but it is important to recognize that the previously published and larger SPRINT MIND trial did not achieve its endpoint. In that study, the protection against dementia was nonsignificant (HR, 0.83; 95% confidence interval, 0.67-1.04).

In addition, the lower loss in white matter volume with intensive blood pressure lowering in the MRI substudy was accompanied with a greater loss in total brain volume (–30.6 vs. –26.9 cm³), which is considered a potentially negative effect.

As a result, the picture for risk management remains unclear, according to an editorial that accompanied publication of both studies.

“The important clinical question is whether changes of a few cubic millimeters in white matter hyperintensity volume or brain make a difference on brain function,” observed the author of the editorial, Shyam Prabhakaran, MD, of the department of neurology at the University of Chicago.

He believes that there are several findings from both studies that are “encouraging” in regard to blood pressure control for the prevention of dementia, but he also listed many unanswered questions, including why benefits observed to date have been so modest. He speculated that meaningful clinical benefits might depend on a multimodal approach that includes modification of other vascular risk factors, such as elevated lipids.

He also suggested that many issues regarding intensive blood pressure control for preventing dementia are unresolved, suggesting the need for more studies.

Not least, “later blood-pressure lowering interventions require careful monitoring for the potential cognitive harm associated with late-life hypotension,” Dr. Prabhakaran noted. Calling the effects of blood pressure control on brain health “nuanced,” he concluded that there is an opportunity for blood pressure modifications to prevent dementia, but stressed that optimal blood pressure targets for the purposes of preventing dementia are unknown.

The ARIC and SPRINT studies are supported by the National Institutes of Health. Several authors reported relationships with industry but no conflicts of interest relevant to this study.

SOURCES: Walker KA et al. JAMA. 2019;322(6):535-45; SPRINT MIND investigators. JAMA. 2019;322(6):524-34; Prabhakaran S. JAMA. 2019;322(6):512-3

 

Uncontrolled hypertension among individuals aged 45-65 years of age is associated with an increased risk of subsequent dementia, according to a relatively large prospective population-based cohort study that followed patients for almost 30 years.

Ingram Publishing/ThinkStock

Even though previously published studies have not conclusively linked blood pressure control with a reduction in dementia risk, a second study, published simultaneously, did link blood pressure control with a smaller increase in white matter lesions, which are a marker of dementia risk. However, a reduction in total brain volume that accompanied this protection raised concern.

In the first of the two reports published Aug. 13 in JAMA, individuals 45-65 years of age participating in the Atherosclerosis Risk in Communities (ARIC) study were followed for cognitive function in relation to blood pressure. The baseline visit took place in 1987-1989. Cognitive function was also evaluated at the fifth visit, which took place in 2011-2013, and the sixth visit, which took place in 2016-2017.

At the sixth visit, the incidence of dementia among patients who were normotensive at baseline and also normotensive at the fifth visit was 1.31 per 100 person-years. For those with hypertension (greater than 140/90 mm Hg) at the fifth visit but normotensive at baseline, the incidence was 1.99 per 100 patient-years. For those with hypertension at both time points, the incidence was 4.26 per 100 patient-years.

When translated into hazard ratios, those with midlife and late-life hypertension were nearly 50% more likely to develop dementia (HR, 1.49) relative to those who remained normotensive. For those who had only midlife hypertension, the risk was also significantly increased (HR, 1.41) relative to those who remained normotensive at both time points.

Those with midlife hypertension but late-life hypotension were also found to be at greater risk of dementia (HR, 1.62) relative to those who remained normotensive.

These data support the premise that uncontrolled midlife hypertension increases risk of dementia but do not touch on whether blood pressure reductions reduce this risk. However, a second study published simultaneously provided at least some evidence that blood pressure control might offer some protection.

In this report, which is a substudy of the previously published Systolic Blood Pressure Intervention Trial (SPRINT) MIND trial, brain volume changes were evaluated via MRI in 449 of the more than 2,000 patients included in the previously published trial (Williamson JD et al. JAMA. 2019;321[6]:553-61).

After a median 3.4 years of follow-up, mean white matter lesion volume increased only 0.92 cm³ in patients receiving intensive systolic blood pressure control, defined as less than 120 mm Hg, versus 1.45 cm³ in those with higher systolic blood pressures.

These substudy data are encouraging, but it is important to recognize that the previously published and larger SPRINT MIND trial did not achieve its endpoint. In that study, the protection against dementia was nonsignificant (HR, 0.83; 95% confidence interval, 0.67-1.04).

In addition, the lower loss in white matter volume with intensive blood pressure lowering in the MRI substudy was accompanied with a greater loss in total brain volume (–30.6 vs. –26.9 cm³), which is considered a potentially negative effect.

As a result, the picture for risk management remains unclear, according to an editorial that accompanied publication of both studies.

“The important clinical question is whether changes of a few cubic millimeters in white matter hyperintensity volume or brain make a difference on brain function,” observed the author of the editorial, Shyam Prabhakaran, MD, of the department of neurology at the University of Chicago.

He believes that there are several findings from both studies that are “encouraging” in regard to blood pressure control for the prevention of dementia, but he also listed many unanswered questions, including why benefits observed to date have been so modest. He speculated that meaningful clinical benefits might depend on a multimodal approach that includes modification of other vascular risk factors, such as elevated lipids.

He also suggested that many issues regarding intensive blood pressure control for preventing dementia are unresolved, suggesting the need for more studies.

Not least, “later blood-pressure lowering interventions require careful monitoring for the potential cognitive harm associated with late-life hypotension,” Dr. Prabhakaran noted. Calling the effects of blood pressure control on brain health “nuanced,” he concluded that there is an opportunity for blood pressure modifications to prevent dementia, but stressed that optimal blood pressure targets for the purposes of preventing dementia are unknown.

The ARIC and SPRINT studies are supported by the National Institutes of Health. Several authors reported relationships with industry but no conflicts of interest relevant to this study.

SOURCES: Walker KA et al. JAMA. 2019;322(6):535-45; SPRINT MIND investigators. JAMA. 2019;322(6):524-34; Prabhakaran S. JAMA. 2019;322(6):512-3

 

Uncontrolled hypertension among individuals aged 45-65 years of age is associated with an increased risk of subsequent dementia, according to a relatively large prospective population-based cohort study that followed patients for almost 30 years.

Ingram Publishing/ThinkStock

Even though previously published studies have not conclusively linked blood pressure control with a reduction in dementia risk, a second study, published simultaneously, did link blood pressure control with a smaller increase in white matter lesions, which are a marker of dementia risk. However, a reduction in total brain volume that accompanied this protection raised concern.

In the first of the two reports published Aug. 13 in JAMA, individuals 45-65 years of age participating in the Atherosclerosis Risk in Communities (ARIC) study were followed for cognitive function in relation to blood pressure. The baseline visit took place in 1987-1989. Cognitive function was also evaluated at the fifth visit, which took place in 2011-2013, and the sixth visit, which took place in 2016-2017.

At the sixth visit, the incidence of dementia among patients who were normotensive at baseline and also normotensive at the fifth visit was 1.31 per 100 person-years. For those with hypertension (greater than 140/90 mm Hg) at the fifth visit but normotensive at baseline, the incidence was 1.99 per 100 patient-years. For those with hypertension at both time points, the incidence was 4.26 per 100 patient-years.

