Alzheimer's Association International Conference 2012 (AAIC)

VANCOUVER, B.C. – Certain patterns of alcohol consumption appear detrimental to older adults’ cognitive health, according to a pair of longitudinal cohort studies.

In a study of older women, moderate drinking at a mean age of 81 years and initiation of drinking after a mean age of 68 years increased the odds of cognitive impairment. In a study of older men and women, those consuming large amounts of alcohol in a single sitting, so-called binge drinking, were more likely to be in the top decile of cognitive decline over time.

©Yuri_Arcurs/iStockphoto.com

These new findings call into question what constitutes risky drinking in older adults and conventional practices of risk assessment, investigators reported at the Alzheimer’s Association International Conference 2012.

Drinking Patterns in Older Women

A team led by Tina D. Hoang, M.S.P.H., of the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, analyzed data from 1,306 community-dwelling, dementia-free women aged 65 years or older from the Study of Osteoporotic Fractures.

Research has suggested a J-shaped association between alcohol intake and dementia risk, whereby moderate alcohol intake is protective, she noted. However, "in most of the studies for dementia that are prospective, the follow-up time is between 5 and 6 years, and in terms of assessment of alcohol use, it’s primarily at baseline, focusing on midlife and early late-life stages of alcohol use. Few studies have really looked at patterns of use or changes in use over time."

The women studied had serial assessments of drinking over time and a cognitive evaluation at year 20, when they were, on average, 88 years old. At that time, 41% had cognitive impairment.

Adjusted analyses showed that women who, at baseline, reported drinking more in the past had 1.3-fold higher odds of developing cognitive impairment relative to their counterparts who had not changed their drinking habits up to that point.

With regard to current drinking, light and moderate drinkers had nonsignificantly reduced odds of cognitive impairment relative to nondrinkers at mean ages of 68 and 75 years. But moderate drinkers at a mean age of 81 years had 1.6-fold higher odds of cognitive impairment as same-aged nondrinkers.

Finally, with respect to patterns of use over the first 16 years of follow-up, women who started drinking during this time had threefold higher odds of cognitive impairment than did their counterparts who were consistently nondrinkers.

"It may be that alcohol use has different effects throughout the life course," Ms. Hoang commented. "As adults age, they may be taking more medications, and it may be ... there are interactions of alcohol with those medications."

Alternately, there may be interactions with apolipoprotein e (APOE) genotype, not assessed in the study, or the brains of the oldest old adults may be more vulnerable to the effects of alcohol. Finally, changing patterns of use over time may just be indicators of events such as illness, which themselves might increase risk of cognitive impairment.

"The American Geriatric Society recommends screening older adults for at-risk drinking, defined as drinking greater than one drink per day for older adults," Ms. Hoang noted. "We think that our findings suggest that it may be important to not just screen older adults for at-risk drinking or alcohol abuse, but also to look at history of past use and changes in use that may be associated with cognitive impairment.

"We think our findings also indicate that moderate use may not be protective in the oldest old, and it just shows the need for more life-course research so we can understand the effects of moderate alcohol use at different stages of life," she concluded.

Binge Drinking in Older Men and Women

A team led by Iain A. Lang, Ph.D., of Peninsula College of Medicine and Dentistry in Exeter, Devon, England, studied binge drinking among 5,075 U.S. community-dwelling men and women aged 65 years or older from the Health and Retirement Study.

Research on alcohol consumption and cognitive decline has generally not included many heavy drinkers, he pointed out. "I think this is because of what may be a recurring problem in studies of this type, that people who are heavy drinkers either don’t participate in cohort studies or else misrepresent their drinking levels."

Cognitive well-being was assessed in the older adults over an 8-year period with the Telephone Interview for Cognitive Status (TICS) total score and memory component.

Results showed that at baseline, 4.3% of the participants binge drank (consumed at least four drinks on a single occasion) at least once monthly, and 2% did so at least twice monthly.

In multivariate analyses, the older adults binge drinking at least once monthly had 1.62-fold higher odds of being in the top 10% of cognitive decline, and those binge drinking at least twice monthly had 2.47-fold higher odds. Additionally, the latter had 2.49-fold higher odds of being in the top 10% of memory decline.

"The findings are fairly robust, and I think that the main implication is that older adults should be aware that heavy episodic drinking is associated with an increased risk of cognitive decline," Dr. Lang said. The J-shaped risk curve whereby moderate drinking is protective may well exist, but previous studies have overlooked the pattern of drinking that people engage in, he said.

He proposed that there may well be a big difference between consuming seven drinks on one occasion, versus a single drink a day for seven days – even though people are often simply asked how much they drink in a week.

"Older adults and their care providers and others should be aware that these drinking patterns are important," he said, adding that physicians who are concerned about their patients’ alcohol drinking "ought to be aware that it’s the pattern of drinking and not just the total amount that’s of consequence here."

Additionally, "I think it’s quite important that we don’t consider binge drinking simply to be a problem of younger adults, which is often what we see," maintained Dr. Lang. "A lot of the media attention and research attention is focused on adolescents, college students, and younger adults in whom binge drinking is more common. We need to be aware that binge drinking goes on and is a health problem in older adults as well."

Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – Certain patterns of alcohol consumption appear detrimental to older adults’ cognitive health, according to a pair of longitudinal cohort studies.

In a study of older women, moderate drinking at a mean age of 81 years and initiation of drinking after a mean age of 68 years increased the odds of cognitive impairment. In a study of older men and women, those consuming large amounts of alcohol in a single sitting, so-called binge drinking, were more likely to be in the top decile of cognitive decline over time.

©Yuri_Arcurs/iStockphoto.com

These new findings call into question what constitutes risky drinking in older adults and conventional practices of risk assessment, investigators reported at the Alzheimer’s Association International Conference 2012.

