Alzheimer's & Cognition

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

The percentage of Americans with Alzheimer’s disease and related dementias will double by 2060, with the greatest increase among Hispanic Americans, according to a study in Alzheimer’s and Dementia.

Courtesy CDC

Prior to this study, no research had defined future estimates based on projected changes among demographic groups.

Researchers combined information about the prevalence of Alzheimer’s disease and related dementias (ADRD) by demographic group in 2014 Medicare-Fee-for-Service data with population projections data from the U.S. Census Bureau to assess how existing disparities by demographic group will change as those demographic groups become more or less represented in the U.S. population. They estimated the future prevalence of ADRD for 70 subgroups; these groups were defined by sex, seven racial and ethnic groups, and five age groups. The researchers estimated that in 2014 African Americans had the highest prevalence of ADRD at 13.8%, followed by Hispanics at 12.2%, non-Hispanic whites at 10.3%, American Indian and Alaska Natives at 9.1%, and Asian and Pacific Islanders at 8.4%.

The researchers estimated an overall increase from about 5.0 million people (1.9% of the U.S. population) in 2014 to about 13.9 million (3.3% of the population) in 2060. The non-Hispanic whites group will have the largest total number of cases of ADRD in 2060 because of its relative size, compared with other subgroups, going from about 3.7 million in 2014 to 7.1 million. The ADRD prevalence in non-Hispanic whites will begin to plateau around 2030, whereas the Hispanic population is expected to see the greatest increase, going from 430,000 in 2014 to 3.2 million in 2060.

Some of the limitations of the study include the assumption that the Medicare Fee-for-Service population is representative of the U.S. population and that these prevalences will remain constant over time.

“These estimates can be used for public health planning related to providing culturally competent care for the ADRD population and supporting caregivers from diverse backgrounds,” the researchers concluded.

[email protected]

SOURCE: Matthews KA et al. Alzheimers Dement. 2018 Sep 19. doi: 10.1016/j.jalz.2018.06.3063.

This article was updated 10/4/18.

The percentage of Americans with Alzheimer’s disease and related dementias will double by 2060, with the greatest increase among Hispanic Americans, according to a study in Alzheimer’s and Dementia.

Courtesy CDC

Prior to this study, no research had defined future estimates based on projected changes among demographic groups.

Researchers combined information about the prevalence of Alzheimer’s disease and related dementias (ADRD) by demographic group in 2014 Medicare-Fee-for-Service data with population projections data from the U.S. Census Bureau to assess how existing disparities by demographic group will change as those demographic groups become more or less represented in the U.S. population. They estimated the future prevalence of ADRD for 70 subgroups; these groups were defined by sex, seven racial and ethnic groups, and five age groups. The researchers estimated that in 2014 African Americans had the highest prevalence of ADRD at 13.8%, followed by Hispanics at 12.2%, non-Hispanic whites at 10.3%, American Indian and Alaska Natives at 9.1%, and Asian and Pacific Islanders at 8.4%.

The researchers estimated an overall increase from about 5.0 million people (1.9% of the U.S. population) in 2014 to about 13.9 million (3.3% of the population) in 2060. The non-Hispanic whites group will have the largest total number of cases of ADRD in 2060 because of its relative size, compared with other subgroups, going from about 3.7 million in 2014 to 7.1 million. The ADRD prevalence in non-Hispanic whites will begin to plateau around 2030, whereas the Hispanic population is expected to see the greatest increase, going from 430,000 in 2014 to 3.2 million in 2060.

Some of the limitations of the study include the assumption that the Medicare Fee-for-Service population is representative of the U.S. population and that these prevalences will remain constant over time.

“These estimates can be used for public health planning related to providing culturally competent care for the ADRD population and supporting caregivers from diverse backgrounds,” the researchers concluded.

[email protected]

SOURCE: Matthews KA et al. Alzheimers Dement. 2018 Sep 19. doi: 10.1016/j.jalz.2018.06.3063.

This article was updated 10/4/18.

The percentage of Americans with Alzheimer’s disease and related dementias will double by 2060, with the greatest increase among Hispanic Americans, according to a study in Alzheimer’s and Dementia.

Courtesy CDC

Prior to this study, no research had defined future estimates based on projected changes among demographic groups.

Researchers combined information about the prevalence of Alzheimer’s disease and related dementias (ADRD) by demographic group in 2014 Medicare-Fee-for-Service data with population projections data from the U.S. Census Bureau to assess how existing disparities by demographic group will change as those demographic groups become more or less represented in the U.S. population. They estimated the future prevalence of ADRD for 70 subgroups; these groups were defined by sex, seven racial and ethnic groups, and five age groups. The researchers estimated that in 2014 African Americans had the highest prevalence of ADRD at 13.8%, followed by Hispanics at 12.2%, non-Hispanic whites at 10.3%, American Indian and Alaska Natives at 9.1%, and Asian and Pacific Islanders at 8.4%.