When translated into hazard ratios, those with midlife and late-life hypertension were nearly 50% more likely to develop dementia (HR, 1.49) relative to those who remained normotensive. For those who had only midlife hypertension, the risk was also significantly increased (HR, 1.41) relative to those who remained normotensive at both time points.

Those with midlife hypertension but late-life hypotension were also found to be at greater risk of dementia (HR, 1.62) relative to those who remained normotensive.

These data support the premise that uncontrolled midlife hypertension increases risk of dementia but do not touch on whether blood pressure reductions reduce this risk. However, a second study published simultaneously provided at least some evidence that blood pressure control might offer some protection.

In this report, which is a substudy of the previously published Systolic Blood Pressure Intervention Trial (SPRINT) MIND trial, brain volume changes were evaluated via MRI in 449 of the more than 2,000 patients included in the previously published trial (Williamson JD et al. JAMA. 2019;321[6]:553-61).

After a median 3.4 years of follow-up, mean white matter lesion volume increased only 0.92 cm³ in patients receiving intensive systolic blood pressure control, defined as less than 120 mm Hg, versus 1.45 cm³ in those with higher systolic blood pressures.

These substudy data are encouraging, but it is important to recognize that the previously published and larger SPRINT MIND trial did not achieve its endpoint. In that study, the protection against dementia was nonsignificant (HR, 0.83; 95% confidence interval, 0.67-1.04).

In addition, the lower loss in white matter volume with intensive blood pressure lowering in the MRI substudy was accompanied with a greater loss in total brain volume (–30.6 vs. –26.9 cm³), which is considered a potentially negative effect.

As a result, the picture for risk management remains unclear, according to an editorial that accompanied publication of both studies.

“The important clinical question is whether changes of a few cubic millimeters in white matter hyperintensity volume or brain make a difference on brain function,” observed the author of the editorial, Shyam Prabhakaran, MD, of the department of neurology at the University of Chicago.

He believes that there are several findings from both studies that are “encouraging” in regard to blood pressure control for the prevention of dementia, but he also listed many unanswered questions, including why benefits observed to date have been so modest. He speculated that meaningful clinical benefits might depend on a multimodal approach that includes modification of other vascular risk factors, such as elevated lipids.

He also suggested that many issues regarding intensive blood pressure control for preventing dementia are unresolved, suggesting the need for more studies.

Not least, “later blood-pressure lowering interventions require careful monitoring for the potential cognitive harm associated with late-life hypotension,” Dr. Prabhakaran noted. Calling the effects of blood pressure control on brain health “nuanced,” he concluded that there is an opportunity for blood pressure modifications to prevent dementia, but stressed that optimal blood pressure targets for the purposes of preventing dementia are unknown.

The ARIC and SPRINT studies are supported by the National Institutes of Health. Several authors reported relationships with industry but no conflicts of interest relevant to this study.

SOURCES: Walker KA et al. JAMA. 2019;322(6):535-45; SPRINT MIND investigators. JAMA. 2019;322(6):524-34; Prabhakaran S. JAMA. 2019;322(6):512-3

 

LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.

After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.

Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.

The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.

The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.

Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.

The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”

Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.

Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.

Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.

Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.

Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.

“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.

Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.

“It’s something of great interest, we think, and deserves to be investigated.”

[email protected]

SOURCE: Missling C et al. AAIC 2019, Abstract 32260.

 

LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.

After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.

Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.

The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.

The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.

Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.

The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”

Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.

Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.

Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.

Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.

Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.

“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.

Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.

“It’s something of great interest, we think, and deserves to be investigated.”

[email protected]

SOURCE: Missling C et al. AAIC 2019, Abstract 32260.

 

LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.

After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.

Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.

The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.

The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.

Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.

The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”

Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.

Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.

Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.

Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.

Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.

“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.

Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.

“It’s something of great interest, we think, and deserves to be investigated.”

[email protected]

SOURCE: Missling C et al. AAIC 2019, Abstract 32260.

LOS ANGELES – While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.

Nastasic/iStockphoto.com

Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep – especially from insomnia, sleep deprivation, or obstructive sleep apnea – is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.

At the Alzheimer’s Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
 

Sex- and race-based differences in risk

Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia – but only in white adults. Dr. Leng presented findings from the National Institutes of Health–funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications “often” or “almost always.”

Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.

The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.

Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.


“Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?” Dr. Leng said, adding: “I am a big advocate of behavioral sleep interventions.” People with clinical sleep problems “should be referred to sleep centers” for a fuller assessment before medication is prescribed, she said.

Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.

The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer’s disease than did men who did not use sleep aids (HR, 3.604; P = .0001).

Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer’s disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer’s risk of about one-third associated with the use of sleep medications.

Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.

 

Common sleep drugs linked to cognitive aging

Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)

At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer’s disease, both classes of drugs were associated with “slight signals in neuronal loss” in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing “an increase in cognitive aging” which could bear on Alzheimer’s risk without being directly causative.
 

Newer sleep drugs may help Alzheimer’s patients

Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer’s disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer’s disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.

Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer’s disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer’s disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
 

Trazodone linked to slower cognitive decline

An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer’s disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.

 

Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance.

Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer’s disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.

In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.

Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. “You’re not going to see long-term cognitive benefits if it’s not improving your sleep,” Dr. Karageorgiou said. “So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise.”

He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.

“Trazodone is not the magic bullet, and I don’t think we will ever have a magic bullet,” Dr. Karageorgiou said. “Because when our brain degenerates, it’s not just one chemical, or one system, it’s many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us.”

None of the investigators outside of the industry-sponsored studies had relevant disclosures.

LOS ANGELES – While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.

Nastasic/iStockphoto.com

Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep – especially from insomnia, sleep deprivation, or obstructive sleep apnea – is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.

At the Alzheimer’s Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
 

Sex- and race-based differences in risk

Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia – but only in white adults. Dr. Leng presented findings from the National Institutes of Health–funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications “often” or “almost always.”

Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.

The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.

Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.


“Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?” Dr. Leng said, adding: “I am a big advocate of behavioral sleep interventions.” People with clinical sleep problems “should be referred to sleep centers” for a fuller assessment before medication is prescribed, she said.

Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.

The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer’s disease than did men who did not use sleep aids (HR, 3.604; P = .0001).

Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer’s disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer’s risk of about one-third associated with the use of sleep medications.

Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.

 

Common sleep drugs linked to cognitive aging

Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)

At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer’s disease, both classes of drugs were associated with “slight signals in neuronal loss” in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing “an increase in cognitive aging” which could bear on Alzheimer’s risk without being directly causative.
 

Newer sleep drugs may help Alzheimer’s patients

Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer’s disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer’s disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.

Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer’s disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer’s disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
 

Trazodone linked to slower cognitive decline

An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer’s disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.

 

Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance.

Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer’s disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.

In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.

Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. “You’re not going to see long-term cognitive benefits if it’s not improving your sleep,” Dr. Karageorgiou said. “So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise.”

He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.

“Trazodone is not the magic bullet, and I don’t think we will ever have a magic bullet,” Dr. Karageorgiou said. “Because when our brain degenerates, it’s not just one chemical, or one system, it’s many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us.”