Drinking Patterns in Older Women

A team led by Tina D. Hoang, M.S.P.H., of the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, analyzed data from 1,306 community-dwelling, dementia-free women aged 65 years or older from the Study of Osteoporotic Fractures.

Research has suggested a J-shaped association between alcohol intake and dementia risk, whereby moderate alcohol intake is protective, she noted. However, "in most of the studies for dementia that are prospective, the follow-up time is between 5 and 6 years, and in terms of assessment of alcohol use, it’s primarily at baseline, focusing on midlife and early late-life stages of alcohol use. Few studies have really looked at patterns of use or changes in use over time."

The women studied had serial assessments of drinking over time and a cognitive evaluation at year 20, when they were, on average, 88 years old. At that time, 41% had cognitive impairment.

Adjusted analyses showed that women who, at baseline, reported drinking more in the past had 1.3-fold higher odds of developing cognitive impairment relative to their counterparts who had not changed their drinking habits up to that point.

With regard to current drinking, light and moderate drinkers had nonsignificantly reduced odds of cognitive impairment relative to nondrinkers at mean ages of 68 and 75 years. But moderate drinkers at a mean age of 81 years had 1.6-fold higher odds of cognitive impairment as same-aged nondrinkers.

Finally, with respect to patterns of use over the first 16 years of follow-up, women who started drinking during this time had threefold higher odds of cognitive impairment than did their counterparts who were consistently nondrinkers.

"It may be that alcohol use has different effects throughout the life course," Ms. Hoang commented. "As adults age, they may be taking more medications, and it may be ... there are interactions of alcohol with those medications."

Alternately, there may be interactions with apolipoprotein e (APOE) genotype, not assessed in the study, or the brains of the oldest old adults may be more vulnerable to the effects of alcohol. Finally, changing patterns of use over time may just be indicators of events such as illness, which themselves might increase risk of cognitive impairment.

"The American Geriatric Society recommends screening older adults for at-risk drinking, defined as drinking greater than one drink per day for older adults," Ms. Hoang noted. "We think that our findings suggest that it may be important to not just screen older adults for at-risk drinking or alcohol abuse, but also to look at history of past use and changes in use that may be associated with cognitive impairment.

"We think our findings also indicate that moderate use may not be protective in the oldest old, and it just shows the need for more life-course research so we can understand the effects of moderate alcohol use at different stages of life," she concluded.

Binge Drinking in Older Men and Women

A team led by Iain A. Lang, Ph.D., of Peninsula College of Medicine and Dentistry in Exeter, Devon, England, studied binge drinking among 5,075 U.S. community-dwelling men and women aged 65 years or older from the Health and Retirement Study.

Research on alcohol consumption and cognitive decline has generally not included many heavy drinkers, he pointed out. "I think this is because of what may be a recurring problem in studies of this type, that people who are heavy drinkers either don’t participate in cohort studies or else misrepresent their drinking levels."

Cognitive well-being was assessed in the older adults over an 8-year period with the Telephone Interview for Cognitive Status (TICS) total score and memory component.

Results showed that at baseline, 4.3% of the participants binge drank (consumed at least four drinks on a single occasion) at least once monthly, and 2% did so at least twice monthly.

In multivariate analyses, the older adults binge drinking at least once monthly had 1.62-fold higher odds of being in the top 10% of cognitive decline, and those binge drinking at least twice monthly had 2.47-fold higher odds. Additionally, the latter had 2.49-fold higher odds of being in the top 10% of memory decline.

"The findings are fairly robust, and I think that the main implication is that older adults should be aware that heavy episodic drinking is associated with an increased risk of cognitive decline," Dr. Lang said. The J-shaped risk curve whereby moderate drinking is protective may well exist, but previous studies have overlooked the pattern of drinking that people engage in, he said.

He proposed that there may well be a big difference between consuming seven drinks on one occasion, versus a single drink a day for seven days – even though people are often simply asked how much they drink in a week.

"Older adults and their care providers and others should be aware that these drinking patterns are important," he said, adding that physicians who are concerned about their patients’ alcohol drinking "ought to be aware that it’s the pattern of drinking and not just the total amount that’s of consequence here."

Additionally, "I think it’s quite important that we don’t consider binge drinking simply to be a problem of younger adults, which is often what we see," maintained Dr. Lang. "A lot of the media attention and research attention is focused on adolescents, college students, and younger adults in whom binge drinking is more common. We need to be aware that binge drinking goes on and is a health problem in older adults as well."

Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – Certain patterns of alcohol consumption appear detrimental to older adults’ cognitive health, according to a pair of longitudinal cohort studies.

In a study of older women, moderate drinking at a mean age of 81 years and initiation of drinking after a mean age of 68 years increased the odds of cognitive impairment. In a study of older men and women, those consuming large amounts of alcohol in a single sitting, so-called binge drinking, were more likely to be in the top decile of cognitive decline over time.

©Yuri_Arcurs/iStockphoto.com

These new findings call into question what constitutes risky drinking in older adults and conventional practices of risk assessment, investigators reported at the Alzheimer’s Association International Conference 2012.

Drinking Patterns in Older Women

A team led by Tina D. Hoang, M.S.P.H., of the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, analyzed data from 1,306 community-dwelling, dementia-free women aged 65 years or older from the Study of Osteoporotic Fractures.

Research has suggested a J-shaped association between alcohol intake and dementia risk, whereby moderate alcohol intake is protective, she noted. However, "in most of the studies for dementia that are prospective, the follow-up time is between 5 and 6 years, and in terms of assessment of alcohol use, it’s primarily at baseline, focusing on midlife and early late-life stages of alcohol use. Few studies have really looked at patterns of use or changes in use over time."

The women studied had serial assessments of drinking over time and a cognitive evaluation at year 20, when they were, on average, 88 years old. At that time, 41% had cognitive impairment.