The researchers estimated an overall increase from about 5.0 million people (1.9% of the U.S. population) in 2014 to about 13.9 million (3.3% of the population) in 2060. The non-Hispanic whites group will have the largest total number of cases of ADRD in 2060 because of its relative size, compared with other subgroups, going from about 3.7 million in 2014 to 7.1 million. The ADRD prevalence in non-Hispanic whites will begin to plateau around 2030, whereas the Hispanic population is expected to see the greatest increase, going from 430,000 in 2014 to 3.2 million in 2060.

Some of the limitations of the study include the assumption that the Medicare Fee-for-Service population is representative of the U.S. population and that these prevalences will remain constant over time.

“These estimates can be used for public health planning related to providing culturally competent care for the ADRD population and supporting caregivers from diverse backgrounds,” the researchers concluded.

[email protected]

SOURCE: Matthews KA et al. Alzheimers Dement. 2018 Sep 19. doi: 10.1016/j.jalz.2018.06.3063.

This article was updated 10/4/18.

PET imaging with an investigational tau tracer, ¹⁸F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.

PET with ¹⁸F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.

copyright alexdans/Thinkstock

SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.

PET imaging with an investigational tau tracer, ¹⁸F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.

PET with ¹⁸F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.

copyright alexdans/Thinkstock

SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.

PET imaging with an investigational tau tracer, ¹⁸F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.

PET with ¹⁸F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.

copyright alexdans/Thinkstock

SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO – There’s another reason to worry about hypertension in children: cognitive decline later in life.

In a pilot study, Marc Lande, MD, a professor of pediatric nephrology at the University of Rochester (N.Y.), and his colleagues found evidence of impaired white matter integrity on MRI in a handful of hypertensive children, similar to what’s found in adults with cognitive impairment from hypertension.

The work is ongoing, but it helps explain the subtle deficits on cognitive testing that have been previously demonstrated in children with hypertension.

“The fact that we are finding anything at this very early stage of disease is striking and somewhat bothersome. The hope is that, by improving blood pressure in children, you can improve subsequent cognition and maybe even delay the onset of dementia further down the road,” Dr. Lande said.

For now, the findings underscore the need to diagnose and manage hypertension in children, but there might be additional treatment implications in the future, especially if blood pressure targets are found that ameliorate the problem.

Dr. Lande explained the issues and the emerging evidence in a video interview at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

[email protected]

CHICAGO—Lowering systolic blood pressure to a target of 120 mm Hg or less in people with cardiovascular risk factors reduces the risk of mild cognitive impairment (MCI) by 19% and reduces the risk of probable all-cause dementia by 17%, compared with achieving a less intensive target of lower than 140 mm Hg, according to research presented at AAIC 2018.

The class of antihypertensive did not affect the association. Generic drugs were as effective as branded drugs. Antihypertensive agents provided equal benefits to men, women, whites, blacks, and Hispanics. Furthermore, maintaining systolic blood pressure at 120 mm Hg or lower prevented MCI as well in patients older than 75 as it did in younger patients.

Jeff D. Williamson, MD, Chief of Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, presented the results of the four-year SPRINT MIND study. Strict blood pressure control (ie, a systolic target of 120 mm Hg or lower) for 3.2 years reduced the incidence of MCI to a greater extent than any amyloid-targeting investigational drug has done.

“This is the first disease-modifying strategy to reduce the risk of MCI,” said Dr. Williamson. Although the effect of strict blood pressure control on the primary end point (ie, a 17% risk reduction for probable all-cause dementia) was not statistically significant, “it is comforting to see that the benefit went in the same direction and was of the same magnitude,” said Dr. Williamson. “Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. Participants who underwent strict blood pressure control had 18% fewer white matter hyperintensities after four years of follow-up than other participants.

The results may represent a step forward in a field that has seen few of them recently. Generic antihypertensive agents can be inexpensive. They are widely available and confer benefits not only on cardiovascular health, but on kidney health as well, said Dr. Williamson.

“Hypertension is a highly prevalent condition…. The 19% overall risk reduction for MCI will have a huge impact,” he added.

“The most we can say right now is that we are able to reduce risk,” said Maria Carrillo, PhD, Chief Scientific Officer of the Alzheimer’s Association, in an interview. “Reducing the risk of MCI by 19% will have a huge impact on dementia overall. Slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, then I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

A Substudy of the SPRINT Trial

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target systolic blood pressure of less than 120 mm Hg, and the standard care strategy had a target of less than 140 mm Hg. SPRINT showed that intensive blood pressure control reduced the risk of cardiovascular events, stroke, and cardiovascular death by 30%. The study results helped inform the 2017 American Heart Association and American College of Cardiology clinical guidelines for treating high blood pressure.