None of the investigators outside of the industry-sponsored studies had relevant disclosures.

LOS ANGELES – While a large number of older adults take prescription and nonprescription medications to help them sleep, the effect of these medications on dementia risk is unclear, with most researchers advocating a cautious and conservative approach to prescribing.

Nastasic/iStockphoto.com

Research is increasingly revealing a bidirectional relationship between sleep and dementia. Poor sleep – especially from insomnia, sleep deprivation, or obstructive sleep apnea – is known to increase dementia risk. Dementias, meanwhile, are associated with serious circadian rhythm disturbances, leading to nighttime sleep loss and increasing the likelihood of institutionalization.

At the Alzheimer’s Association International Conference, researchers presented findings assessing the links between sleep medication use and dementia and also what agents or approaches might safely improve sleep in people with sleep disorders who are at risk for dementia or who have been diagnosed with dementia.
 

Sex- and race-based differences in risk

Yue Leng, PhD, of the University of California, San Francisco, reported a link between frequent sleep medication use and later dementia – but only in white adults. Dr. Leng presented findings from the National Institutes of Health–funded Health, Aging, and Body Composition Study, which recruited 3,068 subjects aged 70-79 and followed them for 15 years. At baseline, 2.7% of African Americans and 7.7% of whites in the study reported taking sleep medications “often” or “almost always.”

Dr. Leng and her colleagues found that white subjects who reported taking sleep aids five or more times a month at baseline had a nearly 80% higher risk of developing dementia during the course of the study (hazard ratio, 1.79; 95% confidence interval, 1.21-2.66), compared with people who reported never taking sleep aids or taking them less frequently.

The researchers saw no between-sex differences for this finding, and adjusted for a variety of genetic and lifestyle confounders. Importantly, no significant increase in dementia risk was seen for black subjects, who made up more than one-third of the cohort.

Dr. Leng told the conference that the researchers could not explain why black participants did not see similarly increased dementia risk. Also, she noted, researchers did not have information on the specific sleep medications people used: benzodiazepines, antihistamines, antidepressants, or other types of drugs. Nonetheless, she told the conference, the findings ratified the cautious approach many dementia experts are already stressing.


“Do we really need to prescribe so many sleep meds to older adults who are already at risk for cognitive impairment?” Dr. Leng said, adding: “I am a big advocate of behavioral sleep interventions.” People with clinical sleep problems “should be referred to sleep centers” for a fuller assessment before medication is prescribed, she said.

Findings from another cohort study, meanwhile, suggest that there could be sex-related differences in how sleep aids affect dementia risk. Investigators at Utah State University in Logan used data from some 3,656 older adults in the Cache County Study on Memory and Aging, an NIH-backed cohort study of white adults in Utah without dementia at baseline who were followed for 12 years.

The investigators, led by doctoral student Elizabeth Vernon, found that men reporting use of sleep medication saw more than threefold higher risk of developing Alzheimer’s disease than did men who did not use sleep aids (HR, 3.604; P = .0001).

Women who did not report having sleep disturbance but used sleep-inducing medications were at nearly fourfold greater risk for developing Alzheimer’s disease (HR, 3.916; P = .0001). Women who self-reported sleep disturbances at baseline, meanwhile, saw a reduction in Alzheimer’s risk of about one-third associated with the use of sleep medications.

Ms. Vernon told the conference that, despite the finding of risk reduction for this particular group of women, caution in prescribing sleep aids was warranted.

 

Common sleep drugs linked to cognitive aging

Chris Fox, MD, a researcher at the University of East Anglia in Norwich, England, and his colleagues demonstrated in 2018 that long-term exposure to anticholinergic drugs, a class that includes some antidepressants and antihistamines used to promote sleep, was associated with a higher risk of dementia, while use of benzodiazepines, a class of sedatives used commonly in older people as sleep aids, was not. (Whether benzodiazepine exposure relates to dementia remains controversial.)

At AAIC 2019, Dr. Fox presented findings from a study of 337 brains in a U.K. brain bank, of which 17% and 21% came from users of benzodiazepines and anticholinergic drugs, whose usage history was well documented. Dr. Fox and his colleagues found that, while neither anticholinergic nor benzodiazepine exposure was associated with brain pathology specific to that seen in Alzheimer’s disease, both classes of drugs were associated with “slight signals in neuronal loss” in one brain region, the nucleus basalis of Meynert. Dr. Fox described the drugs as causing “an increase in cognitive aging” which could bear on Alzheimer’s risk without being directly causative.
 

Newer sleep drugs may help Alzheimer’s patients

Scientists working for drug manufacturers presented findings on agents to counter the circadian rhythm disturbances seen in people with Alzheimer’s disease. Margaret Moline, PhD, of Eisai in Woodcliff Lake, N.J., showed some results from a phase 2, dose-ranging, placebo-controlled study of the experimental agent lemborexant in 62 subjects aged 60-90 with mild to moderate Alzheimer’s disease and sleep disturbances. (Lemborexant, an orexin receptor agonist that acts to regulate wakefulness, is being investigated in a broad range of sleep disorders.) Patients were randomized to one of four doses of lemborexant or placebo and wore a device for sleep monitoring. Nighttime activity indicating arousal was significantly lower for people in two dosage arms, 5 mg and 10 mg, compared with placebo, and treatment groups saw trends toward less sleep fragmentation and higher total sleep time, Dr. Moline told the conference.

Suvorexant (Belsomra), the only orexin receptor antagonist currently licensed as a sleep aid, is also being tested in people with Alzheimer’s disease. At AAIC 2019, Joseph Herring, MD, PhD, of Merck in Kenilworth, N.J., presented results from a placebo-controlled trial of 277 patients with Alzheimer’s disease and insomnia, and reported that treatment with 10 or 20 mg of suvorexant over 4 weeks was associated with about an extra half hour of total nightly sleep, with a 73-minute mean increase from baseline, compared with 45 minutes for patients receiving placebo (95% CI, 11-45; P less than .005).
 

Trazodone linked to slower cognitive decline

An inexpensive antidepressant used in low doses as a sleep aid, including in people with Alzheimer’s disease, was associated with a delay in cognitive decline in older adults, according to results from a retrospective study. Elissaios Karageorgiou, MD, PhD, of the University of California, San Francisco, and the Neurological Institute of Athens presented results derived from two cohorts: patients enrolled at the UCSF Memory and Aging Center and women enrolled in the Study for Osteoporotic Fractures (SOF) in Women. The investigators were able to identify trazodone users in the studies (with two or more contiguous study visits reporting trazodone use) and match them with control patients from the same cohorts who did not use trazodone.

 

Trazodone was studied because previous research suggests it increases total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance.

Trazodone-using patients in the UCSF cohort (n = 25) saw significantly less decline in Mini Mental State Exam (MMSE) scores over 4 years, compared with nonusers (0.27 vs. 0.70 points per year; P = .023), an effect that remained statistically significant even after adjusting for sedative and stimulant use and the expected progression of Alzheimer’s disease pathology. Importantly, the slower decline was seen only among subjects with sleep complaints at baseline and especially those whose sleep improved over time, suggesting that the cognitive benefit was mediated by improved sleep.