Adjusted analyses showed that women who, at baseline, reported drinking more in the past had 1.3-fold higher odds of developing cognitive impairment relative to their counterparts who had not changed their drinking habits up to that point.

With regard to current drinking, light and moderate drinkers had nonsignificantly reduced odds of cognitive impairment relative to nondrinkers at mean ages of 68 and 75 years. But moderate drinkers at a mean age of 81 years had 1.6-fold higher odds of cognitive impairment as same-aged nondrinkers.

Finally, with respect to patterns of use over the first 16 years of follow-up, women who started drinking during this time had threefold higher odds of cognitive impairment than did their counterparts who were consistently nondrinkers.

"It may be that alcohol use has different effects throughout the life course," Ms. Hoang commented. "As adults age, they may be taking more medications, and it may be ... there are interactions of alcohol with those medications."

Alternately, there may be interactions with apolipoprotein e (APOE) genotype, not assessed in the study, or the brains of the oldest old adults may be more vulnerable to the effects of alcohol. Finally, changing patterns of use over time may just be indicators of events such as illness, which themselves might increase risk of cognitive impairment.

"The American Geriatric Society recommends screening older adults for at-risk drinking, defined as drinking greater than one drink per day for older adults," Ms. Hoang noted. "We think that our findings suggest that it may be important to not just screen older adults for at-risk drinking or alcohol abuse, but also to look at history of past use and changes in use that may be associated with cognitive impairment.

"We think our findings also indicate that moderate use may not be protective in the oldest old, and it just shows the need for more life-course research so we can understand the effects of moderate alcohol use at different stages of life," she concluded.

Binge Drinking in Older Men and Women

A team led by Iain A. Lang, Ph.D., of Peninsula College of Medicine and Dentistry in Exeter, Devon, England, studied binge drinking among 5,075 U.S. community-dwelling men and women aged 65 years or older from the Health and Retirement Study.

Research on alcohol consumption and cognitive decline has generally not included many heavy drinkers, he pointed out. "I think this is because of what may be a recurring problem in studies of this type, that people who are heavy drinkers either don’t participate in cohort studies or else misrepresent their drinking levels."

Cognitive well-being was assessed in the older adults over an 8-year period with the Telephone Interview for Cognitive Status (TICS) total score and memory component.

Results showed that at baseline, 4.3% of the participants binge drank (consumed at least four drinks on a single occasion) at least once monthly, and 2% did so at least twice monthly.

In multivariate analyses, the older adults binge drinking at least once monthly had 1.62-fold higher odds of being in the top 10% of cognitive decline, and those binge drinking at least twice monthly had 2.47-fold higher odds. Additionally, the latter had 2.49-fold higher odds of being in the top 10% of memory decline.

"The findings are fairly robust, and I think that the main implication is that older adults should be aware that heavy episodic drinking is associated with an increased risk of cognitive decline," Dr. Lang said. The J-shaped risk curve whereby moderate drinking is protective may well exist, but previous studies have overlooked the pattern of drinking that people engage in, he said.

He proposed that there may well be a big difference between consuming seven drinks on one occasion, versus a single drink a day for seven days – even though people are often simply asked how much they drink in a week.

"Older adults and their care providers and others should be aware that these drinking patterns are important," he said, adding that physicians who are concerned about their patients’ alcohol drinking "ought to be aware that it’s the pattern of drinking and not just the total amount that’s of consequence here."

Additionally, "I think it’s quite important that we don’t consider binge drinking simply to be a problem of younger adults, which is often what we see," maintained Dr. Lang. "A lot of the media attention and research attention is focused on adolescents, college students, and younger adults in whom binge drinking is more common. We need to be aware that binge drinking goes on and is a health problem in older adults as well."

Ms. Hoang disclosed no relevant conflicts of interest. Dr. Lang disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.

In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.

Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.

Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.

"Here, we show evidence that man can conquer nature," commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.

"The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk," she maintained.

"As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance," she added.

The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. "What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives," said Dr. Lipton of Albert Einstein College of Medicine, New York.

And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset "seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented." He speculated that "this might have been due to age being such a dominant factor."

Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.

After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.

In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).

In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.

In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.

Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).

Dr. Xu disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.

In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.

Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.

Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.

"Here, we show evidence that man can conquer nature," commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.

"The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk," she maintained.

"As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance," she added.

The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. "What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives," said Dr. Lipton of Albert Einstein College of Medicine, New York.

And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset "seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented." He speculated that "this might have been due to age being such a dominant factor."

Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.

After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.

In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).

In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.

In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.

Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).

Dr. Xu disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – Potentially modifiable environmental factors protect against Alzheimer’s disease in older adults carrying the apolipoprotein E e4 allele, a major susceptibility gene for the late-onset form of the disease and also a risk factor for other types of dementia.

In a cohort study of 932 cognitively healthy people aged 75 years or older, those carrying the ApoE e4 allele had a higher risk of developing Alzheimer’s disease than did noncarriers during a 9-year follow-up, researchers reported at the Alzheimer’s Association International Conference 2012.

Carriers who had more education or a high level of leisure-time activities, and those who did not have any vascular risk factors, were roughly half as likely to develop the disease as other carriers.

Having all three protective factors largely offset the risk of carrying the e4 allele in terms of developing any type of dementia. Together, they delayed the onset of dementia by about 1.2 years.

"Here, we show evidence that man can conquer nature," commented first author Dr. Weili L. Xu, an epidemiologist and a postdoctoral researcher at the Aging Research Center of the Karolinska Institute, Stockholm, and Stockholm University.

"The risk effect of e4 on dementia may be attenuated by these potential protective factors. They seem to delay dementia onset in a way that e4 and non-e4 carriers have similar dementia-free survival time. Our study provides further evidence not only for the combined effect of genetic and environmental factors on dementia, but also the possibility that environmental factors may diminish genetic risk," she maintained.