The SPRINT MIND substudy examined whether intensive blood pressure management affected the risk of probable all-cause dementia or MCI or affected white matter lesion volume and brain volume.

The investigators examined data for 9,361 SPRINT subjects who were age 50 or older (mean age, 68) and had at least one cardiovascular risk factor. Approximately 30% of participants were black, and 10% were Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but were encouraged to use drugs with the strongest evidence of cardiovascular benefit. These drugs included thiazide-type diuretics, loop diuretics, and beta-adrenergic blockers. About 90% of the drugs used during the study were generic.

Subjects were seen monthly for the first three months. During this time, medications were adjusted to achieve the target blood pressure. After the third month, subjects were examined every three months. Medications could be adjusted monthly.

Results Favored Intensive Treatment

At one year, mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped early after a median follow-up of 3.26 years because of the observed cardiovascular disease benefit.

The SPRINT MIND study did not meet its primary end point. Incident probable all-cause dementia occurred in 175 people in the standard care group and 147 people in the intensive treatment group. The difference between groups in the rate of 17% risk reduction was not statistically significant.

The results for both secondary end points were significant, however. Incident MCI occurred in 348 participants in the standard treatment group and 285 participants in the intensive treatment group. The difference indicated a statistically significant 19% risk reduction associated with intensive treatment. Furthermore, intensive treatment significantly reduced the risk of the combined secondary end point of MCI and probable dementia by 15%. In all, 463 participants in the standard care group met this end point, compared with 398 in the intensive care group.

The imaging study included 454 subjects who had brain MRI at baseline and at four years after randomization. Total brain volume did not change, said Ilya Nasrallah, MD, Assistant Professor of Radiology at the University of Pennsylvania in Philadelphia. Patients in the intensively managed group, however, had 18% lower white matter lesion load than those in the standard care group.

White matter lesions often indicate small-vessel disease, which is associated with vascular dementia and, perhaps, Alzheimer’s disease. Most patients with Alzheimer’s disease have a mixed dementia that includes a vascular component, said Dr. Carrillo.

The Gravity of MCI

SPRINT MIND did not follow subjects for longer than four years or include follow-up for amyloid positivity or Alzheimer’s disease diagnosis. Nevertheless, preventing MCI is a significant achievement, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“There is nothing benign about MCI,” said Dr. Knopman. “It is the first sign of overt cognitive dysfunction, and although the rate at which MCI progresses to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think this study is going to change clinical practice for people in primary care, and the benefits at the population level are going to be substantial.”

Physicians may want to think about how the SPRINT MIND results might apply to younger patients with hypertension, whether they have other cardiovascular risk factors or not, said Dr. Williamson. “I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg and certainly start treating people in their 50s, and probably in their 40s,” he concluded.

—Michele G. Sullivan

Suggested Reading

SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.

CHICAGO—Lowering systolic blood pressure to a target of 120 mm Hg or less in people with cardiovascular risk factors reduces the risk of mild cognitive impairment (MCI) by 19% and reduces the risk of probable all-cause dementia by 17%, compared with achieving a less intensive target of lower than 140 mm Hg, according to research presented at AAIC 2018.

The class of antihypertensive did not affect the association. Generic drugs were as effective as branded drugs. Antihypertensive agents provided equal benefits to men, women, whites, blacks, and Hispanics. Furthermore, maintaining systolic blood pressure at 120 mm Hg or lower prevented MCI as well in patients older than 75 as it did in younger patients.

Jeff D. Williamson, MD, Chief of Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, presented the results of the four-year SPRINT MIND study. Strict blood pressure control (ie, a systolic target of 120 mm Hg or lower) for 3.2 years reduced the incidence of MCI to a greater extent than any amyloid-targeting investigational drug has done.

“This is the first disease-modifying strategy to reduce the risk of MCI,” said Dr. Williamson. Although the effect of strict blood pressure control on the primary end point (ie, a 17% risk reduction for probable all-cause dementia) was not statistically significant, “it is comforting to see that the benefit went in the same direction and was of the same magnitude,” said Dr. Williamson. “Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. Participants who underwent strict blood pressure control had 18% fewer white matter hyperintensities after four years of follow-up than other participants.

The results may represent a step forward in a field that has seen few of them recently. Generic antihypertensive agents can be inexpensive. They are widely available and confer benefits not only on cardiovascular health, but on kidney health as well, said Dr. Williamson.