In the SOF cohort of 46 trazodone users matched with 148 nonusers, no significant protective or negative effect related to long-term trazodone use was found using the MMSE or the Trails Making Test. In this analysis, however, baseline and longitudinal sleep quality was not captured in the group-matching process, neither was the use of other medications. The patient group was slightly older, and all patients were women.

Dr. Karageorgiou said in an interview that the link between improved sleep, trazodone, and cognition needs to be validated in prospective intervention studies. Trazodone, he said, appears to work best in people with a specific type of insomnia characterized by cortical and behavioral hyperarousal, and its cognitive effect appears limited to people whose sleep improves with treatment. “You’re not going to see long-term cognitive benefits if it’s not improving your sleep,” Dr. Karageorgiou said. “So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it, because it is unlikely to help their cognition otherwise.”

He stressed that physicians need to be broadly focused on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms.

“Trazodone is not the magic bullet, and I don’t think we will ever have a magic bullet,” Dr. Karageorgiou said. “Because when our brain degenerates, it’s not just one chemical, or one system, it’s many. And our body changes as well. The important thing is to help the patient consolidate their rhythms, whether through light therapy, daily exercise, cognitive behavioral therapy for insomnia, or other evidence-based interventions and their combination. The same applies for a person with dementia as for the rest of us.”

None of the investigators outside of the industry-sponsored studies had relevant disclosures.

LOS ANGELES – Benzodiazepines and hypnotics, including the so-called “Z drugs,” don’t significantly increase the pathological features typical of Alzheimer’s disease but long-term users may experience some neuronal loss in the nucleus basalis, Chris Fox, MD, reported at the Alzheimer’s Association International Conference.

Michele G. Sullivan/MDedge News

The nucleus basalis is rich in cholinergic neurons and associated with arousing stimuli, including positive and aversive appetite, sustained attention, and the interplay of reality and visual perception.

“Neuronal loss in the nucleus basalis offers mechanisms for the impact of benzodiazepine and anticholinergic drug use on the aging brain and highlights important areas for future research,” said Dr. Fox, professor of clinical psychiatry at the University of East Anglia, Norwich, England.

“The risk [for taking a Z drug] in the United Kingdom is high, with about 7.5 million older adults using potentially inappropriately prescribed anticholinergic and/or Z-drug medications. Despite well-documented cognitive impairment associated with these medicines, hypnotics are still used for long durations and exceed the recommended limits,” Dr. Fox said. “There’s no association with better cognition, quality of life, or improved behavior when they are given to people with dementia. In fact, we’ve seen a 60% increased risk of hip fractures – an increase from a 3% to a 15% yearly risk.”

Dr. Fox and colleagues studied the brains of 337 subjects who were included in the U.K. Medical Research Council’s Cognitive Function and Ageing Studies (CFAS). The study was intended to explore the incidence of dementia in the United Kingdom, examine incidence variation among regions, and explore factors increasing dementia risk and rate of progression.

The first study, which began in 1989 and lasted until 2015, followed subjects older than 65 years for up to 12 years. Each subject was regularly interviewed and underwent cognitive testing about every 1.5 years. Benzodiazepine use was considered an especially important aspect, because the medications are frequently used in the elderly and seem linked to injuries and cognitive status at last follow-up.

In CFAS, 21% of subjects reported at least one incidence of anticholinergic use, and 12% reported recurrent use. Another 17% reported any hypnotic use, and 11% reported recurrent use. The main indications were as an antidepressant (13%), for urological issues (4%), as antiparkinsonism drugs (1%), as antipsychotics (3%), and as antihistamines (3%). Overall, 18% reported concurrent use of benzodiazepines and hypnotics. At time of death, 46% had a diagnosis of dementia.

“Those reporting benzodiazepine use were more likely to be women and to have depression or sleep problems,” Dr. Fox noted, although he didn’t give specific hazard ratios. After adjustment for numerous factors, including age, sex, stroke, hypertension, depression, anxiety, asthma, Parkinson’s disease, duration of sleep problems, education, and smoking, he found no statistically increased risk of amyloid brain plaques or tau tangles, the pathologic hallmarks of Alzheimer’s disease.

Anticholinergic use was associated with a significant 60% reduction in cortical atrophy (odds ratio, 0.40) and recurrent use with a 61% reduction in amyloid angiopathy (OR, 0.39).

However, both medication classes were associated with greater neuronal loss in the nucleus basalis. Recurrent use of anticholinergic drugs increased neuronal loss by 300% (OR, 4.12), while any use nearly tripled it (OR, 2.87). Recurrent use of benzodiazepines was associated with increased neuronal loss in the region (OR, 3.76) as well. However, these associations did not reach statistical significance. But there was a statistically significant association with any use of benzodiazepines and neuronal loss in the nucleus basalis (OR, 6.84).

“We did find greater neuronal loss in the nucleus basalis associated with benzodiazepine and anticholinergic drugs use,” Dr. Fox said. “The nucleus basalis is rich in neurons that stimulate the cholinergic system of the neocortex. Neuronal loss in this region is thought to occur in the early stages of Alzheimer’s. Other studies have suggested that volume loss in the basal forebrain cholinergic site leads to widespread cortical atrophy in patients with mild cognitive impairment. We did not observe the widespread cortical atrophy, however.

“Given that the strongest associations were observed for benzodiazepines and neuronal loss in the nucleus basalis, it may be that the drugs were prescribed to treat the symptoms of ‘cholinergic deficiency syndrome,’ Our findings suggest that the symptoms of dementia lead to an increase of benzodiazepines as opposed to the medications actually causing Alzheimer’s disease,” he said.

Dr. Fox reported no financial disclosures.

[email protected]

SOURCE: Fox C et al. AAIC 2019, Abstract 34017.

LOS ANGELES – Benzodiazepines and hypnotics, including the so-called “Z drugs,” don’t significantly increase the pathological features typical of Alzheimer’s disease but long-term users may experience some neuronal loss in the nucleus basalis, Chris Fox, MD, reported at the Alzheimer’s Association International Conference.

Michele G. Sullivan/MDedge News

The nucleus basalis is rich in cholinergic neurons and associated with arousing stimuli, including positive and aversive appetite, sustained attention, and the interplay of reality and visual perception.

“Neuronal loss in the nucleus basalis offers mechanisms for the impact of benzodiazepine and anticholinergic drug use on the aging brain and highlights important areas for future research,” said Dr. Fox, professor of clinical psychiatry at the University of East Anglia, Norwich, England.

“The risk [for taking a Z drug] in the United Kingdom is high, with about 7.5 million older adults using potentially inappropriately prescribed anticholinergic and/or Z-drug medications. Despite well-documented cognitive impairment associated with these medicines, hypnotics are still used for long durations and exceed the recommended limits,” Dr. Fox said. “There’s no association with better cognition, quality of life, or improved behavior when they are given to people with dementia. In fact, we’ve seen a 60% increased risk of hip fractures – an increase from a 3% to a 15% yearly risk.”