"As 70% of dementia cases occur in elderly people aged 75-plus, gaining 1 year without dementia is of great importance," she added.

The findings could be interpreted differently, however, noted session attendee Dr. Richard B. Lipton. "What you said was that environmental factors can protect against the effect of genes, but the other way of looking at it is that environmental factors seem more important in genetically vulnerable subgroups, because the effect of education and low cardiovascular risk didn’t look very protective in the e4-negatives," said Dr. Lipton of Albert Einstein College of Medicine, New York.

And session cochair Dr. James Mortimer of the University of South Florida, Tampa, commented that the 1.2-year delay in dementia onset "seems very modest, actually. I’m quite surprised, given the reasonably large effect sizes you presented." He speculated that "this might have been due to age being such a dominant factor."

Dr. Xu and her colleagues studied participants in the Kungsholmen Project, a population-based prospective cohort study on aging and dementia. Analyses were based on adults from the community who were at least 75 years of age at baseline and had normal cognitive function. ApoE genotyping identified 28% as carriers of the e4 allele.

After 9 years of follow-up, 39% of carriers had developed dementia (predominantly Alzheimer’s disease), compared with 33% of noncarriers. Even among carriers who were homozygous for e4, only slightly more than half developed dementia, suggesting that other factors were at play, she noted.

In adjusted analysis, compared with noncarriers, carriers had an elevated risk of Alzheimer’s disease (hazard ratio [HR], 1.52) and of any dementia (HR, 1.39).

In analyses restricted to carriers, however, the risk of Alzheimer’s disease was lower for those having more vs. less than 8 years of education (HR, 0.55); having a high vs. low level of leisure-time activities, a composite of social, mental, and physical activities (HR, 0.49); and lacking all of five common vascular risk factors vs. having any (HR, 0.61). The findings were similar for any dementia.

In stratified analyses, the three factors were protective for any form of dementia among noncarriers but more so among carriers, Dr. Xu said.

Compared with carriers lacking all three protective factors, carriers having all three had a sharply reduced risk of any dementia (HR, 0.62) that was similar to that of noncarriers lacking all three protective factors (HR, 0.75).

Dr. Xu disclosed no relevant conflicts of interest.

VANCOUVER, B.C.  – Long-term coffee consumption may protect against dementia in the elderly, according to an Italian study presented at the Alzheimer’s Association International Conference 2012.

In the prospective population-based cohort study of adults aged 80 years or older, about three-fourths drank coffee, having started on average at the age of 19 years.

Among those who were dementia-free at baseline, coffee drinkers were 32% less likely to develop dementia over the next 5½ years, compared with their counterparts who had never consumed the beverage, reported lead investigator Ugo Lucca, M.Sc., head of the laboratory of geriatric neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milan.

Photo s-photo/iStockphoto.com

"Recent findings have suggested that coffee consumption may have neuroprotective effects," he noted. "Long-term caffeine consumption could, in fact, reduce amyloid beta production and aggregation through suppression of both beta- and gamma-secretase activities."

"What about reverse causality, with dementia causing a decrease in coffee consumption?" one attendee asked.

Mr. Lucca acknowledged that coffee consumption did indeed fall with increasing severity of dementia at baseline, but he also noted that 41% of participants with severe dementia still drank at least some. "The only explanation could be that, even in this population, drinking coffee is protective for survival," he said. "In a subpopulation of those with dementia, probably drinking coffee is not protective for survival."

The investigators studied 2,198 participants in the Monzino 80-Plus Study, conducted in the Varese province of Italy. Participants or relatives reported the number of cups of coffee consumed daily, in the past and at present.

Study participants were 90 years old and had 5 years of education, on average, and 73% were women. Their mean Mini-Mental State Examination score was 20.5.

Overall, about three-fourths of participants reported drinking coffee, with about one-third drinking two or more cups daily.

"Though the average daily coffee intake tends to decrease from midlife, coffee consumption remains common in the very old," Mr. Lucca observed. The average intake was 2.3 cups daily at the age of 50 years, but still 1.5 cups daily at the age of 87 years.

In the cross-sectional part of the study, the prevalence of dementia was about 51% among participants who drank less than one cup of coffee daily, 34% among those drinking one cup daily, and 23% among those drinking two or more cups daily, he reported.

In a multivariate analysis, participants who drank coffee were 29% less likely to have dementia (odds ratio, 0.71; P = .008).

In the longitudinal part of the study, the incidence of dementia over 5.5 years among the 1,097 participants who were free of dementia at baseline was significantly lower for coffee drinkers than for never-drinkers (P less than .0001), with a widening gap over time.

The incidence was 45% among participants drinking less than one cup of coffee daily, 31% among those drinking one cup daily, and 29% among those drinking two or more cups daily, Mr. Lucca reported.

In a multivariate analysis, compared with never-drinkers, coffee drinkers as a whole were about one-third less likely to develop dementia (hazard ratio [HR], 0.68; P = .006). The benefit was similar whether they consumed one cup daily (HR, 0.68; P = .01) or two or more cups daily (HR, 0.66; P = .02).

Mr. Lucca disclosed no conflicts of interest related to the research.

VANCOUVER, B.C.  – Long-term coffee consumption may protect against dementia in the elderly, according to an Italian study presented at the Alzheimer’s Association International Conference 2012.

In the prospective population-based cohort study of adults aged 80 years or older, about three-fourths drank coffee, having started on average at the age of 19 years.

Among those who were dementia-free at baseline, coffee drinkers were 32% less likely to develop dementia over the next 5½ years, compared with their counterparts who had never consumed the beverage, reported lead investigator Ugo Lucca, M.Sc., head of the laboratory of geriatric neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milan.