“Hypertension is a highly prevalent condition…. The 19% overall risk reduction for MCI will have a huge impact,” he added.

“The most we can say right now is that we are able to reduce risk,” said Maria Carrillo, PhD, Chief Scientific Officer of the Alzheimer’s Association, in an interview. “Reducing the risk of MCI by 19% will have a huge impact on dementia overall. Slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, then I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

A Substudy of the SPRINT Trial

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target systolic blood pressure of less than 120 mm Hg, and the standard care strategy had a target of less than 140 mm Hg. SPRINT showed that intensive blood pressure control reduced the risk of cardiovascular events, stroke, and cardiovascular death by 30%. The study results helped inform the 2017 American Heart Association and American College of Cardiology clinical guidelines for treating high blood pressure.

The SPRINT MIND substudy examined whether intensive blood pressure management affected the risk of probable all-cause dementia or MCI or affected white matter lesion volume and brain volume.

The investigators examined data for 9,361 SPRINT subjects who were age 50 or older (mean age, 68) and had at least one cardiovascular risk factor. Approximately 30% of participants were black, and 10% were Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but were encouraged to use drugs with the strongest evidence of cardiovascular benefit. These drugs included thiazide-type diuretics, loop diuretics, and beta-adrenergic blockers. About 90% of the drugs used during the study were generic.

Subjects were seen monthly for the first three months. During this time, medications were adjusted to achieve the target blood pressure. After the third month, subjects were examined every three months. Medications could be adjusted monthly.

Results Favored Intensive Treatment

At one year, mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped early after a median follow-up of 3.26 years because of the observed cardiovascular disease benefit.

The SPRINT MIND study did not meet its primary end point. Incident probable all-cause dementia occurred in 175 people in the standard care group and 147 people in the intensive treatment group. The difference between groups in the rate of 17% risk reduction was not statistically significant.

The results for both secondary end points were significant, however. Incident MCI occurred in 348 participants in the standard treatment group and 285 participants in the intensive treatment group. The difference indicated a statistically significant 19% risk reduction associated with intensive treatment. Furthermore, intensive treatment significantly reduced the risk of the combined secondary end point of MCI and probable dementia by 15%. In all, 463 participants in the standard care group met this end point, compared with 398 in the intensive care group.

The imaging study included 454 subjects who had brain MRI at baseline and at four years after randomization. Total brain volume did not change, said Ilya Nasrallah, MD, Assistant Professor of Radiology at the University of Pennsylvania in Philadelphia. Patients in the intensively managed group, however, had 18% lower white matter lesion load than those in the standard care group.

White matter lesions often indicate small-vessel disease, which is associated with vascular dementia and, perhaps, Alzheimer’s disease. Most patients with Alzheimer’s disease have a mixed dementia that includes a vascular component, said Dr. Carrillo.

The Gravity of MCI

SPRINT MIND did not follow subjects for longer than four years or include follow-up for amyloid positivity or Alzheimer’s disease diagnosis. Nevertheless, preventing MCI is a significant achievement, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“There is nothing benign about MCI,” said Dr. Knopman. “It is the first sign of overt cognitive dysfunction, and although the rate at which MCI progresses to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think this study is going to change clinical practice for people in primary care, and the benefits at the population level are going to be substantial.”

Physicians may want to think about how the SPRINT MIND results might apply to younger patients with hypertension, whether they have other cardiovascular risk factors or not, said Dr. Williamson. “I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg and certainly start treating people in their 50s, and probably in their 40s,” he concluded.

—Michele G. Sullivan

Suggested Reading

SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.

CHICAGO—Lowering systolic blood pressure to a target of 120 mm Hg or less in people with cardiovascular risk factors reduces the risk of mild cognitive impairment (MCI) by 19% and reduces the risk of probable all-cause dementia by 17%, compared with achieving a less intensive target of lower than 140 mm Hg, according to research presented at AAIC 2018.

The class of antihypertensive did not affect the association. Generic drugs were as effective as branded drugs. Antihypertensive agents provided equal benefits to men, women, whites, blacks, and Hispanics. Furthermore, maintaining systolic blood pressure at 120 mm Hg or lower prevented MCI as well in patients older than 75 as it did in younger patients.

Jeff D. Williamson, MD, Chief of Geriatric Medicine at Wake Forest University in Winston-Salem, North Carolina, presented the results of the four-year SPRINT MIND study. Strict blood pressure control (ie, a systolic target of 120 mm Hg or lower) for 3.2 years reduced the incidence of MCI to a greater extent than any amyloid-targeting investigational drug has done.

