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Scientists find brain mechanism behind age-related memory loss
Scientists at Johns Hopkins University have identified a mechanism in the brain behind age-related memory loss, expanding our knowledge of the inner workings of the aging brain and possibly opening the door to new Alzheimer’s treatments.
The researchers looked at the hippocampus, a part of the brain thought to store long-term memories.
Neurons there are responsible for a pair of memory functions – called pattern separation and pattern completion – that work together in young, healthy brains. These functions can swing out of balance with age, impacting memory.
The Johns Hopkins team may have discovered what causes this imbalance. Their findings – reported in a paper in the journal Current Biology – may not only help us improve dementia treatments, but even prevent or delay a loss of thinking skills in the first place, the researchers say.
Pattern separation vs. pattern completion
To understand how the hippocampus changes with age, the researchers looked at rats’ brains. In rats and in humans, pattern separation and pattern completion are present, controlled by neurons in the hippocampus.
As the name suggests, pattern completion is when you take a few details or fragments of information – a few notes of music, or the start of a famous movie quote – and your brain retrieves the full memory. Pattern separation, on the other hand, is being able to tell similar observations or experiences apart (like two visits to the same restaurant) to be stored as separate memories.
These functions occur along a gradient across a tiny region called CA3. That gradient, the study found, disappears with aging, said lead study author Hey-Kyoung Lee, PhD, an assistant research scientist at the university’s Zanvyl Krieger Mind/Brain Institute. “The main consequence of the loss,” Dr. Lee said, “is that pattern completion becomes more dominant in rats as they age.”
What’s happening in the brain
Neurons responsible for pattern completion occupy the “distal” end of CA3, while those in charge of pattern separation reside at the “proximal” end. Dr. Lee said prior studies had not examined the proximal and distal regions separately, as she and her team did in this study.
What was surprising, said Dr. Lee, “was that hyperactivity in aging was observed toward the proximal CA3 region, not the expected distal region.” Contrary to their expectations, that hyperactivity did not enhance function in that area but rather dampened it. Hence: “There is diminished pattern separation and augmented pattern completion,” she said.
– they may recall a certain restaurant they’d been to but not be able to separate what happened during one visit versus another.
Why do some older adults stay sharp?
That memory impairment does not happen to everyone, and it doesn’t happen to all rats either. In fact, the researchers found that some older rats performed spatial-learning tasks as well as young rats did – even though their brains were already beginning to favor pattern completion.
If we can better understand why this happens, we may uncover new therapies for age-related memory loss, Dr. Lee said.
Coauthor Michela Gallagher’s team previously demonstrated that the anti-epilepsy drug levetiracetam improves memory performance by reducing hyperactivity in the hippocampus.
The extra detail this study adds may allow scientists to better aim such drugs in the future, Dr. Lee speculated. “It would give us better control of where we could possibly target the deficits we see.”
A version of this article first appeared on WebMD.com.
Scientists at Johns Hopkins University have identified a mechanism in the brain behind age-related memory loss, expanding our knowledge of the inner workings of the aging brain and possibly opening the door to new Alzheimer’s treatments.
The researchers looked at the hippocampus, a part of the brain thought to store long-term memories.
Neurons there are responsible for a pair of memory functions – called pattern separation and pattern completion – that work together in young, healthy brains. These functions can swing out of balance with age, impacting memory.
The Johns Hopkins team may have discovered what causes this imbalance. Their findings – reported in a paper in the journal Current Biology – may not only help us improve dementia treatments, but even prevent or delay a loss of thinking skills in the first place, the researchers say.
Pattern separation vs. pattern completion
To understand how the hippocampus changes with age, the researchers looked at rats’ brains. In rats and in humans, pattern separation and pattern completion are present, controlled by neurons in the hippocampus.
As the name suggests, pattern completion is when you take a few details or fragments of information – a few notes of music, or the start of a famous movie quote – and your brain retrieves the full memory. Pattern separation, on the other hand, is being able to tell similar observations or experiences apart (like two visits to the same restaurant) to be stored as separate memories.
These functions occur along a gradient across a tiny region called CA3. That gradient, the study found, disappears with aging, said lead study author Hey-Kyoung Lee, PhD, an assistant research scientist at the university’s Zanvyl Krieger Mind/Brain Institute. “The main consequence of the loss,” Dr. Lee said, “is that pattern completion becomes more dominant in rats as they age.”
What’s happening in the brain
Neurons responsible for pattern completion occupy the “distal” end of CA3, while those in charge of pattern separation reside at the “proximal” end. Dr. Lee said prior studies had not examined the proximal and distal regions separately, as she and her team did in this study.
What was surprising, said Dr. Lee, “was that hyperactivity in aging was observed toward the proximal CA3 region, not the expected distal region.” Contrary to their expectations, that hyperactivity did not enhance function in that area but rather dampened it. Hence: “There is diminished pattern separation and augmented pattern completion,” she said.
– they may recall a certain restaurant they’d been to but not be able to separate what happened during one visit versus another.
Why do some older adults stay sharp?
That memory impairment does not happen to everyone, and it doesn’t happen to all rats either. In fact, the researchers found that some older rats performed spatial-learning tasks as well as young rats did – even though their brains were already beginning to favor pattern completion.
If we can better understand why this happens, we may uncover new therapies for age-related memory loss, Dr. Lee said.
Coauthor Michela Gallagher’s team previously demonstrated that the anti-epilepsy drug levetiracetam improves memory performance by reducing hyperactivity in the hippocampus.
The extra detail this study adds may allow scientists to better aim such drugs in the future, Dr. Lee speculated. “It would give us better control of where we could possibly target the deficits we see.”
A version of this article first appeared on WebMD.com.
Scientists at Johns Hopkins University have identified a mechanism in the brain behind age-related memory loss, expanding our knowledge of the inner workings of the aging brain and possibly opening the door to new Alzheimer’s treatments.
The researchers looked at the hippocampus, a part of the brain thought to store long-term memories.
Neurons there are responsible for a pair of memory functions – called pattern separation and pattern completion – that work together in young, healthy brains. These functions can swing out of balance with age, impacting memory.
The Johns Hopkins team may have discovered what causes this imbalance. Their findings – reported in a paper in the journal Current Biology – may not only help us improve dementia treatments, but even prevent or delay a loss of thinking skills in the first place, the researchers say.
Pattern separation vs. pattern completion
To understand how the hippocampus changes with age, the researchers looked at rats’ brains. In rats and in humans, pattern separation and pattern completion are present, controlled by neurons in the hippocampus.
As the name suggests, pattern completion is when you take a few details or fragments of information – a few notes of music, or the start of a famous movie quote – and your brain retrieves the full memory. Pattern separation, on the other hand, is being able to tell similar observations or experiences apart (like two visits to the same restaurant) to be stored as separate memories.
These functions occur along a gradient across a tiny region called CA3. That gradient, the study found, disappears with aging, said lead study author Hey-Kyoung Lee, PhD, an assistant research scientist at the university’s Zanvyl Krieger Mind/Brain Institute. “The main consequence of the loss,” Dr. Lee said, “is that pattern completion becomes more dominant in rats as they age.”
What’s happening in the brain
Neurons responsible for pattern completion occupy the “distal” end of CA3, while those in charge of pattern separation reside at the “proximal” end. Dr. Lee said prior studies had not examined the proximal and distal regions separately, as she and her team did in this study.
What was surprising, said Dr. Lee, “was that hyperactivity in aging was observed toward the proximal CA3 region, not the expected distal region.” Contrary to their expectations, that hyperactivity did not enhance function in that area but rather dampened it. Hence: “There is diminished pattern separation and augmented pattern completion,” she said.
– they may recall a certain restaurant they’d been to but not be able to separate what happened during one visit versus another.
Why do some older adults stay sharp?
That memory impairment does not happen to everyone, and it doesn’t happen to all rats either. In fact, the researchers found that some older rats performed spatial-learning tasks as well as young rats did – even though their brains were already beginning to favor pattern completion.
If we can better understand why this happens, we may uncover new therapies for age-related memory loss, Dr. Lee said.
Coauthor Michela Gallagher’s team previously demonstrated that the anti-epilepsy drug levetiracetam improves memory performance by reducing hyperactivity in the hippocampus.