Photo s-photo/iStockphoto.com

"Recent findings have suggested that coffee consumption may have neuroprotective effects," he noted. "Long-term caffeine consumption could, in fact, reduce amyloid beta production and aggregation through suppression of both beta- and gamma-secretase activities."

"What about reverse causality, with dementia causing a decrease in coffee consumption?" one attendee asked.

Mr. Lucca acknowledged that coffee consumption did indeed fall with increasing severity of dementia at baseline, but he also noted that 41% of participants with severe dementia still drank at least some. "The only explanation could be that, even in this population, drinking coffee is protective for survival," he said. "In a subpopulation of those with dementia, probably drinking coffee is not protective for survival."

The investigators studied 2,198 participants in the Monzino 80-Plus Study, conducted in the Varese province of Italy. Participants or relatives reported the number of cups of coffee consumed daily, in the past and at present.

Study participants were 90 years old and had 5 years of education, on average, and 73% were women. Their mean Mini-Mental State Examination score was 20.5.

Overall, about three-fourths of participants reported drinking coffee, with about one-third drinking two or more cups daily.

"Though the average daily coffee intake tends to decrease from midlife, coffee consumption remains common in the very old," Mr. Lucca observed. The average intake was 2.3 cups daily at the age of 50 years, but still 1.5 cups daily at the age of 87 years.

In the cross-sectional part of the study, the prevalence of dementia was about 51% among participants who drank less than one cup of coffee daily, 34% among those drinking one cup daily, and 23% among those drinking two or more cups daily, he reported.

In a multivariate analysis, participants who drank coffee were 29% less likely to have dementia (odds ratio, 0.71; P = .008).

In the longitudinal part of the study, the incidence of dementia over 5.5 years among the 1,097 participants who were free of dementia at baseline was significantly lower for coffee drinkers than for never-drinkers (P less than .0001), with a widening gap over time.

The incidence was 45% among participants drinking less than one cup of coffee daily, 31% among those drinking one cup daily, and 29% among those drinking two or more cups daily, Mr. Lucca reported.

In a multivariate analysis, compared with never-drinkers, coffee drinkers as a whole were about one-third less likely to develop dementia (hazard ratio [HR], 0.68; P = .006). The benefit was similar whether they consumed one cup daily (HR, 0.68; P = .01) or two or more cups daily (HR, 0.66; P = .02).

Mr. Lucca disclosed no conflicts of interest related to the research.

VANCOUVER, B.C.  – Long-term coffee consumption may protect against dementia in the elderly, according to an Italian study presented at the Alzheimer’s Association International Conference 2012.

In the prospective population-based cohort study of adults aged 80 years or older, about three-fourths drank coffee, having started on average at the age of 19 years.

Among those who were dementia-free at baseline, coffee drinkers were 32% less likely to develop dementia over the next 5½ years, compared with their counterparts who had never consumed the beverage, reported lead investigator Ugo Lucca, M.Sc., head of the laboratory of geriatric neuropsychiatry at the Mario Negri Institute for Pharmacological Research in Milan.

Photo s-photo/iStockphoto.com

"Recent findings have suggested that coffee consumption may have neuroprotective effects," he noted. "Long-term caffeine consumption could, in fact, reduce amyloid beta production and aggregation through suppression of both beta- and gamma-secretase activities."

"What about reverse causality, with dementia causing a decrease in coffee consumption?" one attendee asked.

Mr. Lucca acknowledged that coffee consumption did indeed fall with increasing severity of dementia at baseline, but he also noted that 41% of participants with severe dementia still drank at least some. "The only explanation could be that, even in this population, drinking coffee is protective for survival," he said. "In a subpopulation of those with dementia, probably drinking coffee is not protective for survival."

The investigators studied 2,198 participants in the Monzino 80-Plus Study, conducted in the Varese province of Italy. Participants or relatives reported the number of cups of coffee consumed daily, in the past and at present.

Study participants were 90 years old and had 5 years of education, on average, and 73% were women. Their mean Mini-Mental State Examination score was 20.5.

Overall, about three-fourths of participants reported drinking coffee, with about one-third drinking two or more cups daily.

"Though the average daily coffee intake tends to decrease from midlife, coffee consumption remains common in the very old," Mr. Lucca observed. The average intake was 2.3 cups daily at the age of 50 years, but still 1.5 cups daily at the age of 87 years.

In the cross-sectional part of the study, the prevalence of dementia was about 51% among participants who drank less than one cup of coffee daily, 34% among those drinking one cup daily, and 23% among those drinking two or more cups daily, he reported.

In a multivariate analysis, participants who drank coffee were 29% less likely to have dementia (odds ratio, 0.71; P = .008).

In the longitudinal part of the study, the incidence of dementia over 5.5 years among the 1,097 participants who were free of dementia at baseline was significantly lower for coffee drinkers than for never-drinkers (P less than .0001), with a widening gap over time.

The incidence was 45% among participants drinking less than one cup of coffee daily, 31% among those drinking one cup daily, and 29% among those drinking two or more cups daily, Mr. Lucca reported.

In a multivariate analysis, compared with never-drinkers, coffee drinkers as a whole were about one-third less likely to develop dementia (hazard ratio [HR], 0.68; P = .006). The benefit was similar whether they consumed one cup daily (HR, 0.68; P = .01) or two or more cups daily (HR, 0.66; P = .02).

Mr. Lucca disclosed no conflicts of interest related to the research.

VANCOUVER, B.C. – The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.

So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. "Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers]."

The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. "One gets the sense that there are newer, better tests ... that might have picked up cross-sectionally the differences," said Dr. Howard Chertkow of McGill University in Montreal.

Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.

"The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. ... Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease," said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.

Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.

Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. "Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years," he said.

"Extrapolating from these group analyses," Dr. Caselli said, "neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like ... the lorazepam challenge," for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).

A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.

The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).

Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.

"Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills," Dr. Caselli commented.

In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.

Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.

Dr. Caselli disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.

So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. "Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers]."

The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. "One gets the sense that there are newer, better tests ... that might have picked up cross-sectionally the differences," said Dr. Howard Chertkow of McGill University in Montreal.

Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.

"The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. ... Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease," said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.

Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.

Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. "Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years," he said.

"Extrapolating from these group analyses," Dr. Caselli said, "neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like ... the lorazepam challenge," for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).

A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.

The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).

Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.

"Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills," Dr. Caselli commented.

In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.

Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.

Dr. Caselli disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – The first evidence of emerging Alzheimer’s disease surfaces at least 1 decade before the onset of the disorder, based on new neuropsychological data reported at the Alzheimer’s Association International Conference 2012.

So far, though, there is no single test or battery of tests that can be performed at baseline to predict preclinical Alzheimer’s disease, acknowledged lead investigator Dr. Richard J. Caselli. "Cross-sectional comparisons of the most sensitive longitudinal measures still fail to distinguish preclinical-stage Alzheimer’s [having epsilon 4 homozygotes] from normal [epsilon 4 noncarriers]."

The early diagnosis glass may still be half full, however. The study, designed over a decade ago, relied on conventional measures that are part of most clinical neuropsychological batteries. "One gets the sense that there are newer, better tests ... that might have picked up cross-sectionally the differences," said Dr. Howard Chertkow of McGill University in Montreal.

Yet, threads of data are coming together to make possible early diagnosis and potentially early intervention for slowing the progression of Alzheimer’s disease.

"The concept of preclinical Alzheimer’s disease has gotten a lot of traction in the past year or two, particularly with the advent of [cerebrospinal fluid] levels of biomarkers and amyloid antigen. ... Putting these pieces together – the imaging, the pathology, the cognition – we know that there is this entity now that has been recognized as preclinical Alzheimer’s disease," said Dr. Caselli of the Mayo Clinic in Scottsdale, Ariz.

Dr. Caselli reported longitudinal data from 813 cognitively healthy adults who underwent serial assessments every 1-2 years for an average of 8 years. Study participants underwent an extensive neuropsychological battery that tested memory, executive function, language, and visuospatial ability.

Participants who carried any copies of the apolipoprotein E (apo E) epsilon 4 allele, a risk factor for Alzheimer disease, had more rapid declines in performance on some tests of memory and were less proficient at learning new information than were participants who lacked the apolipoprotein E (apo E) epsilon 4 allele. "Preclinical Alzheimer’s begins in [epsilon 4] carriers on average in the 50s, with a clinical lag time of 10-15 years," he said.

"Extrapolating from these group analyses," Dr. Caselli said, "neuropsychological assessment of preclinical Alzheimer’s disease in individuals might be based upon either longitudinal memory performance (particularly verbal memory) or some form of cognitive stress test, like ... the lorazepam challenge," for which previous research has shown a greater impact of the drug on memory in epsilon 4 carriers (J. Clin. Psychiatry 2009;70:1379-84).

A first analysis of the continuing study included data from 680 cognitively healthy adults from the Arizona apo E cohort. Participants range in age from their 20s to their 80s. On average, they are 57 years old and have 16 years of education. Overall, 42% carry at least one epsilon 4 allele (30% heterozygous; 12% homozygous). The mean duration of follow-up was about 8 years.

The WCST (Wisconsin Card-Sorting Test), a test of executive function, showed a greater-than-1% annual decline in scores in those aged 50-70 years regardless of epsilon 4 carrier status. In tests of memory, allele carriers additionally had declines of at least 1% annually in scores on tests of memory, such as the AVLT (Auditory Verbal Learning Test) and the VRT (Visual Retention Test).

Noncarrier participants actually improved over time on some memory tests, showing a greater-than-1% annual improvement in scores as a result of learning from repeated test taking. One example was the SRT (Selective Reminding Test). Carriers, however, did not improve over time.

"Longitudinally, cognitive aging is most prominently reflected in executive skills, but preclinical Alzheimer’s disease is characterized most consistently by declining memory skills," Dr. Caselli commented.

In a second analysis, the investigators studied a combined cohort consisting of the Arizona apo E cohort plus an additional 133 initially cognitively healthy older adults from the Arizona Alzheimer’s Disease Center cohort.

Quadratic models comparing epsilon 4 carriers vs. noncarriers showed significantly accelerated decline for the former only in the tests of memory, according to Dr. Caselli. Additionally, there was a gene-dose effect for most of the memory tests.

Dr. Caselli disclosed no relevant conflicts of interest.

VANCOUVER, B.C. – Nonpharmacologic interventions bestow clinically meaningful benefits on patients with dementia, a literature review has concluded.

But these aren’t one-size-fits-all activities, Dr. Clive Ballard said at the Alzheimer’s Association International Conference. Different activities improve different problems, leading to the possibility of targeted treatment.

"Reminiscence improves depression but no other neuropsychiatric symptom. Social interaction and pleasant activities improve agitation but not mood," said Dr. Ballard, a professor of age-related diseases at King’s College London. "There is a substantial amount of data emerging that shows not only that these interventions are helpful, but that we can target them to specific symptoms."

Nonpharmacologic interventions have several benefits for patients who are living in an institutional setting: They produce results, they don’t come with the baggage of physical side effects, and – perhaps most importantly – they are simple.

"If you’re going to do something in a nursing home, it has to be easy and practical. If it’s not simple, you can’t implement it."

Dr. Ballard and his colleagues reviewed 56 studies of nondrug interventions designed to improve dementia care in nursing homes; 32 of these have been published since 2008, which he said is "very encouraging."

The studies varied widely in duration, from 1 to 24 weeks. The investigators grouped the interventions into broad categories: social interaction, exercise, personalized care, and person-centered care.