Dr. Fox and colleagues studied the brains of 337 subjects who were included in the U.K. Medical Research Council’s Cognitive Function and Ageing Studies (CFAS). The study was intended to explore the incidence of dementia in the United Kingdom, examine incidence variation among regions, and explore factors increasing dementia risk and rate of progression.

The first study, which began in 1989 and lasted until 2015, followed subjects older than 65 years for up to 12 years. Each subject was regularly interviewed and underwent cognitive testing about every 1.5 years. Benzodiazepine use was considered an especially important aspect, because the medications are frequently used in the elderly and seem linked to injuries and cognitive status at last follow-up.

In CFAS, 21% of subjects reported at least one incidence of anticholinergic use, and 12% reported recurrent use. Another 17% reported any hypnotic use, and 11% reported recurrent use. The main indications were as an antidepressant (13%), for urological issues (4%), as antiparkinsonism drugs (1%), as antipsychotics (3%), and as antihistamines (3%). Overall, 18% reported concurrent use of benzodiazepines and hypnotics. At time of death, 46% had a diagnosis of dementia.

“Those reporting benzodiazepine use were more likely to be women and to have depression or sleep problems,” Dr. Fox noted, although he didn’t give specific hazard ratios. After adjustment for numerous factors, including age, sex, stroke, hypertension, depression, anxiety, asthma, Parkinson’s disease, duration of sleep problems, education, and smoking, he found no statistically increased risk of amyloid brain plaques or tau tangles, the pathologic hallmarks of Alzheimer’s disease.

Anticholinergic use was associated with a significant 60% reduction in cortical atrophy (odds ratio, 0.40) and recurrent use with a 61% reduction in amyloid angiopathy (OR, 0.39).

However, both medication classes were associated with greater neuronal loss in the nucleus basalis. Recurrent use of anticholinergic drugs increased neuronal loss by 300% (OR, 4.12), while any use nearly tripled it (OR, 2.87). Recurrent use of benzodiazepines was associated with increased neuronal loss in the region (OR, 3.76) as well. However, these associations did not reach statistical significance. But there was a statistically significant association with any use of benzodiazepines and neuronal loss in the nucleus basalis (OR, 6.84).

“We did find greater neuronal loss in the nucleus basalis associated with benzodiazepine and anticholinergic drugs use,” Dr. Fox said. “The nucleus basalis is rich in neurons that stimulate the cholinergic system of the neocortex. Neuronal loss in this region is thought to occur in the early stages of Alzheimer’s. Other studies have suggested that volume loss in the basal forebrain cholinergic site leads to widespread cortical atrophy in patients with mild cognitive impairment. We did not observe the widespread cortical atrophy, however.

“Given that the strongest associations were observed for benzodiazepines and neuronal loss in the nucleus basalis, it may be that the drugs were prescribed to treat the symptoms of ‘cholinergic deficiency syndrome,’ Our findings suggest that the symptoms of dementia lead to an increase of benzodiazepines as opposed to the medications actually causing Alzheimer’s disease,” he said.

Dr. Fox reported no financial disclosures.

[email protected]

SOURCE: Fox C et al. AAIC 2019, Abstract 34017.

LOS ANGELES – Benzodiazepines and hypnotics, including the so-called “Z drugs,” don’t significantly increase the pathological features typical of Alzheimer’s disease but long-term users may experience some neuronal loss in the nucleus basalis, Chris Fox, MD, reported at the Alzheimer’s Association International Conference.

Michele G. Sullivan/MDedge News

The nucleus basalis is rich in cholinergic neurons and associated with arousing stimuli, including positive and aversive appetite, sustained attention, and the interplay of reality and visual perception.

“Neuronal loss in the nucleus basalis offers mechanisms for the impact of benzodiazepine and anticholinergic drug use on the aging brain and highlights important areas for future research,” said Dr. Fox, professor of clinical psychiatry at the University of East Anglia, Norwich, England.

“The risk [for taking a Z drug] in the United Kingdom is high, with about 7.5 million older adults using potentially inappropriately prescribed anticholinergic and/or Z-drug medications. Despite well-documented cognitive impairment associated with these medicines, hypnotics are still used for long durations and exceed the recommended limits,” Dr. Fox said. “There’s no association with better cognition, quality of life, or improved behavior when they are given to people with dementia. In fact, we’ve seen a 60% increased risk of hip fractures – an increase from a 3% to a 15% yearly risk.”

Dr. Fox and colleagues studied the brains of 337 subjects who were included in the U.K. Medical Research Council’s Cognitive Function and Ageing Studies (CFAS). The study was intended to explore the incidence of dementia in the United Kingdom, examine incidence variation among regions, and explore factors increasing dementia risk and rate of progression.

The first study, which began in 1989 and lasted until 2015, followed subjects older than 65 years for up to 12 years. Each subject was regularly interviewed and underwent cognitive testing about every 1.5 years. Benzodiazepine use was considered an especially important aspect, because the medications are frequently used in the elderly and seem linked to injuries and cognitive status at last follow-up.

In CFAS, 21% of subjects reported at least one incidence of anticholinergic use, and 12% reported recurrent use. Another 17% reported any hypnotic use, and 11% reported recurrent use. The main indications were as an antidepressant (13%), for urological issues (4%), as antiparkinsonism drugs (1%), as antipsychotics (3%), and as antihistamines (3%). Overall, 18% reported concurrent use of benzodiazepines and hypnotics. At time of death, 46% had a diagnosis of dementia.

“Those reporting benzodiazepine use were more likely to be women and to have depression or sleep problems,” Dr. Fox noted, although he didn’t give specific hazard ratios. After adjustment for numerous factors, including age, sex, stroke, hypertension, depression, anxiety, asthma, Parkinson’s disease, duration of sleep problems, education, and smoking, he found no statistically increased risk of amyloid brain plaques or tau tangles, the pathologic hallmarks of Alzheimer’s disease.

Anticholinergic use was associated with a significant 60% reduction in cortical atrophy (odds ratio, 0.40) and recurrent use with a 61% reduction in amyloid angiopathy (OR, 0.39).

However, both medication classes were associated with greater neuronal loss in the nucleus basalis. Recurrent use of anticholinergic drugs increased neuronal loss by 300% (OR, 4.12), while any use nearly tripled it (OR, 2.87). Recurrent use of benzodiazepines was associated with increased neuronal loss in the region (OR, 3.76) as well. However, these associations did not reach statistical significance. But there was a statistically significant association with any use of benzodiazepines and neuronal loss in the nucleus basalis (OR, 6.84).

“We did find greater neuronal loss in the nucleus basalis associated with benzodiazepine and anticholinergic drugs use,” Dr. Fox said. “The nucleus basalis is rich in neurons that stimulate the cholinergic system of the neocortex. Neuronal loss in this region is thought to occur in the early stages of Alzheimer’s. Other studies have suggested that volume loss in the basal forebrain cholinergic site leads to widespread cortical atrophy in patients with mild cognitive impairment. We did not observe the widespread cortical atrophy, however.

“Given that the strongest associations were observed for benzodiazepines and neuronal loss in the nucleus basalis, it may be that the drugs were prescribed to treat the symptoms of ‘cholinergic deficiency syndrome,’ Our findings suggest that the symptoms of dementia lead to an increase of benzodiazepines as opposed to the medications actually causing Alzheimer’s disease,” he said.