The extra detail this study adds may allow scientists to better aim such drugs in the future, Dr. Lee speculated. “It would give us better control of where we could possibly target the deficits we see.”
A version of this article first appeared on WebMD.com.
FROM CURRENT BIOLOGY
Can bone density scans help predict dementia risk?
, new research suggests.
In an analysis of more than 900 study participants, women in their 70s with more advanced abdominal aortic calcification (AAC) seen on lateral spine images during dual-energy x-ray absorptiometry (DXA) had a two- to fourfold higher risk for late-life dementia than those with low AAC.
This finding was independent of cardiovascular risk factors and apolipoprotein E (APOE ) genotype.
“While these results are exciting, we now need to undertake further large screening studies in older men and women using this approach to show that the findings are generalizable to older men and can identify people with greater cognitive decline,” coinvestigator Marc Sim, PhD, Edith Cowan University, Joondalup, Australia, said in an interview.
“This will hopefully open the door to studies of early disease-modifying interventions,” Sim said.
The findings were published online in The Lancet Regional Health – Western Pacific.
AAC and cognition
Late-life dementia occurring after age 80 is increasingly common because of both vascular and nonvascular risk factors.
Two recent studies in middle-aged and older men and women showed that AAC identified on bone densitometry was associated with poorer cognition, suggesting it may be related to cognitive decline and increased dementia risk.
This provided the rationale for the current study, Dr. Sim noted.
The researchers assessed AAC using DXA lateral spine images captured in the late 1990s in a prospective cohort of 958 older women who were participating in an osteoporosis study.
AAC was classified into established low, moderate, and extensive categories. At baseline, all women were aged 70 and older, and 45% had low AAC, 36% had moderate AAC, and 19% had extensive AAC.
Over 14.5 years, 150 women (15.7%) had a late-life hospitalization and/or died.
Improved risk prediction
Results showed that, compared with women who had low AAC, women with moderate and extensive AAC were more likely to experience late-life dementia hospitalization (9.3% low, 15.5% moderate, and 18.3% extensive) and death (2.8%, 8.3%, and 9.4%, respectively).
After multivariable adjustment, women with moderate AAC had a two- and threefold increased relative risk for late-life dementia hospitalization or death, compared with their peers who had low AAC.
Women with extensive AAC had a two- and fourfold increase in the adjusted relative risk for late-life dementia hospitalization or death.
“To our knowledge this is the first time it has been shown that AAC from these scans is related to late-life dementia,” Dr. Sim said.
“We demonstrated that AAC improved risk prediction in addition to cardiovascular risk factors and APOE genotype, a genetic risk factor for Alzheimer’s disease, the major form of dementia,” he added.
Dr. Sim noted “these additional lateral spine images” can be taken at the same time that hip and spine bone density tests are done.
“This provides an opportunity to identify AAC in large numbers of people,” he said.
He cautioned, however, that further studies with detailed dementia-related phenotypes, brain imaging, and measures of cognition are needed to confirm whether AAC will add value to dementia risk prediction.
‘Not surprising’
Commenting on the findings for this article, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, Chicago, noted that AAC is a marker of atherosclerosis and is associated with vascular health outcomes.
Therefore, it is “not surprising it would be associated with dementia too. There’s been previous research linking atherosclerosis and Alzheimer’s disease,” Dr. Sexton said.
“What’s novel about this research is that it’s looking at AAC specifically, which can be identified through a relatively simple test that is already in widespread use,” she added.
Dr. Sexton noted that “much more research” is now needed in larger, more diverse populations in order to better understand the link between AAC and dementia – and whether bone density testing may be an appropriate dementia-screening tool.
“The good news is vascular conditions like atherosclerosis can be managed through lifestyle changes like eating a healthy diet and getting regular exercise. And research tells us what’s good for the heart is good for the brain,” Dr. Sexton said.
The study was funded by Kidney Health Australia, Healthway Health Promotion Foundation of Western Australia, Sir Charles Gairdner Hospital Research Advisory Committee Grant, and the National Health and Medical Research Council of Australia. Dr. Sim and Dr. Sexton have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
In an analysis of more than 900 study participants, women in their 70s with more advanced abdominal aortic calcification (AAC) seen on lateral spine images during dual-energy x-ray absorptiometry (DXA) had a two- to fourfold higher risk for late-life dementia than those with low AAC.
This finding was independent of cardiovascular risk factors and apolipoprotein E (APOE ) genotype.
“While these results are exciting, we now need to undertake further large screening studies in older men and women using this approach to show that the findings are generalizable to older men and can identify people with greater cognitive decline,” coinvestigator Marc Sim, PhD, Edith Cowan University, Joondalup, Australia, said in an interview.
“This will hopefully open the door to studies of early disease-modifying interventions,” Sim said.
The findings were published online in The Lancet Regional Health – Western Pacific.
AAC and cognition
Late-life dementia occurring after age 80 is increasingly common because of both vascular and nonvascular risk factors.
Two recent studies in middle-aged and older men and women showed that AAC identified on bone densitometry was associated with poorer cognition, suggesting it may be related to cognitive decline and increased dementia risk.
This provided the rationale for the current study, Dr. Sim noted.
The researchers assessed AAC using DXA lateral spine images captured in the late 1990s in a prospective cohort of 958 older women who were participating in an osteoporosis study.
AAC was classified into established low, moderate, and extensive categories. At baseline, all women were aged 70 and older, and 45% had low AAC, 36% had moderate AAC, and 19% had extensive AAC.
Over 14.5 years, 150 women (15.7%) had a late-life hospitalization and/or died.
Improved risk prediction
Results showed that, compared with women who had low AAC, women with moderate and extensive AAC were more likely to experience late-life dementia hospitalization (9.3% low, 15.5% moderate, and 18.3% extensive) and death (2.8%, 8.3%, and 9.4%, respectively).
After multivariable adjustment, women with moderate AAC had a two- and threefold increased relative risk for late-life dementia hospitalization or death, compared with their peers who had low AAC.
Women with extensive AAC had a two- and fourfold increase in the adjusted relative risk for late-life dementia hospitalization or death.
“To our knowledge this is the first time it has been shown that AAC from these scans is related to late-life dementia,” Dr. Sim said.
“We demonstrated that AAC improved risk prediction in addition to cardiovascular risk factors and APOE genotype, a genetic risk factor for Alzheimer’s disease, the major form of dementia,” he added.
Dr. Sim noted “these additional lateral spine images” can be taken at the same time that hip and spine bone density tests are done.
“This provides an opportunity to identify AAC in large numbers of people,” he said.
He cautioned, however, that further studies with detailed dementia-related phenotypes, brain imaging, and measures of cognition are needed to confirm whether AAC will add value to dementia risk prediction.
‘Not surprising’
Commenting on the findings for this article, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, Chicago, noted that AAC is a marker of atherosclerosis and is associated with vascular health outcomes.
Therefore, it is “not surprising it would be associated with dementia too. There’s been previous research linking atherosclerosis and Alzheimer’s disease,” Dr. Sexton said.
“What’s novel about this research is that it’s looking at AAC specifically, which can be identified through a relatively simple test that is already in widespread use,” she added.
Dr. Sexton noted that “much more research” is now needed in larger, more diverse populations in order to better understand the link between AAC and dementia – and whether bone density testing may be an appropriate dementia-screening tool.
“The good news is vascular conditions like atherosclerosis can be managed through lifestyle changes like eating a healthy diet and getting regular exercise. And research tells us what’s good for the heart is good for the brain,” Dr. Sexton said.
The study was funded by Kidney Health Australia, Healthway Health Promotion Foundation of Western Australia, Sir Charles Gairdner Hospital Research Advisory Committee Grant, and the National Health and Medical Research Council of Australia. Dr. Sim and Dr. Sexton have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
In an analysis of more than 900 study participants, women in their 70s with more advanced abdominal aortic calcification (AAC) seen on lateral spine images during dual-energy x-ray absorptiometry (DXA) had a two- to fourfold higher risk for late-life dementia than those with low AAC.
This finding was independent of cardiovascular risk factors and apolipoprotein E (APOE ) genotype.
“While these results are exciting, we now need to undertake further large screening studies in older men and women using this approach to show that the findings are generalizable to older men and can identify people with greater cognitive decline,” coinvestigator Marc Sim, PhD, Edith Cowan University, Joondalup, Australia, said in an interview.