“This is the first disease-modifying strategy to reduce the risk of MCI,” said Dr. Williamson. Although the effect of strict blood pressure control on the primary end point (ie, a 17% risk reduction for probable all-cause dementia) was not statistically significant, “it is comforting to see that the benefit went in the same direction and was of the same magnitude,” said Dr. Williamson. “Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. Participants who underwent strict blood pressure control had 18% fewer white matter hyperintensities after four years of follow-up than other participants.

The results may represent a step forward in a field that has seen few of them recently. Generic antihypertensive agents can be inexpensive. They are widely available and confer benefits not only on cardiovascular health, but on kidney health as well, said Dr. Williamson.

“Hypertension is a highly prevalent condition…. The 19% overall risk reduction for MCI will have a huge impact,” he added.

“The most we can say right now is that we are able to reduce risk,” said Maria Carrillo, PhD, Chief Scientific Officer of the Alzheimer’s Association, in an interview. “Reducing the risk of MCI by 19% will have a huge impact on dementia overall. Slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, then I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

A Substudy of the SPRINT Trial

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target systolic blood pressure of less than 120 mm Hg, and the standard care strategy had a target of less than 140 mm Hg. SPRINT showed that intensive blood pressure control reduced the risk of cardiovascular events, stroke, and cardiovascular death by 30%. The study results helped inform the 2017 American Heart Association and American College of Cardiology clinical guidelines for treating high blood pressure.

The SPRINT MIND substudy examined whether intensive blood pressure management affected the risk of probable all-cause dementia or MCI or affected white matter lesion volume and brain volume.

The investigators examined data for 9,361 SPRINT subjects who were age 50 or older (mean age, 68) and had at least one cardiovascular risk factor. Approximately 30% of participants were black, and 10% were Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but were encouraged to use drugs with the strongest evidence of cardiovascular benefit. These drugs included thiazide-type diuretics, loop diuretics, and beta-adrenergic blockers. About 90% of the drugs used during the study were generic.

Subjects were seen monthly for the first three months. During this time, medications were adjusted to achieve the target blood pressure. After the third month, subjects were examined every three months. Medications could be adjusted monthly.

Results Favored Intensive Treatment

At one year, mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped early after a median follow-up of 3.26 years because of the observed cardiovascular disease benefit.

The SPRINT MIND study did not meet its primary end point. Incident probable all-cause dementia occurred in 175 people in the standard care group and 147 people in the intensive treatment group. The difference between groups in the rate of 17% risk reduction was not statistically significant.

The results for both secondary end points were significant, however. Incident MCI occurred in 348 participants in the standard treatment group and 285 participants in the intensive treatment group. The difference indicated a statistically significant 19% risk reduction associated with intensive treatment. Furthermore, intensive treatment significantly reduced the risk of the combined secondary end point of MCI and probable dementia by 15%. In all, 463 participants in the standard care group met this end point, compared with 398 in the intensive care group.

The imaging study included 454 subjects who had brain MRI at baseline and at four years after randomization. Total brain volume did not change, said Ilya Nasrallah, MD, Assistant Professor of Radiology at the University of Pennsylvania in Philadelphia. Patients in the intensively managed group, however, had 18% lower white matter lesion load than those in the standard care group.

White matter lesions often indicate small-vessel disease, which is associated with vascular dementia and, perhaps, Alzheimer’s disease. Most patients with Alzheimer’s disease have a mixed dementia that includes a vascular component, said Dr. Carrillo.

The Gravity of MCI

SPRINT MIND did not follow subjects for longer than four years or include follow-up for amyloid positivity or Alzheimer’s disease diagnosis. Nevertheless, preventing MCI is a significant achievement, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“There is nothing benign about MCI,” said Dr. Knopman. “It is the first sign of overt cognitive dysfunction, and although the rate at which MCI progresses to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think this study is going to change clinical practice for people in primary care, and the benefits at the population level are going to be substantial.”

Physicians may want to think about how the SPRINT MIND results might apply to younger patients with hypertension, whether they have other cardiovascular risk factors or not, said Dr. Williamson. “I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg and certainly start treating people in their 50s, and probably in their 40s,” he concluded.

—Michele G. Sullivan

Suggested Reading

SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.

CHICAGO—Nabilone, a synthetic cannabinoid, may effectively treat agitation in people with Alzheimer’s disease, according to a randomized, double-blind clinical trial presented at AAIC 2018.

“Agitation, including verbal or physical outbursts, general emotional distress, restlessness, and pacing, is one of the most common behavioral changes associated with Alzheimer’s disease as it progresses and can be a significant cause of caregiver stress,” said Krista L. Lanctôt, PhD, Senior Scientist at Sunnybrook Health Sciences Centre and Professor of Pharmacology and Psychiatry at the University of Toronto.