Dr. Fox reported no financial disclosures.

[email protected]

SOURCE: Fox C et al. AAIC 2019, Abstract 34017.

In patients with chronic traumatic encephalopathy (CTE), dementia likely results from neuropathologic changes associated with repetitive head impact (e.g., white matter rarefaction and tau accumulation) and pathologic changes unrelated to head trauma (e.g., arteriolosclerosis), according to a cross-sectional study published online Aug. 5 in JAMA Neurology.

solar22/Thinkstock

The study of older, deceased former American football players with CTE showed that more years of play were associated with more severe white matter rarefaction and greater burden of neurofibrillary tau tangles in the dorsolateral frontal cortex, wrote Michael L. Alosco, PhD, assistant professor of neurology at Boston University’s CTE Center, and colleagues.
 

An analysis of donated brains

Repetitive head impacts are associated with CTE. The clinical presentation of CTE includes cognitive, behavioral, and mood changes that can progress to dementia. The contributions of pathologic changes in phosphorylated tau, white matter degeneration, and cerebrovascular disease to dementia in the context of CTE are poorly understood. Dr. Alosco and colleagues examined arteriosclerosis, infarcts, microinfarcts, microbleeds, and white matter rarefaction in donated brains to illuminate these contributions.

The researchers examined data from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study and Veterans Affairs–Boston University–Concussion Legacy Foundation brain bank. The population included deceased men who had played football and had received a neuropathologic diagnosis of CTE. Eligible participants had a history of repetitive head impacts. Brains that had been donated after a prolonged time postmortem and those with poor tissue quality were excluded.

Neuropathologists blinded to clinical data analyzed patients’ CTE stage and severity of neurofibrillary tangle burden in the dorsolateral frontal cortex as semiquantitative scales of phosphorylated tau severity. Neurofibrillary tangle burden was dichotomized as none or mild versus moderate or severe. The neuropathologists also rated white matter rarefaction and arteriolosclerosis severity using a scale of 0 points (i.e., none) to 3 points (i.e., severe changes). The investigators obtained clinical data through online surveys and retrospective telephone interviews with informants. They adjudicated consensus diagnoses of dementia based on modified criteria from DSM-IV.
 

White matter rarefaction was common

Dr. Alosco and colleagues included 180 individuals in their analysis, excluding those aged younger than 40 years because of low pathologic burden and minimal presence of dementia. Mean age at death was nearly 68 years. Fifty patients had no or mild neurofibrillary tangle burden, and 130 had moderate to severe burden. Thirty-five patients had CTE at stage I or II, and 145 had CTE at stage III or IV. In all, 120 patients were determined to have had dementia. About 47% of the sample had moderate to severe white matter rarefaction, and about 47% had arteriolosclerosis. Infarcts, microinfarcts, and microbleeds were uncommon.

When the investigators created a simultaneous equations regression model and controlled for age and race, they found that more years of play was associated with more severe white matter rarefaction, greater phosphorylated tau accumulation, and high CTE stage. Furthermore, white matter rarefaction and dorsolateral frontal cortex neurofibrillary tangles were associated with dementia. The association of years of play with dementia was mediated by white matter rarefaction and neurofibrillary tangle burden. Arteriolosclerosis was not associated with years of play, but arteriolosclerosis was independently associated with dementia.

The odds ratio for dementia was 1.69 among participants with more severe white matter rarefaction and 1.81 among patients with arteriolosclerosis. After the researchers controlled for age and race, the odds ratio of dementia was 2.65 among participants with a high neurofibrillary tangle burden, compared with participants with a low burden.


“Studies that include direct cardiovascular disease and repetitive head impacts metrics and refined measures of white matter integrity are needed to improve understanding of the pathogenesis of white matter rarefaction and cerebral small vessel changes in CTE,” Dr. Alosco and colleagues wrote.

The study was funded by grants from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Department of Veterans Affairs, the Nick and Lynn Buoniconti Foundation, and the National Center for Advancing Translational Sciences. Some of the authors reported financial ties to the pharmaceutical industry and serving on professional sports committees.

[email protected]

SOURCE: Alosco ML et al. JAMA Neurol. 2019 Aug 5. doi: 10.1001/jamaneurol.2019.2244.

In patients with chronic traumatic encephalopathy (CTE), dementia likely results from neuropathologic changes associated with repetitive head impact (e.g., white matter rarefaction and tau accumulation) and pathologic changes unrelated to head trauma (e.g., arteriolosclerosis), according to a cross-sectional study published online Aug. 5 in JAMA Neurology.

solar22/Thinkstock

The study of older, deceased former American football players with CTE showed that more years of play were associated with more severe white matter rarefaction and greater burden of neurofibrillary tau tangles in the dorsolateral frontal cortex, wrote Michael L. Alosco, PhD, assistant professor of neurology at Boston University’s CTE Center, and colleagues.
 

An analysis of donated brains

Repetitive head impacts are associated with CTE. The clinical presentation of CTE includes cognitive, behavioral, and mood changes that can progress to dementia. The contributions of pathologic changes in phosphorylated tau, white matter degeneration, and cerebrovascular disease to dementia in the context of CTE are poorly understood. Dr. Alosco and colleagues examined arteriosclerosis, infarcts, microinfarcts, microbleeds, and white matter rarefaction in donated brains to illuminate these contributions.

The researchers examined data from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study and Veterans Affairs–Boston University–Concussion Legacy Foundation brain bank. The population included deceased men who had played football and had received a neuropathologic diagnosis of CTE. Eligible participants had a history of repetitive head impacts. Brains that had been donated after a prolonged time postmortem and those with poor tissue quality were excluded.

Neuropathologists blinded to clinical data analyzed patients’ CTE stage and severity of neurofibrillary tangle burden in the dorsolateral frontal cortex as semiquantitative scales of phosphorylated tau severity. Neurofibrillary tangle burden was dichotomized as none or mild versus moderate or severe. The neuropathologists also rated white matter rarefaction and arteriolosclerosis severity using a scale of 0 points (i.e., none) to 3 points (i.e., severe changes). The investigators obtained clinical data through online surveys and retrospective telephone interviews with informants. They adjudicated consensus diagnoses of dementia based on modified criteria from DSM-IV.
 

White matter rarefaction was common

Dr. Alosco and colleagues included 180 individuals in their analysis, excluding those aged younger than 40 years because of low pathologic burden and minimal presence of dementia. Mean age at death was nearly 68 years. Fifty patients had no or mild neurofibrillary tangle burden, and 130 had moderate to severe burden. Thirty-five patients had CTE at stage I or II, and 145 had CTE at stage III or IV. In all, 120 patients were determined to have had dementia. About 47% of the sample had moderate to severe white matter rarefaction, and about 47% had arteriolosclerosis. Infarcts, microinfarcts, and microbleeds were uncommon.

When the investigators created a simultaneous equations regression model and controlled for age and race, they found that more years of play was associated with more severe white matter rarefaction, greater phosphorylated tau accumulation, and high CTE stage. Furthermore, white matter rarefaction and dorsolateral frontal cortex neurofibrillary tangles were associated with dementia. The association of years of play with dementia was mediated by white matter rarefaction and neurofibrillary tangle burden. Arteriolosclerosis was not associated with years of play, but arteriolosclerosis was independently associated with dementia.