“This will hopefully open the door to studies of early disease-modifying interventions,” Sim said.
The findings were published online in The Lancet Regional Health – Western Pacific.
AAC and cognition
Late-life dementia occurring after age 80 is increasingly common because of both vascular and nonvascular risk factors.
Two recent studies in middle-aged and older men and women showed that AAC identified on bone densitometry was associated with poorer cognition, suggesting it may be related to cognitive decline and increased dementia risk.
This provided the rationale for the current study, Dr. Sim noted.
The researchers assessed AAC using DXA lateral spine images captured in the late 1990s in a prospective cohort of 958 older women who were participating in an osteoporosis study.
AAC was classified into established low, moderate, and extensive categories. At baseline, all women were aged 70 and older, and 45% had low AAC, 36% had moderate AAC, and 19% had extensive AAC.
Over 14.5 years, 150 women (15.7%) had a late-life hospitalization and/or died.
Improved risk prediction
Results showed that, compared with women who had low AAC, women with moderate and extensive AAC were more likely to experience late-life dementia hospitalization (9.3% low, 15.5% moderate, and 18.3% extensive) and death (2.8%, 8.3%, and 9.4%, respectively).
After multivariable adjustment, women with moderate AAC had a two- and threefold increased relative risk for late-life dementia hospitalization or death, compared with their peers who had low AAC.
Women with extensive AAC had a two- and fourfold increase in the adjusted relative risk for late-life dementia hospitalization or death.
“To our knowledge this is the first time it has been shown that AAC from these scans is related to late-life dementia,” Dr. Sim said.
“We demonstrated that AAC improved risk prediction in addition to cardiovascular risk factors and APOE genotype, a genetic risk factor for Alzheimer’s disease, the major form of dementia,” he added.
Dr. Sim noted “these additional lateral spine images” can be taken at the same time that hip and spine bone density tests are done.
“This provides an opportunity to identify AAC in large numbers of people,” he said.
He cautioned, however, that further studies with detailed dementia-related phenotypes, brain imaging, and measures of cognition are needed to confirm whether AAC will add value to dementia risk prediction.
‘Not surprising’
Commenting on the findings for this article, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, Chicago, noted that AAC is a marker of atherosclerosis and is associated with vascular health outcomes.
Therefore, it is “not surprising it would be associated with dementia too. There’s been previous research linking atherosclerosis and Alzheimer’s disease,” Dr. Sexton said.
“What’s novel about this research is that it’s looking at AAC specifically, which can be identified through a relatively simple test that is already in widespread use,” she added.
Dr. Sexton noted that “much more research” is now needed in larger, more diverse populations in order to better understand the link between AAC and dementia – and whether bone density testing may be an appropriate dementia-screening tool.
“The good news is vascular conditions like atherosclerosis can be managed through lifestyle changes like eating a healthy diet and getting regular exercise. And research tells us what’s good for the heart is good for the brain,” Dr. Sexton said.
The study was funded by Kidney Health Australia, Healthway Health Promotion Foundation of Western Australia, Sir Charles Gairdner Hospital Research Advisory Committee Grant, and the National Health and Medical Research Council of Australia. Dr. Sim and Dr. Sexton have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET REGIONAL HEALTH – WESTERN PACIFIC
More evidence the flu vaccine may guard against Alzheimer’s
In a large propensity-matched cohort of older adults, those who had received at least one influenza inoculation were 40% less likely than unvaccinated peers to develop AD over the course of 4 years.
“Influenza infection can cause serious health complications, particularly in adults 65 and older. Our study’s findings – that vaccination against the flu virus may also reduce the risk of Alzheimer’s dementia for at least a few years – adds to the already compelling reasons get the flu vaccine annually,” Avram Bukhbinder, MD, of the University of Texas, Houston, said in an interview.
The new findings support earlier work by the same researchers that also suggested a protective effect of flu vaccination on dementia risk.
The latest study was published online in the Journal of Alzheimer’s Disease.
40% lower risk
Prior studies have found a lower risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions.
However, the effect of influenza vaccination on AD risk in a general cohort of older U.S. adults has not been characterized.
Dr. Bukhbinder and colleagues used claims data to create a propensity-matched cohort of 935,887 influenza-vaccinated adults and a like number of unvaccinated adults aged 65 and older.
The median age of the persons in the matched sample was 73.7 years, and 57% were women. All were free of dementia during the 6-year look-back study period.
During median follow-up of 46 months, 47,889 (5.1%) flu-vaccinated adults and 79,630 (8.5%) unvaccinated adults developed AD.
The risk of AD was 40% lower in the vaccinated group (relative risk, 0.60; 95% confidence interval, 0.59-0.61). The absolute risk reduction was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4.
Mechanism unclear
“Our study does not address the mechanism(s) underlying the apparent effect of influenza vaccination on Alzheimer’s risk, but we look forward to future research investigating this important question,” Dr. Bukhbinder said.
“One possible mechanism is that, by helping to prevent or mitigate infection with the flu virus and the systemic inflammation that follows such an infection, the flu vaccine helps to decrease the systemic inflammation that may have otherwise occurred,” he explained.
It’s also possible that influenza vaccination may trigger non–influenza-specific changes in the immune system that help to reduce the damage caused by AD pathology, including amyloid plaques and neurofibrillary tangles, he said.
“For example, the influenza vaccine may alter the brain’s immune cells such that they are better at clearing Alzheimer’s pathologies, an effect that has been seen in mice, or it may reprogram these immune cells to respond to Alzheimer’s pathologies in ways that are less likely to damage nearby healthy brain cells, or it may do both,” Dr. Bukhbinder noted.
Alzheimer’s expert weighs in
Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, said this study “suggests that flu vaccination may be valuable for maintaining cognition and memory as we age. This is even more relevant today in the COVID-19 environment.
“It is too early to tell if getting flu vaccine, on its own, can reduce risk of Alzheimer’s. More research is needed to understand the biological mechanisms behind the results in this study,” Dr. Snyder said in an interview.
“For example, it is possible that people who are getting vaccinated also take better care of their health in other ways, and these things add up to lower risk of Alzheimer’s and other dementias,” she noted.
“It is also possible that there are issues related to unequal access and/or vaccine hesitancy and how this may influence the study population and the research results,” Dr. Snyder said.
The study had no specific funding. Dr. Bukhbinder and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large propensity-matched cohort of older adults, those who had received at least one influenza inoculation were 40% less likely than unvaccinated peers to develop AD over the course of 4 years.
“Influenza infection can cause serious health complications, particularly in adults 65 and older. Our study’s findings – that vaccination against the flu virus may also reduce the risk of Alzheimer’s dementia for at least a few years – adds to the already compelling reasons get the flu vaccine annually,” Avram Bukhbinder, MD, of the University of Texas, Houston, said in an interview.
The new findings support earlier work by the same researchers that also suggested a protective effect of flu vaccination on dementia risk.
The latest study was published online in the Journal of Alzheimer’s Disease.
40% lower risk
Prior studies have found a lower risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions.
However, the effect of influenza vaccination on AD risk in a general cohort of older U.S. adults has not been characterized.
Dr. Bukhbinder and colleagues used claims data to create a propensity-matched cohort of 935,887 influenza-vaccinated adults and a like number of unvaccinated adults aged 65 and older.
The median age of the persons in the matched sample was 73.7 years, and 57% were women. All were free of dementia during the 6-year look-back study period.
During median follow-up of 46 months, 47,889 (5.1%) flu-vaccinated adults and 79,630 (8.5%) unvaccinated adults developed AD.
The risk of AD was 40% lower in the vaccinated group (relative risk, 0.60; 95% confidence interval, 0.59-0.61). The absolute risk reduction was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4.
Mechanism unclear
“Our study does not address the mechanism(s) underlying the apparent effect of influenza vaccination on Alzheimer’s risk, but we look forward to future research investigating this important question,” Dr. Bukhbinder said.
“One possible mechanism is that, by helping to prevent or mitigate infection with the flu virus and the systemic inflammation that follows such an infection, the flu vaccine helps to decrease the systemic inflammation that may have otherwise occurred,” he explained.
It’s also possible that influenza vaccination may trigger non–influenza-specific changes in the immune system that help to reduce the damage caused by AD pathology, including amyloid plaques and neurofibrillary tangles, he said.