CHICAGO—Nabilone, a synthetic cannabinoid, may effectively treat agitation in people with Alzheimer’s disease, according to a randomized, double-blind clinical trial presented at AAIC 2018.

“Agitation, including verbal or physical outbursts, general emotional distress, restlessness, and pacing, is one of the most common behavioral changes associated with Alzheimer’s disease as it progresses and can be a significant cause of caregiver stress,” said Krista L. Lanctôt, PhD, Senior Scientist at Sunnybrook Health Sciences Centre and Professor of Pharmacology and Psychiatry at the University of Toronto.

CHICAGO—Nabilone, a synthetic cannabinoid, may effectively treat agitation in people with Alzheimer’s disease, according to a randomized, double-blind clinical trial presented at AAIC 2018.

“Agitation, including verbal or physical outbursts, general emotional distress, restlessness, and pacing, is one of the most common behavioral changes associated with Alzheimer’s disease as it progresses and can be a significant cause of caregiver stress,” said Krista L. Lanctôt, PhD, Senior Scientist at Sunnybrook Health Sciences Centre and Professor of Pharmacology and Psychiatry at the University of Toronto.

CHICAGO—More pregnancies and a longer span of reproductive years appear to protect women against dementia, according to a study presented at AAIC 2018. The results suggest that lifetime estrogen exposure may be an important modulator of long-term cognitive health.

The study by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente in Oakland, California, and colleagues included more than 14,500 women and 50 years of follow-up data. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.

Reproductive Years

The researchers analyzed data from a cohort of 14,595 women in the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup between 1964 and 1973 when they were ages 40 to 55. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the women in the group (68%) were white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996 to 2017, when the women were ages 62 to 86.

A multivariate regression model controlled for age, race, education, midlife health issues (eg, hypertension, smoking, and BMI), hysterectomy, and late-life health issues (eg, stroke, heart failure, and diabetes).

Half of the cohort had at least three children, and 75% had at least one miscarriage. The average age at menarche was 13, and the average age at last natural menstrual period was 47. This equated to an average reproductive period of 34 years.

At the end of follow-up, 36% of the cohort had developed dementia.

Women with at least three children were 12% less likely to develop dementia, compared with those with one child. The association remained significant even after researchers controlled for age, race, education, and hysterectomy.

Miscarriages also influenced the risk of dementia. Those who did not report a miscarriage were 20% less likely to develop dementia than were those who had experienced at least one miscarriage. The benefit of no miscarriage was greater among women with at least three children, conferring a 28% reduced risk.

A shorter reproductive period increased the risk of dementia. Those who experienced menarche at age 16 or older had a 31% increased risk of dementia, and those who experienced their last period at age 45 or younger had a 28% greater risk. Each additional year of reproductive capability was associated with a 2% decreased risk.

Women with between 21 and 30 reproductive years were 33% more likely to develop dementia than were those with longer reproductive periods.

Renewed Interest

“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period, may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieus that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”

Researchers are exploring the link between hormones and cognition with renewed interest, said Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, North Carolina, who moderated a press briefing on the topic. The Women’s Heath Initiative study had a chilling effect on funding for this area of research, Dr. Craft said. “But now I think the pendulum is slowly moving back” toward supporting investigations of hormones and cognition. “It’s clear that something is going on, that there is a link. I am glad we are starting to explore this again.”

—Michele G. Sullivan

CHICAGO—More pregnancies and a longer span of reproductive years appear to protect women against dementia, according to a study presented at AAIC 2018. The results suggest that lifetime estrogen exposure may be an important modulator of long-term cognitive health.

The study by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente in Oakland, California, and colleagues included more than 14,500 women and 50 years of follow-up data. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.

Reproductive Years

The researchers analyzed data from a cohort of 14,595 women in the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup between 1964 and 1973 when they were ages 40 to 55. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the women in the group (68%) were white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996 to 2017, when the women were ages 62 to 86.

A multivariate regression model controlled for age, race, education, midlife health issues (eg, hypertension, smoking, and BMI), hysterectomy, and late-life health issues (eg, stroke, heart failure, and diabetes).

Half of the cohort had at least three children, and 75% had at least one miscarriage. The average age at menarche was 13, and the average age at last natural menstrual period was 47. This equated to an average reproductive period of 34 years.

At the end of follow-up, 36% of the cohort had developed dementia.

Women with at least three children were 12% less likely to develop dementia, compared with those with one child. The association remained significant even after researchers controlled for age, race, education, and hysterectomy.

Miscarriages also influenced the risk of dementia. Those who did not report a miscarriage were 20% less likely to develop dementia than were those who had experienced at least one miscarriage. The benefit of no miscarriage was greater among women with at least three children, conferring a 28% reduced risk.