The odds ratio for dementia was 1.69 among participants with more severe white matter rarefaction and 1.81 among patients with arteriolosclerosis. After the researchers controlled for age and race, the odds ratio of dementia was 2.65 among participants with a high neurofibrillary tangle burden, compared with participants with a low burden.


“Studies that include direct cardiovascular disease and repetitive head impacts metrics and refined measures of white matter integrity are needed to improve understanding of the pathogenesis of white matter rarefaction and cerebral small vessel changes in CTE,” Dr. Alosco and colleagues wrote.

The study was funded by grants from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Department of Veterans Affairs, the Nick and Lynn Buoniconti Foundation, and the National Center for Advancing Translational Sciences. Some of the authors reported financial ties to the pharmaceutical industry and serving on professional sports committees.

[email protected]

SOURCE: Alosco ML et al. JAMA Neurol. 2019 Aug 5. doi: 10.1001/jamaneurol.2019.2244.

In patients with chronic traumatic encephalopathy (CTE), dementia likely results from neuropathologic changes associated with repetitive head impact (e.g., white matter rarefaction and tau accumulation) and pathologic changes unrelated to head trauma (e.g., arteriolosclerosis), according to a cross-sectional study published online Aug. 5 in JAMA Neurology.

solar22/Thinkstock

The study of older, deceased former American football players with CTE showed that more years of play were associated with more severe white matter rarefaction and greater burden of neurofibrillary tau tangles in the dorsolateral frontal cortex, wrote Michael L. Alosco, PhD, assistant professor of neurology at Boston University’s CTE Center, and colleagues.
 

An analysis of donated brains

Repetitive head impacts are associated with CTE. The clinical presentation of CTE includes cognitive, behavioral, and mood changes that can progress to dementia. The contributions of pathologic changes in phosphorylated tau, white matter degeneration, and cerebrovascular disease to dementia in the context of CTE are poorly understood. Dr. Alosco and colleagues examined arteriosclerosis, infarcts, microinfarcts, microbleeds, and white matter rarefaction in donated brains to illuminate these contributions.

The researchers examined data from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study and Veterans Affairs–Boston University–Concussion Legacy Foundation brain bank. The population included deceased men who had played football and had received a neuropathologic diagnosis of CTE. Eligible participants had a history of repetitive head impacts. Brains that had been donated after a prolonged time postmortem and those with poor tissue quality were excluded.

Neuropathologists blinded to clinical data analyzed patients’ CTE stage and severity of neurofibrillary tangle burden in the dorsolateral frontal cortex as semiquantitative scales of phosphorylated tau severity. Neurofibrillary tangle burden was dichotomized as none or mild versus moderate or severe. The neuropathologists also rated white matter rarefaction and arteriolosclerosis severity using a scale of 0 points (i.e., none) to 3 points (i.e., severe changes). The investigators obtained clinical data through online surveys and retrospective telephone interviews with informants. They adjudicated consensus diagnoses of dementia based on modified criteria from DSM-IV.
 

White matter rarefaction was common

Dr. Alosco and colleagues included 180 individuals in their analysis, excluding those aged younger than 40 years because of low pathologic burden and minimal presence of dementia. Mean age at death was nearly 68 years. Fifty patients had no or mild neurofibrillary tangle burden, and 130 had moderate to severe burden. Thirty-five patients had CTE at stage I or II, and 145 had CTE at stage III or IV. In all, 120 patients were determined to have had dementia. About 47% of the sample had moderate to severe white matter rarefaction, and about 47% had arteriolosclerosis. Infarcts, microinfarcts, and microbleeds were uncommon.

When the investigators created a simultaneous equations regression model and controlled for age and race, they found that more years of play was associated with more severe white matter rarefaction, greater phosphorylated tau accumulation, and high CTE stage. Furthermore, white matter rarefaction and dorsolateral frontal cortex neurofibrillary tangles were associated with dementia. The association of years of play with dementia was mediated by white matter rarefaction and neurofibrillary tangle burden. Arteriolosclerosis was not associated with years of play, but arteriolosclerosis was independently associated with dementia.

The odds ratio for dementia was 1.69 among participants with more severe white matter rarefaction and 1.81 among patients with arteriolosclerosis. After the researchers controlled for age and race, the odds ratio of dementia was 2.65 among participants with a high neurofibrillary tangle burden, compared with participants with a low burden.


“Studies that include direct cardiovascular disease and repetitive head impacts metrics and refined measures of white matter integrity are needed to improve understanding of the pathogenesis of white matter rarefaction and cerebral small vessel changes in CTE,” Dr. Alosco and colleagues wrote.

The study was funded by grants from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Department of Veterans Affairs, the Nick and Lynn Buoniconti Foundation, and the National Center for Advancing Translational Sciences. Some of the authors reported financial ties to the pharmaceutical industry and serving on professional sports committees.

[email protected]

SOURCE: Alosco ML et al. JAMA Neurol. 2019 Aug 5. doi: 10.1001/jamaneurol.2019.2244.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

[email protected]

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

[email protected]

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

[email protected]

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

 

LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.

At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.

While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.

Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).

Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.

“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”

A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).

In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”

Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”

Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.

“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.

Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”

Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”

Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.

 

LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.

At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.

While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.

Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).

Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.

“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”

A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).

In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”

Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”

Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.

“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.

Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”

Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”

Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.

 

LOS ANGELES – Neurofilament light, or NfL, is an increasingly studied biomarker of axonal damage across a range of neurodegenerative diseases, including Alzheimer’s disease. And because it is a biomarker that can be measured in blood, it is a less invasive measure of disease progression in Alzheimer’s than cerebrospinal fluid markers.

At the Alzheimer’s Association International Conference, scientists studying the world’s largest cohort of early-onset Alzheimer’s families presented results from a cross-sectional and longitudinal study of more than 2,000 carriers and noncarriers of a single Alzheimer’s-causing mutation (Presenilin 1 E280A) that occurs in an extended Colombian family.

While previous studies have also looked at NfL in cohorts of autosomal dominant mutation carriers, this study strengthens evidence for NfL as an Alzheimer’s biomarker in the largest single-mutation cohort to date.

Yakeel Quiroz, PhD, of Harvard University in Boston and colleagues reported that, in a cross-sectional study of 1,070 mutation carriers and 1,074 noncarriers aged 8-75 years (mean age, 29-30 years; 46% male), mean plasma NfL levels were elevated in cognitively unimpaired carriers (18.08 pg/mL), compared with noncarriers (9.09 pg/mL; P less than .0001).

Longitudinal data from 504 of those carriers and noncarriers showed that NfL levels begin to diverge significantly between the groups at age 22, more than 2 decades before the mean onset of mild cognitive impairment for this cohort (44 years). The between-group differences in NfL continued to widen with advancing age.

“At approximately age 22, the axons, the neurons are already changing, and this measure serves as an early sign of degeneration,” Dr. Quiroz said in an interview. “This is really telling us about neurodegeneration related to Alzheimer’s disease because these are people destined to develop Alzheimer’s dementia later in life and have no age-related comorbidities that could cause elevation in NfL.”