“For example, the influenza vaccine may alter the brain’s immune cells such that they are better at clearing Alzheimer’s pathologies, an effect that has been seen in mice, or it may reprogram these immune cells to respond to Alzheimer’s pathologies in ways that are less likely to damage nearby healthy brain cells, or it may do both,” Dr. Bukhbinder noted.
Alzheimer’s expert weighs in
Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, said this study “suggests that flu vaccination may be valuable for maintaining cognition and memory as we age. This is even more relevant today in the COVID-19 environment.
“It is too early to tell if getting flu vaccine, on its own, can reduce risk of Alzheimer’s. More research is needed to understand the biological mechanisms behind the results in this study,” Dr. Snyder said in an interview.
“For example, it is possible that people who are getting vaccinated also take better care of their health in other ways, and these things add up to lower risk of Alzheimer’s and other dementias,” she noted.
“It is also possible that there are issues related to unequal access and/or vaccine hesitancy and how this may influence the study population and the research results,” Dr. Snyder said.
The study had no specific funding. Dr. Bukhbinder and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large propensity-matched cohort of older adults, those who had received at least one influenza inoculation were 40% less likely than unvaccinated peers to develop AD over the course of 4 years.
“Influenza infection can cause serious health complications, particularly in adults 65 and older. Our study’s findings – that vaccination against the flu virus may also reduce the risk of Alzheimer’s dementia for at least a few years – adds to the already compelling reasons get the flu vaccine annually,” Avram Bukhbinder, MD, of the University of Texas, Houston, said in an interview.
The new findings support earlier work by the same researchers that also suggested a protective effect of flu vaccination on dementia risk.
The latest study was published online in the Journal of Alzheimer’s Disease.
40% lower risk
Prior studies have found a lower risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions.
However, the effect of influenza vaccination on AD risk in a general cohort of older U.S. adults has not been characterized.
Dr. Bukhbinder and colleagues used claims data to create a propensity-matched cohort of 935,887 influenza-vaccinated adults and a like number of unvaccinated adults aged 65 and older.
The median age of the persons in the matched sample was 73.7 years, and 57% were women. All were free of dementia during the 6-year look-back study period.
During median follow-up of 46 months, 47,889 (5.1%) flu-vaccinated adults and 79,630 (8.5%) unvaccinated adults developed AD.
The risk of AD was 40% lower in the vaccinated group (relative risk, 0.60; 95% confidence interval, 0.59-0.61). The absolute risk reduction was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4.
Mechanism unclear
“Our study does not address the mechanism(s) underlying the apparent effect of influenza vaccination on Alzheimer’s risk, but we look forward to future research investigating this important question,” Dr. Bukhbinder said.
“One possible mechanism is that, by helping to prevent or mitigate infection with the flu virus and the systemic inflammation that follows such an infection, the flu vaccine helps to decrease the systemic inflammation that may have otherwise occurred,” he explained.
It’s also possible that influenza vaccination may trigger non–influenza-specific changes in the immune system that help to reduce the damage caused by AD pathology, including amyloid plaques and neurofibrillary tangles, he said.
“For example, the influenza vaccine may alter the brain’s immune cells such that they are better at clearing Alzheimer’s pathologies, an effect that has been seen in mice, or it may reprogram these immune cells to respond to Alzheimer’s pathologies in ways that are less likely to damage nearby healthy brain cells, or it may do both,” Dr. Bukhbinder noted.
Alzheimer’s expert weighs in
Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, said this study “suggests that flu vaccination may be valuable for maintaining cognition and memory as we age. This is even more relevant today in the COVID-19 environment.
“It is too early to tell if getting flu vaccine, on its own, can reduce risk of Alzheimer’s. More research is needed to understand the biological mechanisms behind the results in this study,” Dr. Snyder said in an interview.
“For example, it is possible that people who are getting vaccinated also take better care of their health in other ways, and these things add up to lower risk of Alzheimer’s and other dementias,” she noted.
“It is also possible that there are issues related to unequal access and/or vaccine hesitancy and how this may influence the study population and the research results,” Dr. Snyder said.
The study had no specific funding. Dr. Bukhbinder and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S DISEASE
COVID-19 tied to increased risk for Alzheimer’s disease and Parkinson’s disease
a new study suggests. However, the research also showed there was no excess risk of these neurologic disorders following COVID than other respiratory infections such as influenza or community-acquired bacterial pneumonia.
Considering these results, study investigator Pardis Zarifkar, MD, department of neurology, Rigshospitalet, Copenhagen University Hospital, urged doctors to “keep an eye on” COVID patients and use “a critical mindset” if these patients present with neurologic issues.
“They should consider whether the patient’s condition is something new or if there were already signs and symptoms before they had COVID-19,” she said.
The findings were presented at the 2022 congress of the European Academy of Neurology and published online in Frontiers in Neurology.
‘Surprising’ increased risk
Previous research shows more than 80% of patients hospitalized with COVID-19 have neurologic symptoms including anosmia, dysgeusia, headache, dizziness, memory and concentration difficulties, fatigue, and irritability.
However, it’s unclear whether COVID-19 affects the risk for specific neurologic diseases and if so, whether this association differs from other respiratory infections.
From electronic health records covering about half the Danish population, researchers identified adults who were tested for COVID-19 or diagnosed with community-acquired bacterial pneumonia from February 2020 to November 2021. They also flagged individuals with influenza in the corresponding prepandemic period (February 2018–November 2019).
Dr. Zarifkar noted influenza A or B and community-acquired bacterial pneumonia are two of the most common respiratory tract infections.
The investigators tracked neurologic diseases up to 12 months after a positive test. They looked at two neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease, as well as cerebrovascular disorders including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
The study included 43,262 individuals with a positive COVID test without a history of influenza A/B in the past year and 876,356 without a positive COVID test. It also included 1,474 individuals with community-acquired pneumonia without a history of COVID and 8,102 with influenza A or B.
“We wanted to investigate whether COVID-19 is really that much worse than all these other common respiratory infections that we have had for ages and see every single year,” said Dr. Zarifkar.
After 12 months, the relative risk for Alzheimer’s disease was 3.4 (95% confidence interval, 2.3-5.1) in the COVID-positive group versus the COVID-negative group. The risks were greater among inpatients versus outpatients.
These results were rather unexpected, said Dr. Zarifkar. “I would have expected a small increase, but the extent of the increase was quite surprising.”
However, there was no difference when comparing the COVID-19 group with the influenza or bacterial pneumonia groups, which Dr. Zarifkar said was “very reassuring.”
The findings were similar for Parkinson’s disease, where there was a 2.2-fold increased risk of a Parkinson’s disease diagnosis within the first 12 months in COVID-positive individuals, compared with COVID-negative people (RR, 2.2; 95% CI, 1.5-3.4). Again, there was no excess risk, compared with influenza or bacterial pneumonia.
Potential mechanisms
Dr. Zarifkar believes a “constellation” of factors may explain higher risks of these diagnoses in COVID patients. Part of it could be a result of neuroinflammation, which can lead to a toxic accumulation of beta amyloid in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease.
“It can accelerate a neurodegenerative disease already in the making,” she said. But perhaps the biggest driver of differences between the groups is the “scientific focus” on COVID patients. “In Denmark, almost everyone who has had COVID-19, especially severe COVID-19, is offered some sort of cognitive testing, and if you hand out MoCAs [Montreal Cognitive Assessments] which is the cognitive test we use, to almost everyone you’re meeting, you’re going to catch these disorders earlier than you might have otherwise.”
As for cerebrovascular disorders, the study showed an increased risk of ischemic stroke in COVID-positive versus COVID-negative subjects at 12 months (RR, 2.87; 95% confidence interval, 2.2-3.2).
The relatively strong inflammatory response associated with COVID-19, which may create a hypercoagulable state, may help explain the increased ischemic stroke risk in COVID patients, said Dr. Zarifkar.
The study did not show an increased risk for subarachnoid hemorrhage in COVID-positive, compared with COVID-negative, subjects but did reveal an increased risk of intracerebral hemorrhage after 12 months (RR, 4.8; 95% CI, 1.8-12.9).
This could be explained by COVID-positive subjects having a higher risk for ischemic stroke and receiving thrombolysis that may increase risk for bleeding in the brain. However, an analysis accounting for medication use found differences in thrombolysis rates didn’t change the result, said Dr. Zarifkar.