A shorter reproductive period increased the risk of dementia. Those who experienced menarche at age 16 or older had a 31% increased risk of dementia, and those who experienced their last period at age 45 or younger had a 28% greater risk. Each additional year of reproductive capability was associated with a 2% decreased risk.

Women with between 21 and 30 reproductive years were 33% more likely to develop dementia than were those with longer reproductive periods.

Renewed Interest

“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period, may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieus that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”

Researchers are exploring the link between hormones and cognition with renewed interest, said Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, North Carolina, who moderated a press briefing on the topic. The Women’s Heath Initiative study had a chilling effect on funding for this area of research, Dr. Craft said. “But now I think the pendulum is slowly moving back” toward supporting investigations of hormones and cognition. “It’s clear that something is going on, that there is a link. I am glad we are starting to explore this again.”

—Michele G. Sullivan

CHICAGO—More pregnancies and a longer span of reproductive years appear to protect women against dementia, according to a study presented at AAIC 2018. The results suggest that lifetime estrogen exposure may be an important modulator of long-term cognitive health.

The study by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente in Oakland, California, and colleagues included more than 14,500 women and 50 years of follow-up data. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.

Reproductive Years

The researchers analyzed data from a cohort of 14,595 women in the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup between 1964 and 1973 when they were ages 40 to 55. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the women in the group (68%) were white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996 to 2017, when the women were ages 62 to 86.

A multivariate regression model controlled for age, race, education, midlife health issues (eg, hypertension, smoking, and BMI), hysterectomy, and late-life health issues (eg, stroke, heart failure, and diabetes).

Half of the cohort had at least three children, and 75% had at least one miscarriage. The average age at menarche was 13, and the average age at last natural menstrual period was 47. This equated to an average reproductive period of 34 years.

At the end of follow-up, 36% of the cohort had developed dementia.

Women with at least three children were 12% less likely to develop dementia, compared with those with one child. The association remained significant even after researchers controlled for age, race, education, and hysterectomy.

Miscarriages also influenced the risk of dementia. Those who did not report a miscarriage were 20% less likely to develop dementia than were those who had experienced at least one miscarriage. The benefit of no miscarriage was greater among women with at least three children, conferring a 28% reduced risk.

A shorter reproductive period increased the risk of dementia. Those who experienced menarche at age 16 or older had a 31% increased risk of dementia, and those who experienced their last period at age 45 or younger had a 28% greater risk. Each additional year of reproductive capability was associated with a 2% decreased risk.

Women with between 21 and 30 reproductive years were 33% more likely to develop dementia than were those with longer reproductive periods.

Renewed Interest

“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period, may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieus that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”

Researchers are exploring the link between hormones and cognition with renewed interest, said Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, North Carolina, who moderated a press briefing on the topic. The Women’s Heath Initiative study had a chilling effect on funding for this area of research, Dr. Craft said. “But now I think the pendulum is slowly moving back” toward supporting investigations of hormones and cognition. “It’s clear that something is going on, that there is a link. I am glad we are starting to explore this again.”

—Michele G. Sullivan

CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.

Imbalanced Treatment Groups

The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.

“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”

Regulators Influenced the Trial

Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”

“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”

Treatment Reduced Amyloid Levels

In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.

—Michele G. Sullivan

CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.

Imbalanced Treatment Groups

The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.

“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”

Regulators Influenced the Trial

Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”

“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”

Treatment Reduced Amyloid Levels

In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.

—Michele G. Sullivan

CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.

Imbalanced Treatment Groups

The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.

“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”

Regulators Influenced the Trial

Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.

“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”

“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”

Treatment Reduced Amyloid Levels

In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.

—Michele G. Sullivan

CHICAGO—Nonbenzodiazepine hypnotic “Z-drugs” (eg, zolpidem, zopiclone, and zaleplon) increase the risk of fractures in a dose-dependent manner in people with dementia, according to research presented at AAIC 2018. Patients with dementia who are receiving these drugs should be monitored, according to the researchers.

Approximately 60% of people with dementia have sleep disturbance. Z-drugs are often prescribed to help treat insomnia in older adults, but observers have raised concerns that these treatments may cause problems such as falls and fractures and increase confusion. Researchers have not fully investigated the safety and efficacy of Z-drugs in this patient population, however.

Chris Fox, MD, Professor of Psychiatry at Norwich Medical School at the University of East Anglia in the United Kingdom, and colleagues analyzed cohort studies using primary care data from the UK Clinical Practice Research Datalink that was linked to hospital admissions data. They also examined data from three clinical studies of people with dementia. To evaluate the benefits and harms of these medicines, the researchers compared data for 2,952 people with dementia who were newly prescribed Z-drugs with data for 1,651 people who were not prescribed sedatives or hypnotics.