A study published early this year in a different cohort of about 400 autosomal dominant Alzheimer’s disease mutation carriers and noncarriers found that the longitudinal rate of change of serum NfL could discriminate carriers from noncarriers almost a decade earlier than cross-sectional absolute NfL levels – at 16 years and 7 years, respectively, before expected onset of symptoms (Nat Med. 2019 Feb;25[2]:277–83).

In Dr. Quiroz and colleagues’ study, both cross-sectional and longitudinal findings showed carriers to significantly differ from noncarriers by age 22 years. “We’re seeing differences between groups that reach statistical significance earlier” – decades, in this case, before onset of symptoms, Dr. Quiroz said. The current study is distinguished by its exceptional power, she said: “No one has done this with such a large number of carriers with a single genetic mutation.”

Eric Reiman, MD, of Banner Alzheimer’s Institute in Phoenix, the coauthor on the study who presented the findings to the conference, commented in an interview that they illustrate “the opportunity for fluid biomarkers to be used in trials.”

Dr. Reiman cautioned, however, that the NfL measurements are likely a more useful measure of preclinical neurodegeneration in genetic early-onset Alzheimer’s than in late-onset or sporadic disease, which represents the lion’s share of Alzheimer’s cases.

“In autosomal dominant Alzheimer’s disease, these [NfL] changes really go up – probably more so than in late onset,” he said.

Dr. Reiman said these cohort findings add to growing interest in less-invasive biomarkers for Alzheimer’s, both in research and clinical practice. “If NfL is already elevated as a marker of active neurodegeneration, in early phase trials you might think about looking to it as a proof of concept – so where in 6-12 months you can see reductions [in NfL].”

Dr. Reiman added that “there will be other fluid biomarkers coming down the pike that will be exciting as well, and which people will learn a lot more about in the next few months.”

Dr. Quiroz had no disclosures related to her findings. Other authors on the study, including Dr. Reiman, have received research support and/or consulting fees from pharmaceutical manufacturers.

 

Is dementia a diagnosis?

I use it myself, although I find that some neurologists consider this blasphemy.

alexdans/Thinkstock

The problem is that there aren’t many terms to cover cognitive disorders beyond mild cognitive impairment (MCI). Phrases like “cortical degeneration” and “frontotemporal disorder” are difficult for families and patients. They aren’t medically trained and want something easy to write down.

“Alzheimer’s,” or – as one patient’s family member says, “the A-word” – is often more accurate, but has stigma attached to it that many don’t want, especially at a first visit. It also immediately conjures up feared images of nursing homes, wheelchairs, and bed-bound people.

So I use a diagnosis of dementia with many families, at least initially. Since, with occasional exceptions, we tend to perform a work-up of all cognitive disorders the same way, I don’t have a problem with using a more generic blanket term. As I sometimes try to simplify things, I’ll say, “It’s like squares and rectangles. Alzheimer’s disease is a dementia, but not all dementias are Alzheimer’s disease.”

I don’t do this to avoid confrontation, be dishonest, mislead patients and families, or avoid telling the truth. I still make it very clear that this is a progressive neurologic illness that will cause worsening cognitive problems over time. But many times families aren’t ready for “the A-word” early on, or there’s a concern the patient will harm themselves while they still have that capacity. Sometimes, it’s better to use a different phrase.

It may all be semantics, but on a personal level, a word can make a huge difference.

So I say dementia. In spite of some editorials I’ve seen saying we should retire the phrase, I argue that in many circumstances it’s still valid and useful.

It may not be a final, or even specific, diagnosis, but it is often the best and most socially acceptable one at the beginning of the doctor-patient-family relationship. When you’re trying to build rapport with them, that’s equally critical when you know what’s to come down the road.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

 

Is dementia a diagnosis?

I use it myself, although I find that some neurologists consider this blasphemy.

alexdans/Thinkstock

The problem is that there aren’t many terms to cover cognitive disorders beyond mild cognitive impairment (MCI). Phrases like “cortical degeneration” and “frontotemporal disorder” are difficult for families and patients. They aren’t medically trained and want something easy to write down.

“Alzheimer’s,” or – as one patient’s family member says, “the A-word” – is often more accurate, but has stigma attached to it that many don’t want, especially at a first visit. It also immediately conjures up feared images of nursing homes, wheelchairs, and bed-bound people.

So I use a diagnosis of dementia with many families, at least initially. Since, with occasional exceptions, we tend to perform a work-up of all cognitive disorders the same way, I don’t have a problem with using a more generic blanket term. As I sometimes try to simplify things, I’ll say, “It’s like squares and rectangles. Alzheimer’s disease is a dementia, but not all dementias are Alzheimer’s disease.”

I don’t do this to avoid confrontation, be dishonest, mislead patients and families, or avoid telling the truth. I still make it very clear that this is a progressive neurologic illness that will cause worsening cognitive problems over time. But many times families aren’t ready for “the A-word” early on, or there’s a concern the patient will harm themselves while they still have that capacity. Sometimes, it’s better to use a different phrase.

It may all be semantics, but on a personal level, a word can make a huge difference.

So I say dementia. In spite of some editorials I’ve seen saying we should retire the phrase, I argue that in many circumstances it’s still valid and useful.

It may not be a final, or even specific, diagnosis, but it is often the best and most socially acceptable one at the beginning of the doctor-patient-family relationship. When you’re trying to build rapport with them, that’s equally critical when you know what’s to come down the road.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

 

Is dementia a diagnosis?

I use it myself, although I find that some neurologists consider this blasphemy.

alexdans/Thinkstock

The problem is that there aren’t many terms to cover cognitive disorders beyond mild cognitive impairment (MCI). Phrases like “cortical degeneration” and “frontotemporal disorder” are difficult for families and patients. They aren’t medically trained and want something easy to write down.

“Alzheimer’s,” or – as one patient’s family member says, “the A-word” – is often more accurate, but has stigma attached to it that many don’t want, especially at a first visit. It also immediately conjures up feared images of nursing homes, wheelchairs, and bed-bound people.

So I use a diagnosis of dementia with many families, at least initially. Since, with occasional exceptions, we tend to perform a work-up of all cognitive disorders the same way, I don’t have a problem with using a more generic blanket term. As I sometimes try to simplify things, I’ll say, “It’s like squares and rectangles. Alzheimer’s disease is a dementia, but not all dementias are Alzheimer’s disease.”

I don’t do this to avoid confrontation, be dishonest, mislead patients and families, or avoid telling the truth. I still make it very clear that this is a progressive neurologic illness that will cause worsening cognitive problems over time. But many times families aren’t ready for “the A-word” early on, or there’s a concern the patient will harm themselves while they still have that capacity. Sometimes, it’s better to use a different phrase.

It may all be semantics, but on a personal level, a word can make a huge difference.

So I say dementia. In spite of some editorials I’ve seen saying we should retire the phrase, I argue that in many circumstances it’s still valid and useful.

It may not be a final, or even specific, diagnosis, but it is often the best and most socially acceptable one at the beginning of the doctor-patient-family relationship. When you’re trying to build rapport with them, that’s equally critical when you know what’s to come down the road.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.