It’s also possible that extracorporeal membrane oxygenation and mechanical ventilation – interventions more frequently used in COVID-19 patients – may increase the risk for bleeding in brain, she added.
The researchers did not find an increased risk for multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, or narcolepsy in COVID patients. However, Dr. Zarifkar noted that it can take years to detect an association with autoimmune disorders.
The investigators did not stratify risk by disease severity, although this would be an important step, she said. “The threshold of being admitted to the hospital with COVID-19 has been much lower than for influenza or bacterial pneumonia where you’re typically quite ill before you’re admitted, so this might actually dilute the findings and underestimate our findings.”
A national, registry-based study that includes the entire Danish population and additional information on vaccination status, virus variants, socioeconomic status, and comorbidities is needed, said Dr. Zarifkar.
The study was supported by Lundbeck Foundation and Novo Nordisk. Dr. Zarifkar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a new study suggests. However, the research also showed there was no excess risk of these neurologic disorders following COVID than other respiratory infections such as influenza or community-acquired bacterial pneumonia.
Considering these results, study investigator Pardis Zarifkar, MD, department of neurology, Rigshospitalet, Copenhagen University Hospital, urged doctors to “keep an eye on” COVID patients and use “a critical mindset” if these patients present with neurologic issues.
“They should consider whether the patient’s condition is something new or if there were already signs and symptoms before they had COVID-19,” she said.
The findings were presented at the 2022 congress of the European Academy of Neurology and published online in Frontiers in Neurology.
‘Surprising’ increased risk
Previous research shows more than 80% of patients hospitalized with COVID-19 have neurologic symptoms including anosmia, dysgeusia, headache, dizziness, memory and concentration difficulties, fatigue, and irritability.
However, it’s unclear whether COVID-19 affects the risk for specific neurologic diseases and if so, whether this association differs from other respiratory infections.
From electronic health records covering about half the Danish population, researchers identified adults who were tested for COVID-19 or diagnosed with community-acquired bacterial pneumonia from February 2020 to November 2021. They also flagged individuals with influenza in the corresponding prepandemic period (February 2018–November 2019).
Dr. Zarifkar noted influenza A or B and community-acquired bacterial pneumonia are two of the most common respiratory tract infections.
The investigators tracked neurologic diseases up to 12 months after a positive test. They looked at two neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease, as well as cerebrovascular disorders including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
The study included 43,262 individuals with a positive COVID test without a history of influenza A/B in the past year and 876,356 without a positive COVID test. It also included 1,474 individuals with community-acquired pneumonia without a history of COVID and 8,102 with influenza A or B.
“We wanted to investigate whether COVID-19 is really that much worse than all these other common respiratory infections that we have had for ages and see every single year,” said Dr. Zarifkar.
After 12 months, the relative risk for Alzheimer’s disease was 3.4 (95% confidence interval, 2.3-5.1) in the COVID-positive group versus the COVID-negative group. The risks were greater among inpatients versus outpatients.
These results were rather unexpected, said Dr. Zarifkar. “I would have expected a small increase, but the extent of the increase was quite surprising.”
However, there was no difference when comparing the COVID-19 group with the influenza or bacterial pneumonia groups, which Dr. Zarifkar said was “very reassuring.”
The findings were similar for Parkinson’s disease, where there was a 2.2-fold increased risk of a Parkinson’s disease diagnosis within the first 12 months in COVID-positive individuals, compared with COVID-negative people (RR, 2.2; 95% CI, 1.5-3.4). Again, there was no excess risk, compared with influenza or bacterial pneumonia.
Potential mechanisms
Dr. Zarifkar believes a “constellation” of factors may explain higher risks of these diagnoses in COVID patients. Part of it could be a result of neuroinflammation, which can lead to a toxic accumulation of beta amyloid in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease.
“It can accelerate a neurodegenerative disease already in the making,” she said. But perhaps the biggest driver of differences between the groups is the “scientific focus” on COVID patients. “In Denmark, almost everyone who has had COVID-19, especially severe COVID-19, is offered some sort of cognitive testing, and if you hand out MoCAs [Montreal Cognitive Assessments] which is the cognitive test we use, to almost everyone you’re meeting, you’re going to catch these disorders earlier than you might have otherwise.”
As for cerebrovascular disorders, the study showed an increased risk of ischemic stroke in COVID-positive versus COVID-negative subjects at 12 months (RR, 2.87; 95% confidence interval, 2.2-3.2).
The relatively strong inflammatory response associated with COVID-19, which may create a hypercoagulable state, may help explain the increased ischemic stroke risk in COVID patients, said Dr. Zarifkar.
The study did not show an increased risk for subarachnoid hemorrhage in COVID-positive, compared with COVID-negative, subjects but did reveal an increased risk of intracerebral hemorrhage after 12 months (RR, 4.8; 95% CI, 1.8-12.9).
This could be explained by COVID-positive subjects having a higher risk for ischemic stroke and receiving thrombolysis that may increase risk for bleeding in the brain. However, an analysis accounting for medication use found differences in thrombolysis rates didn’t change the result, said Dr. Zarifkar.
It’s also possible that extracorporeal membrane oxygenation and mechanical ventilation – interventions more frequently used in COVID-19 patients – may increase the risk for bleeding in brain, she added.
The researchers did not find an increased risk for multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, or narcolepsy in COVID patients. However, Dr. Zarifkar noted that it can take years to detect an association with autoimmune disorders.
The investigators did not stratify risk by disease severity, although this would be an important step, she said. “The threshold of being admitted to the hospital with COVID-19 has been much lower than for influenza or bacterial pneumonia where you’re typically quite ill before you’re admitted, so this might actually dilute the findings and underestimate our findings.”
A national, registry-based study that includes the entire Danish population and additional information on vaccination status, virus variants, socioeconomic status, and comorbidities is needed, said Dr. Zarifkar.
The study was supported by Lundbeck Foundation and Novo Nordisk. Dr. Zarifkar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
a new study suggests. However, the research also showed there was no excess risk of these neurologic disorders following COVID than other respiratory infections such as influenza or community-acquired bacterial pneumonia.
Considering these results, study investigator Pardis Zarifkar, MD, department of neurology, Rigshospitalet, Copenhagen University Hospital, urged doctors to “keep an eye on” COVID patients and use “a critical mindset” if these patients present with neurologic issues.
“They should consider whether the patient’s condition is something new or if there were already signs and symptoms before they had COVID-19,” she said.
The findings were presented at the 2022 congress of the European Academy of Neurology and published online in Frontiers in Neurology.
‘Surprising’ increased risk
Previous research shows more than 80% of patients hospitalized with COVID-19 have neurologic symptoms including anosmia, dysgeusia, headache, dizziness, memory and concentration difficulties, fatigue, and irritability.
However, it’s unclear whether COVID-19 affects the risk for specific neurologic diseases and if so, whether this association differs from other respiratory infections.
From electronic health records covering about half the Danish population, researchers identified adults who were tested for COVID-19 or diagnosed with community-acquired bacterial pneumonia from February 2020 to November 2021. They also flagged individuals with influenza in the corresponding prepandemic period (February 2018–November 2019).
Dr. Zarifkar noted influenza A or B and community-acquired bacterial pneumonia are two of the most common respiratory tract infections.
The investigators tracked neurologic diseases up to 12 months after a positive test. They looked at two neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease, as well as cerebrovascular disorders including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
The study included 43,262 individuals with a positive COVID test without a history of influenza A/B in the past year and 876,356 without a positive COVID test. It also included 1,474 individuals with community-acquired pneumonia without a history of COVID and 8,102 with influenza A or B.
“We wanted to investigate whether COVID-19 is really that much worse than all these other common respiratory infections that we have had for ages and see every single year,” said Dr. Zarifkar.
After 12 months, the relative risk for Alzheimer’s disease was 3.4 (95% confidence interval, 2.3-5.1) in the COVID-positive group versus the COVID-negative group. The risks were greater among inpatients versus outpatients.
These results were rather unexpected, said Dr. Zarifkar. “I would have expected a small increase, but the extent of the increase was quite surprising.”
However, there was no difference when comparing the COVID-19 group with the influenza or bacterial pneumonia groups, which Dr. Zarifkar said was “very reassuring.”