CHICAGO—Nonbenzodiazepine hypnotic “Z-drugs” (eg, zolpidem, zopiclone, and zaleplon) increase the risk of fractures in a dose-dependent manner in people with dementia, according to research presented at AAIC 2018. Patients with dementia who are receiving these drugs should be monitored, according to the researchers.

Approximately 60% of people with dementia have sleep disturbance. Z-drugs are often prescribed to help treat insomnia in older adults, but observers have raised concerns that these treatments may cause problems such as falls and fractures and increase confusion. Researchers have not fully investigated the safety and efficacy of Z-drugs in this patient population, however.

Chris Fox, MD, Professor of Psychiatry at Norwich Medical School at the University of East Anglia in the United Kingdom, and colleagues analyzed cohort studies using primary care data from the UK Clinical Practice Research Datalink that was linked to hospital admissions data. They also examined data from three clinical studies of people with dementia. To evaluate the benefits and harms of these medicines, the researchers compared data for 2,952 people with dementia who were newly prescribed Z-drugs with data for 1,651 people who were not prescribed sedatives or hypnotics.

CHICAGO—Nonbenzodiazepine hypnotic “Z-drugs” (eg, zolpidem, zopiclone, and zaleplon) increase the risk of fractures in a dose-dependent manner in people with dementia, according to research presented at AAIC 2018. Patients with dementia who are receiving these drugs should be monitored, according to the researchers.

Approximately 60% of people with dementia have sleep disturbance. Z-drugs are often prescribed to help treat insomnia in older adults, but observers have raised concerns that these treatments may cause problems such as falls and fractures and increase confusion. Researchers have not fully investigated the safety and efficacy of Z-drugs in this patient population, however.

Chris Fox, MD, Professor of Psychiatry at Norwich Medical School at the University of East Anglia in the United Kingdom, and colleagues analyzed cohort studies using primary care data from the UK Clinical Practice Research Datalink that was linked to hospital admissions data. They also examined data from three clinical studies of people with dementia. To evaluate the benefits and harms of these medicines, the researchers compared data for 2,952 people with dementia who were newly prescribed Z-drugs with data for 1,651 people who were not prescribed sedatives or hypnotics.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.

BALTIMORE—Among patients with Alzheimer’s disease and related dementias, a lighting intervention may improve sleep, mood, and agitation, according to a study presented at the 32nd Annual Meeting of the Associated Professional Sleep Societies.

The intervention “holds considerable promise as a novel, practically applied, nonpharmacologic intervention” for people with dementia who live in long-term care facilities, said Mariana G. Figueiro, PhD, Director of the Lighting Research Center and Professor of Architecture at Rensselaer Polytechnic Institute in Troy, New York.

People with dementia often have problems related to sleep and daytime irritability. A study in office workers found that exposure to light that stimulates the circadian system early in the day is associated with better sleep and improved behavior and mood. To assess whether a lighting intervention that delivers a circadian stimulus may improve sleep and behavior in patients with dementia in long-term care facilities, Dr. Figueiro and colleagues conducted a crossover, repeated-measures, within-subjects study. The study included 43 subjects (31 female) with Alzheimer’s disease or related dementias and Mini-Mental State Examination scores of less than 24.

The intervention consisted of an LED light table and individual room lights that were placed where patients spent most of their waking hours. The lights were turned on when participants woke up and remained on until 6 PM. Participants wore calibrated light meters that monitored their light exposure.

The trial included four weeks with an active circadian stimulus, four weeks with an inactive lighting intervention, and a four-week washout period in between.

In addition, researchers collected subjective measures of sleep disturbances (Pittsburgh Sleep Quality Index [PSQI]), mood (Cornell Scale for Depression in Dementia [CSDD]), and agitation (Cohen-Mansfield Agitation Index [CMAI]) at baseline and during the last week of the active and placebo intervention periods.

The active lighting intervention significantly decreased scores for sleep disturbances, depression, and agitation, compared with placebo. During the active intervention, mean PSQI scores decreased from 10.3 to 6.7, CSDD scores decreased from 10.5 to 7.3, and CMAI scores decreased from 42.9 to 37.4.

A six-month study of the lighting intervention is underway. “A logical next step would be to test the short- and long-term effects of the tailored lighting intervention among those living at home,” Dr. Figueiro and colleagues said.

—Jake Remaly

Suggested Reading

Figueiro MG, Steverson B, Heerwagen J, et al. The impact of daytime light exposures on sleep and mood in office workers. Sleep Health. 2017;3(3):204-215.