Twelve studies addressed the use of reminiscence. The studies included groups of up to 130 residents, and ran for a median of 7 weeks. "The results were encouraging, and the most consistent outcome was for depression," with the majority of residents showing a significant improvement in that measure, Dr. Ballard said.

"There is increasing controversy about the benefit of antidepressants in the context of dementia, so it’s especially encouraging that there are nondrug interventions" for depression, he said.

Five trials looked at engaging residents in pleasant activities; the median length of intervention was 3.5 weeks. "All four of the trials that looked at agitation as an outcome showed a significant benefit," Dr. Ballard said. "There was less clear-cut evidence of an effect in depression. One trial also reported an improvement in apathy."

Seven studies examined the benefits of exercise; the median study length was 16 weeks. "There was some evidence of improvement in depression, but it was marginal, with two showing a benefit and three not. None of the trials showed that any other neuropsychiatric condition improved." Residents who exercised did, however, show improvements in gait and mobility.

There were 10 studies on personalized music. The results were "not quite as consistent" as those of studies in which patients engaged in pleasant activities, but four of the seven that looked at agitation showed a significant benefit. There wasn’t any benefit for depression. "This one is a really simple thing to do – it can be used as a reminiscence tool or simply having someone sitting with patients and listening together to music the patient likes."

Two trials examined "person-centered care" – care that is individually tailored to the patient’s preferences and goals. These studies compared person-centered care to care as usual. One was a 4-month study of almost 300 patients. There were significant improvements in agitation, but no reduction in antipsychotic use. "The effect on quality of life was marginal," Dr. Ballard said.

The second was a 10-month intervention comparing six facilities that incorporated person-centered care and six having usual care. "These showed a halving in the use of antipsychotic drugs, with no worsening of symptoms. But neither was there an overall improvement in behavior," he said.

However, 42 patients in the active group, who were on antipsychotic drugs at baseline, showed significantly less social withdrawal as the study progressed, Dr. Ballard said. "Their social interaction, activity, and overall well-being significantly increased. It appeared that stopping the antipsychotics led to an improvement in their quality of life, but there was probably not a lot of improvement in those who were not on antipsychotics to start with."

It’s hard to tell why the programs improve behavior and well-being, but Dr. Ballard said one sad fact may hold an answer.

"We have done two studies of dementia care mapping, which involved about 1,000 patients in 30 homes. The residents were observed every 5 minutes over 6 hours of waking time, to ascertain the amount of time spent in social interactions with other residents or staff. It was a total of about 2 minutes. If someone’s life consists of sitting alone all day, with only 2 minutes of interacting with another human, no drug is going to sort that out."

Dr. Ballard disclosed financial relationships with numerous drug companies.

VANCOUVER, B.C. – Nonpharmacologic interventions bestow clinically meaningful benefits on patients with dementia, a literature review has concluded.

But these aren’t one-size-fits-all activities, Dr. Clive Ballard said at the Alzheimer’s Association International Conference. Different activities improve different problems, leading to the possibility of targeted treatment.

"Reminiscence improves depression but no other neuropsychiatric symptom. Social interaction and pleasant activities improve agitation but not mood," said Dr. Ballard, a professor of age-related diseases at King’s College London. "There is a substantial amount of data emerging that shows not only that these interventions are helpful, but that we can target them to specific symptoms."

Nonpharmacologic interventions have several benefits for patients who are living in an institutional setting: They produce results, they don’t come with the baggage of physical side effects, and – perhaps most importantly – they are simple.

"If you’re going to do something in a nursing home, it has to be easy and practical. If it’s not simple, you can’t implement it."

Dr. Ballard and his colleagues reviewed 56 studies of nondrug interventions designed to improve dementia care in nursing homes; 32 of these have been published since 2008, which he said is "very encouraging."

The studies varied widely in duration, from 1 to 24 weeks. The investigators grouped the interventions into broad categories: social interaction, exercise, personalized care, and person-centered care.

Twelve studies addressed the use of reminiscence. The studies included groups of up to 130 residents, and ran for a median of 7 weeks. "The results were encouraging, and the most consistent outcome was for depression," with the majority of residents showing a significant improvement in that measure, Dr. Ballard said.

"There is increasing controversy about the benefit of antidepressants in the context of dementia, so it’s especially encouraging that there are nondrug interventions" for depression, he said.

Five trials looked at engaging residents in pleasant activities; the median length of intervention was 3.5 weeks. "All four of the trials that looked at agitation as an outcome showed a significant benefit," Dr. Ballard said. "There was less clear-cut evidence of an effect in depression. One trial also reported an improvement in apathy."

Seven studies examined the benefits of exercise; the median study length was 16 weeks. "There was some evidence of improvement in depression, but it was marginal, with two showing a benefit and three not. None of the trials showed that any other neuropsychiatric condition improved." Residents who exercised did, however, show improvements in gait and mobility.

There were 10 studies on personalized music. The results were "not quite as consistent" as those of studies in which patients engaged in pleasant activities, but four of the seven that looked at agitation showed a significant benefit. There wasn’t any benefit for depression. "This one is a really simple thing to do – it can be used as a reminiscence tool or simply having someone sitting with patients and listening together to music the patient likes."

Two trials examined "person-centered care" – care that is individually tailored to the patient’s preferences and goals. These studies compared person-centered care to care as usual. One was a 4-month study of almost 300 patients. There were significant improvements in agitation, but no reduction in antipsychotic use. "The effect on quality of life was marginal," Dr. Ballard said.

The second was a 10-month intervention comparing six facilities that incorporated person-centered care and six having usual care. "These showed a halving in the use of antipsychotic drugs, with no worsening of symptoms. But neither was there an overall improvement in behavior," he said.