The findings were similar for Parkinson’s disease, where there was a 2.2-fold increased risk of a Parkinson’s disease diagnosis within the first 12 months in COVID-positive individuals, compared with COVID-negative people (RR, 2.2; 95% CI, 1.5-3.4). Again, there was no excess risk, compared with influenza or bacterial pneumonia.
Potential mechanisms
Dr. Zarifkar believes a “constellation” of factors may explain higher risks of these diagnoses in COVID patients. Part of it could be a result of neuroinflammation, which can lead to a toxic accumulation of beta amyloid in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease.
“It can accelerate a neurodegenerative disease already in the making,” she said. But perhaps the biggest driver of differences between the groups is the “scientific focus” on COVID patients. “In Denmark, almost everyone who has had COVID-19, especially severe COVID-19, is offered some sort of cognitive testing, and if you hand out MoCAs [Montreal Cognitive Assessments] which is the cognitive test we use, to almost everyone you’re meeting, you’re going to catch these disorders earlier than you might have otherwise.”
As for cerebrovascular disorders, the study showed an increased risk of ischemic stroke in COVID-positive versus COVID-negative subjects at 12 months (RR, 2.87; 95% confidence interval, 2.2-3.2).
The relatively strong inflammatory response associated with COVID-19, which may create a hypercoagulable state, may help explain the increased ischemic stroke risk in COVID patients, said Dr. Zarifkar.
The study did not show an increased risk for subarachnoid hemorrhage in COVID-positive, compared with COVID-negative, subjects but did reveal an increased risk of intracerebral hemorrhage after 12 months (RR, 4.8; 95% CI, 1.8-12.9).
This could be explained by COVID-positive subjects having a higher risk for ischemic stroke and receiving thrombolysis that may increase risk for bleeding in the brain. However, an analysis accounting for medication use found differences in thrombolysis rates didn’t change the result, said Dr. Zarifkar.
It’s also possible that extracorporeal membrane oxygenation and mechanical ventilation – interventions more frequently used in COVID-19 patients – may increase the risk for bleeding in brain, she added.
The researchers did not find an increased risk for multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, or narcolepsy in COVID patients. However, Dr. Zarifkar noted that it can take years to detect an association with autoimmune disorders.
The investigators did not stratify risk by disease severity, although this would be an important step, she said. “The threshold of being admitted to the hospital with COVID-19 has been much lower than for influenza or bacterial pneumonia where you’re typically quite ill before you’re admitted, so this might actually dilute the findings and underestimate our findings.”
A national, registry-based study that includes the entire Danish population and additional information on vaccination status, virus variants, socioeconomic status, and comorbidities is needed, said Dr. Zarifkar.
The study was supported by Lundbeck Foundation and Novo Nordisk. Dr. Zarifkar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FRONTIERS IN NEUROLOGY
Study links sleep and objective, subjective cognition
CHARLOTTE, N.C. – , preliminary findings from a pilot study of objective and subjective cognitive measures have shown.
The pilot study underscored the important role of objective sleep measures to better understand discrepancies when patients’ own reports of everyday cognitive function don’t align with objective cognitive profiles, Amy Costa, MA, a graduate student in psychology at the University of Missouri-Columbia, said in reporting the results at the annual meeting of the Associated Professional Sleep Societies.
“Between our previously published paper and these new pilot results, we’re reporting evidence that suggests sleep is playing a role between the objective and subjective cognition relationship,” Ms. Costa said in an interview. “It is possible that these older adults who are sleeping poorly may be worse at understanding how well they’re doing cognitively. That’s really important for doctors. For example, if we can’t diagnose someone with mild cognitive impairment or Alzheimer’s disease or other types of dementia earlier, then we can’t intervene as quickly.”
Sleep efficiency, cognition, and patient complaints
These findings are in agreement with those Ms. Costa and colleagues recently published in the Journal of Clinical Sleep Medicine, she said.
The current pilot study included 35 older adults with an average age of 69 years who had insomnia complaints. They completed one night of home-based polysomnography – specifically with the Sleep Profiler PSG2TM – and a battery of cognitive tests. Their average sleep deficiency was 57%, “indicating potentially pretty severe insomnia,” Ms. Costa said.
“We found that sleep efficiency – that is the percentage of time spent sleeping while in bed – moderated the association between self reports and objective measures of cognitive distractibility,” Ms. Costa said in reporting the results. “In other words, our findings suggest that individuals with lower sleep efficiency who are performing the worst cognitively have the least amount of complaints. Basically, this can be thought of as that they are overestimating their cognitive performance.”
Sleep stage versus working memory and distractibility
The pilot study also focused on how the percentage of lighter-stage sleep, or N1 sleep, moderated the associations between working memory, as measured by Sternberg performance, and memory, distractibility, and blunders measured with the Cognitive Failures Questionnaire.
At the highest percentage of N1 sleep, worse working memory was associated with fewer complaints about memory, distractibility, and blunders, Ms. Costa said.
“The percentage of lighter-stage N1 sleep and sleep efficiency moderated the association between cognitive flexibility and distractibility,” Ms. Costa said. At the lowest percentage of N1 sleep, worse cognitive flexibility was associated with more distractibility, while at the highest percentage of N1 sleep worse cognitive flexibility showed a reverse effect; it was linked to less distractibility. The lowest percentage of sleep efficiency showed an association between worse cognitive flexibility and less distractibility, but the highest percentage of SE showed an association between worse cognitive flexibility and more distractibility.
“So in terms of evaluating their cognitive performance, the worse working memory was associated with more blunder complaints in individuals with the lowest percentage of N1,” she said. “So whenever individuals were spending less time in N1, they were able to better recognized their cognitive ability.”
She added, “Overall, more light and more fragmented sleep moderated the association between worse objective and less cognitive complaints, suggesting that these individuals might be overestimating their cognitive abilities.”
The findings indicate that evaluation of objective sleep should consider objectively measured N1 and sleep efficiency to better understand when subjective cognitive complaints and neurophysiological/objective cognitive profiles don’t align, she said.
Important indicators of cognitive deficits
“Specifically, for an older adult who comes into the clinic with complaints of waking up during the night, low sleep efficiency and more lighter-stage sleep might be really important indicators that they are probably not going to be the best at identifying their cognitive abilities or deficits,” she said.
Future directions for this research include collecting more data and looking at other sleep measures, such as using rapid-eye movement sleep, as potential moderators for the relationship between cognitive outcomes, evaluating sleep architecture more closely, and evaluating outcomes in a longitudinal study, Ms. Costa said.
The importance of objectively measured sleep
“Studies like this one using objectively measured sleep are important because much of the prior literature relied on self-reported sleep measures,” said Brendan P. Lucey, MD, associate professor of neurology and head of the sleep medicine section at Washington University School of Medicine in St. Louis. “This study suggests how objectively measured sleep may mediate discrepancies in objective/subjective cognitive dysfunction. Future studies need to work out if we need to add objective sleep measures when evaluating cognitive complaints in older adults.”
Dr. Lucey, who was not involved in the study, voiced one concern with the pilot study methodology the future research should address: the use of the Sleep Profiler PSG2TM to measure N1 sleep, which, as he noted, records a single-channel electroencephalogram over the forehead. “Scoring N1 sleep relies on attenuation of the alpha rhythm over the occipital region and the Sleep Profiler is not as accurate as in-lab polysomnography for this sleep stage,” he said.
The pilot study received funding from the American Academy of Sleep Medicine Foundation. Ms. Costa and her coauthors have no disclosures. Dr. Lucey disclosed relationships with Merck, Eli Lilly, Eisai, and Beacon Biosignals.
CHARLOTTE, N.C. – , preliminary findings from a pilot study of objective and subjective cognitive measures have shown.
The pilot study underscored the important role of objective sleep measures to better understand discrepancies when patients’ own reports of everyday cognitive function don’t align with objective cognitive profiles, Amy Costa, MA, a graduate student in psychology at the University of Missouri-Columbia, said in reporting the results at the annual meeting of the Associated Professional Sleep Societies.
“Between our previously published paper and these new pilot results, we’re reporting evidence that suggests sleep is playing a role between the objective and subjective cognition relationship,” Ms. Costa said in an interview. “It is possible that these older adults who are sleeping poorly may be worse at understanding how well they’re doing cognitively. That’s really important for doctors. For example, if we can’t diagnose someone with mild cognitive impairment or Alzheimer’s disease or other types of dementia earlier, then we can’t intervene as quickly.”
Sleep efficiency, cognition, and patient complaints
These findings are in agreement with those Ms. Costa and colleagues recently published in the Journal of Clinical Sleep Medicine, she said.
The current pilot study included 35 older adults with an average age of 69 years who had insomnia complaints. They completed one night of home-based polysomnography – specifically with the Sleep Profiler PSG2TM – and a battery of cognitive tests. Their average sleep deficiency was 57%, “indicating potentially pretty severe insomnia,” Ms. Costa said.
“We found that sleep efficiency – that is the percentage of time spent sleeping while in bed – moderated the association between self reports and objective measures of cognitive distractibility,” Ms. Costa said in reporting the results. “In other words, our findings suggest that individuals with lower sleep efficiency who are performing the worst cognitively have the least amount of complaints. Basically, this can be thought of as that they are overestimating their cognitive performance.”
Sleep stage versus working memory and distractibility
The pilot study also focused on how the percentage of lighter-stage sleep, or N1 sleep, moderated the associations between working memory, as measured by Sternberg performance, and memory, distractibility, and blunders measured with the Cognitive Failures Questionnaire.
At the highest percentage of N1 sleep, worse working memory was associated with fewer complaints about memory, distractibility, and blunders, Ms. Costa said.
“The percentage of lighter-stage N1 sleep and sleep efficiency moderated the association between cognitive flexibility and distractibility,” Ms. Costa said. At the lowest percentage of N1 sleep, worse cognitive flexibility was associated with more distractibility, while at the highest percentage of N1 sleep worse cognitive flexibility showed a reverse effect; it was linked to less distractibility. The lowest percentage of sleep efficiency showed an association between worse cognitive flexibility and less distractibility, but the highest percentage of SE showed an association between worse cognitive flexibility and more distractibility.
“So in terms of evaluating their cognitive performance, the worse working memory was associated with more blunder complaints in individuals with the lowest percentage of N1,” she said. “So whenever individuals were spending less time in N1, they were able to better recognized their cognitive ability.”
She added, “Overall, more light and more fragmented sleep moderated the association between worse objective and less cognitive complaints, suggesting that these individuals might be overestimating their cognitive abilities.”
The findings indicate that evaluation of objective sleep should consider objectively measured N1 and sleep efficiency to better understand when subjective cognitive complaints and neurophysiological/objective cognitive profiles don’t align, she said.
Important indicators of cognitive deficits
“Specifically, for an older adult who comes into the clinic with complaints of waking up during the night, low sleep efficiency and more lighter-stage sleep might be really important indicators that they are probably not going to be the best at identifying their cognitive abilities or deficits,” she said.
Future directions for this research include collecting more data and looking at other sleep measures, such as using rapid-eye movement sleep, as potential moderators for the relationship between cognitive outcomes, evaluating sleep architecture more closely, and evaluating outcomes in a longitudinal study, Ms. Costa said.
The importance of objectively measured sleep
“Studies like this one using objectively measured sleep are important because much of the prior literature relied on self-reported sleep measures,” said Brendan P. Lucey, MD, associate professor of neurology and head of the sleep medicine section at Washington University School of Medicine in St. Louis. “This study suggests how objectively measured sleep may mediate discrepancies in objective/subjective cognitive dysfunction. Future studies need to work out if we need to add objective sleep measures when evaluating cognitive complaints in older adults.”
Dr. Lucey, who was not involved in the study, voiced one concern with the pilot study methodology the future research should address: the use of the Sleep Profiler PSG2TM to measure N1 sleep, which, as he noted, records a single-channel electroencephalogram over the forehead. “Scoring N1 sleep relies on attenuation of the alpha rhythm over the occipital region and the Sleep Profiler is not as accurate as in-lab polysomnography for this sleep stage,” he said.
The pilot study received funding from the American Academy of Sleep Medicine Foundation. Ms. Costa and her coauthors have no disclosures. Dr. Lucey disclosed relationships with Merck, Eli Lilly, Eisai, and Beacon Biosignals.
CHARLOTTE, N.C. – , preliminary findings from a pilot study of objective and subjective cognitive measures have shown.
The pilot study underscored the important role of objective sleep measures to better understand discrepancies when patients’ own reports of everyday cognitive function don’t align with objective cognitive profiles, Amy Costa, MA, a graduate student in psychology at the University of Missouri-Columbia, said in reporting the results at the annual meeting of the Associated Professional Sleep Societies.
“Between our previously published paper and these new pilot results, we’re reporting evidence that suggests sleep is playing a role between the objective and subjective cognition relationship,” Ms. Costa said in an interview. “It is possible that these older adults who are sleeping poorly may be worse at understanding how well they’re doing cognitively. That’s really important for doctors. For example, if we can’t diagnose someone with mild cognitive impairment or Alzheimer’s disease or other types of dementia earlier, then we can’t intervene as quickly.”
Sleep efficiency, cognition, and patient complaints
These findings are in agreement with those Ms. Costa and colleagues recently published in the Journal of Clinical Sleep Medicine, she said.
The current pilot study included 35 older adults with an average age of 69 years who had insomnia complaints. They completed one night of home-based polysomnography – specifically with the Sleep Profiler PSG2TM – and a battery of cognitive tests. Their average sleep deficiency was 57%, “indicating potentially pretty severe insomnia,” Ms. Costa said.
“We found that sleep efficiency – that is the percentage of time spent sleeping while in bed – moderated the association between self reports and objective measures of cognitive distractibility,” Ms. Costa said in reporting the results. “In other words, our findings suggest that individuals with lower sleep efficiency who are performing the worst cognitively have the least amount of complaints. Basically, this can be thought of as that they are overestimating their cognitive performance.”
Sleep stage versus working memory and distractibility
The pilot study also focused on how the percentage of lighter-stage sleep, or N1 sleep, moderated the associations between working memory, as measured by Sternberg performance, and memory, distractibility, and blunders measured with the Cognitive Failures Questionnaire.
At the highest percentage of N1 sleep, worse working memory was associated with fewer complaints about memory, distractibility, and blunders, Ms. Costa said.
“The percentage of lighter-stage N1 sleep and sleep efficiency moderated the association between cognitive flexibility and distractibility,” Ms. Costa said. At the lowest percentage of N1 sleep, worse cognitive flexibility was associated with more distractibility, while at the highest percentage of N1 sleep worse cognitive flexibility showed a reverse effect; it was linked to less distractibility. The lowest percentage of sleep efficiency showed an association between worse cognitive flexibility and less distractibility, but the highest percentage of SE showed an association between worse cognitive flexibility and more distractibility.
“So in terms of evaluating their cognitive performance, the worse working memory was associated with more blunder complaints in individuals with the lowest percentage of N1,” she said. “So whenever individuals were spending less time in N1, they were able to better recognized their cognitive ability.”
She added, “Overall, more light and more fragmented sleep moderated the association between worse objective and less cognitive complaints, suggesting that these individuals might be overestimating their cognitive abilities.”
The findings indicate that evaluation of objective sleep should consider objectively measured N1 and sleep efficiency to better understand when subjective cognitive complaints and neurophysiological/objective cognitive profiles don’t align, she said.
Important indicators of cognitive deficits
“Specifically, for an older adult who comes into the clinic with complaints of waking up during the night, low sleep efficiency and more lighter-stage sleep might be really important indicators that they are probably not going to be the best at identifying their cognitive abilities or deficits,” she said.
Future directions for this research include collecting more data and looking at other sleep measures, such as using rapid-eye movement sleep, as potential moderators for the relationship between cognitive outcomes, evaluating sleep architecture more closely, and evaluating outcomes in a longitudinal study, Ms. Costa said.
The importance of objectively measured sleep
“Studies like this one using objectively measured sleep are important because much of the prior literature relied on self-reported sleep measures,” said Brendan P. Lucey, MD, associate professor of neurology and head of the sleep medicine section at Washington University School of Medicine in St. Louis. “This study suggests how objectively measured sleep may mediate discrepancies in objective/subjective cognitive dysfunction. Future studies need to work out if we need to add objective sleep measures when evaluating cognitive complaints in older adults.”
Dr. Lucey, who was not involved in the study, voiced one concern with the pilot study methodology the future research should address: the use of the Sleep Profiler PSG2TM to measure N1 sleep, which, as he noted, records a single-channel electroencephalogram over the forehead. “Scoring N1 sleep relies on attenuation of the alpha rhythm over the occipital region and the Sleep Profiler is not as accurate as in-lab polysomnography for this sleep stage,” he said.
The pilot study received funding from the American Academy of Sleep Medicine Foundation. Ms. Costa and her coauthors have no disclosures. Dr. Lucey disclosed relationships with Merck, Eli Lilly, Eisai, and Beacon Biosignals.
AT SLEEP 2022
FDA panel rejects pimavanserin for Alzheimer’s psychosis
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
Updates in aspirin use, aducanumab, and CKD diagnostic criteria in geriatric medicine
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
Disappointing results for investigational Alzheimer’s drug
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
Long-term erratic sleep may foretell cognitive problems
CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.
“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.
The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.
The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.
The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.
Dr. Keil said the model found, as expected, that the demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).
Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).
Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.
What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.
Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
A newer approach
By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”
Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.
Dr. Keil and Dr. Dzierzewski have no relevant disclosures.
CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.
“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.
The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.
The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.
The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.
Dr. Keil said the model found, as expected, that the demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).
Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).
Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.
What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.
Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
A newer approach
By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”
Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.
Dr. Keil and Dr. Dzierzewski have no relevant disclosures.
CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.
“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.
The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.
The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.
The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.
Dr. Keil said the model found, as expected, that the demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).
Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).
Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.
What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.
Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
A newer approach
By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”
Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.
Dr. Keil and Dr. Dzierzewski have no relevant disclosures.
AT SLEEP 2022
Surprising link between herpes zoster and dementia
Herpes zoster does not appear to increase dementia risk – on the contrary, the viral infection may offer some protection, a large population-based study suggests.
“We were surprised by these results [and] the reasons for the decreased risk are unclear,” study author Sigrun Alba Johannesdottir Schmidt, MD, PhD, with Aarhus (Denmark) University Hospital, said in a news release.
The study was published online in Neurology.
Conflicting findings
Herpes zoster (HZ) is an acute, cutaneous viral infection caused by the reactivation of varicella-zoster virus (VZV). Previous population-based studies have reported both decreased and increased risks of dementia after having HZ.
It’s thought that HZ may contribute to the development of dementia through neuroinflammation, cerebral vasculopathy, or direct neural damage, but epidemiologic evidence is limited.
To investigate further, Dr. Schmidt and colleagues used Danish medical registries to identify 247,305 people who had visited a hospital for HZ or were prescribed antiviral medication for HZ over a 20-year period and matched them to 1,235,890 people who did not have HZ. For both cohorts, the median age was 64 years, and 61% were women.
Dementia was diagnosed in 9.7% of zoster patients and 10.3% of matched control persons during up to 21 years of follow-up.
Contrary to the researchers’ expectation, HZ was associated with a small (7%) decreased relative risk of all-cause dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.90-0.95).
There was no increased long-term risk of dementia in subgroup analyses, except possibly among those with HZ that involved the central nervous system (HR, 1.94; 95% CI, 0.78-4.80), which has been shown before.
However, the population attributable fraction of dementia caused by this rare complication is low (< 1%), suggesting that universal vaccination against VZV in the elderly has limited potential to reduce dementia risk, the investigators noted.
Nonetheless, Dr. Schmidt said shingles vaccination should be encouraged in older people because it can prevent complications from the disease.
The research team admitted that the slightly decreased long-term risk of dementia, including Alzheimer’s disease, was “unexpected.” The reasons for this decreased risk are unclear, they say, and could be explained by missed diagnoses of shingles in people with undiagnosed dementia.
They were not able to examine whether antiviral treatment modifies the association between HZ and dementia and said that this topic merits further research.
The study was supported by the Edel and Wilhelm Daubenmerkls Charitable Foundation. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Herpes zoster does not appear to increase dementia risk – on the contrary, the viral infection may offer some protection, a large population-based study suggests.
“We were surprised by these results [and] the reasons for the decreased risk are unclear,” study author Sigrun Alba Johannesdottir Schmidt, MD, PhD, with Aarhus (Denmark) University Hospital, said in a news release.
The study was published online in Neurology.
Conflicting findings
Herpes zoster (HZ) is an acute, cutaneous viral infection caused by the reactivation of varicella-zoster virus (VZV). Previous population-based studies have reported both decreased and increased risks of dementia after having HZ.
It’s thought that HZ may contribute to the development of dementia through neuroinflammation, cerebral vasculopathy, or direct neural damage, but epidemiologic evidence is limited.
To investigate further, Dr. Schmidt and colleagues used Danish medical registries to identify 247,305 people who had visited a hospital for HZ or were prescribed antiviral medication for HZ over a 20-year period and matched them to 1,235,890 people who did not have HZ. For both cohorts, the median age was 64 years, and 61% were women.
Dementia was diagnosed in 9.7% of zoster patients and 10.3% of matched control persons during up to 21 years of follow-up.
Contrary to the researchers’ expectation, HZ was associated with a small (7%) decreased relative risk of all-cause dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.90-0.95).
There was no increased long-term risk of dementia in subgroup analyses, except possibly among those with HZ that involved the central nervous system (HR, 1.94; 95% CI, 0.78-4.80), which has been shown before.
However, the population attributable fraction of dementia caused by this rare complication is low (< 1%), suggesting that universal vaccination against VZV in the elderly has limited potential to reduce dementia risk, the investigators noted.
Nonetheless, Dr. Schmidt said shingles vaccination should be encouraged in older people because it can prevent complications from the disease.
The research team admitted that the slightly decreased long-term risk of dementia, including Alzheimer’s disease, was “unexpected.” The reasons for this decreased risk are unclear, they say, and could be explained by missed diagnoses of shingles in people with undiagnosed dementia.
They were not able to examine whether antiviral treatment modifies the association between HZ and dementia and said that this topic merits further research.
The study was supported by the Edel and Wilhelm Daubenmerkls Charitable Foundation. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Herpes zoster does not appear to increase dementia risk – on the contrary, the viral infection may offer some protection, a large population-based study suggests.
“We were surprised by these results [and] the reasons for the decreased risk are unclear,” study author Sigrun Alba Johannesdottir Schmidt, MD, PhD, with Aarhus (Denmark) University Hospital, said in a news release.
The study was published online in Neurology.
Conflicting findings
Herpes zoster (HZ) is an acute, cutaneous viral infection caused by the reactivation of varicella-zoster virus (VZV). Previous population-based studies have reported both decreased and increased risks of dementia after having HZ.
It’s thought that HZ may contribute to the development of dementia through neuroinflammation, cerebral vasculopathy, or direct neural damage, but epidemiologic evidence is limited.
To investigate further, Dr. Schmidt and colleagues used Danish medical registries to identify 247,305 people who had visited a hospital for HZ or were prescribed antiviral medication for HZ over a 20-year period and matched them to 1,235,890 people who did not have HZ. For both cohorts, the median age was 64 years, and 61% were women.
Dementia was diagnosed in 9.7% of zoster patients and 10.3% of matched control persons during up to 21 years of follow-up.
Contrary to the researchers’ expectation, HZ was associated with a small (7%) decreased relative risk of all-cause dementia during follow-up (hazard ratio, 0.93; 95% confidence interval, 0.90-0.95).
There was no increased long-term risk of dementia in subgroup analyses, except possibly among those with HZ that involved the central nervous system (HR, 1.94; 95% CI, 0.78-4.80), which has been shown before.
However, the population attributable fraction of dementia caused by this rare complication is low (< 1%), suggesting that universal vaccination against VZV in the elderly has limited potential to reduce dementia risk, the investigators noted.
Nonetheless, Dr. Schmidt said shingles vaccination should be encouraged in older people because it can prevent complications from the disease.
The research team admitted that the slightly decreased long-term risk of dementia, including Alzheimer’s disease, was “unexpected.” The reasons for this decreased risk are unclear, they say, and could be explained by missed diagnoses of shingles in people with undiagnosed dementia.
They were not able to examine whether antiviral treatment modifies the association between HZ and dementia and said that this topic merits further research.
The study was supported by the Edel and Wilhelm Daubenmerkls Charitable Foundation. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.