However, 42 patients in the active group, who were on antipsychotic drugs at baseline, showed significantly less social withdrawal as the study progressed, Dr. Ballard said. "Their social interaction, activity, and overall well-being significantly increased. It appeared that stopping the antipsychotics led to an improvement in their quality of life, but there was probably not a lot of improvement in those who were not on antipsychotics to start with."

It’s hard to tell why the programs improve behavior and well-being, but Dr. Ballard said one sad fact may hold an answer.

"We have done two studies of dementia care mapping, which involved about 1,000 patients in 30 homes. The residents were observed every 5 minutes over 6 hours of waking time, to ascertain the amount of time spent in social interactions with other residents or staff. It was a total of about 2 minutes. If someone’s life consists of sitting alone all day, with only 2 minutes of interacting with another human, no drug is going to sort that out."

Dr. Ballard disclosed financial relationships with numerous drug companies.

VANCOUVER, B.C. – Nonpharmacologic interventions bestow clinically meaningful benefits on patients with dementia, a literature review has concluded.

But these aren’t one-size-fits-all activities, Dr. Clive Ballard said at the Alzheimer’s Association International Conference. Different activities improve different problems, leading to the possibility of targeted treatment.

"Reminiscence improves depression but no other neuropsychiatric symptom. Social interaction and pleasant activities improve agitation but not mood," said Dr. Ballard, a professor of age-related diseases at King’s College London. "There is a substantial amount of data emerging that shows not only that these interventions are helpful, but that we can target them to specific symptoms."

Nonpharmacologic interventions have several benefits for patients who are living in an institutional setting: They produce results, they don’t come with the baggage of physical side effects, and – perhaps most importantly – they are simple.

"If you’re going to do something in a nursing home, it has to be easy and practical. If it’s not simple, you can’t implement it."

Dr. Ballard and his colleagues reviewed 56 studies of nondrug interventions designed to improve dementia care in nursing homes; 32 of these have been published since 2008, which he said is "very encouraging."

The studies varied widely in duration, from 1 to 24 weeks. The investigators grouped the interventions into broad categories: social interaction, exercise, personalized care, and person-centered care.

Twelve studies addressed the use of reminiscence. The studies included groups of up to 130 residents, and ran for a median of 7 weeks. "The results were encouraging, and the most consistent outcome was for depression," with the majority of residents showing a significant improvement in that measure, Dr. Ballard said.

"There is increasing controversy about the benefit of antidepressants in the context of dementia, so it’s especially encouraging that there are nondrug interventions" for depression, he said.

Five trials looked at engaging residents in pleasant activities; the median length of intervention was 3.5 weeks. "All four of the trials that looked at agitation as an outcome showed a significant benefit," Dr. Ballard said. "There was less clear-cut evidence of an effect in depression. One trial also reported an improvement in apathy."

Seven studies examined the benefits of exercise; the median study length was 16 weeks. "There was some evidence of improvement in depression, but it was marginal, with two showing a benefit and three not. None of the trials showed that any other neuropsychiatric condition improved." Residents who exercised did, however, show improvements in gait and mobility.

There were 10 studies on personalized music. The results were "not quite as consistent" as those of studies in which patients engaged in pleasant activities, but four of the seven that looked at agitation showed a significant benefit. There wasn’t any benefit for depression. "This one is a really simple thing to do – it can be used as a reminiscence tool or simply having someone sitting with patients and listening together to music the patient likes."

Two trials examined "person-centered care" – care that is individually tailored to the patient’s preferences and goals. These studies compared person-centered care to care as usual. One was a 4-month study of almost 300 patients. There were significant improvements in agitation, but no reduction in antipsychotic use. "The effect on quality of life was marginal," Dr. Ballard said.

The second was a 10-month intervention comparing six facilities that incorporated person-centered care and six having usual care. "These showed a halving in the use of antipsychotic drugs, with no worsening of symptoms. But neither was there an overall improvement in behavior," he said.

However, 42 patients in the active group, who were on antipsychotic drugs at baseline, showed significantly less social withdrawal as the study progressed, Dr. Ballard said. "Their social interaction, activity, and overall well-being significantly increased. It appeared that stopping the antipsychotics led to an improvement in their quality of life, but there was probably not a lot of improvement in those who were not on antipsychotics to start with."

It’s hard to tell why the programs improve behavior and well-being, but Dr. Ballard said one sad fact may hold an answer.

"We have done two studies of dementia care mapping, which involved about 1,000 patients in 30 homes. The residents were observed every 5 minutes over 6 hours of waking time, to ascertain the amount of time spent in social interactions with other residents or staff. It was a total of about 2 minutes. If someone’s life consists of sitting alone all day, with only 2 minutes of interacting with another human, no drug is going to sort that out."

Dr. Ballard disclosed financial relationships with numerous drug companies.

VANCOUVER, B.C.  – When Alzheimer’s disease patients who took risperidone for psychoses discontinued the drug, they were more than four times more likely to relapse than were those who continued treatment in a randomized, placebo-controlled trial.

The ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial suggests that at least some patients might benefit from a longer course of antipsychotic treatment, Dr. Davangere Devanand said at the Alzheimer’s Association International Conference 2012.

The ADAD trial began with a 16-week, open label phase in which 180 patients with dementia and psychotic symptoms or agitation and aggression received a flexible dose of risperidone. At the end of that period, 110 responders were randomized to one of three 32-week arms: continued risperidone treatment; placebo for 32 weeks; or risperidone for 16 weeks followed by 16 weeks of placebo.

The mean daily dose was small, at 0.97 mg. The primary outcome was relapse to psychotic symptoms. At the end of the run-in period, the average total Neuropsychiatric Inventory score had decreased from 36 to 9.

In the first half of the randomization period, 60% of those on placebo relapsed, compared with 33% of those who continued the drug (hazard ratio, 1.97).

The second 16-week period evaluated the change in those who switched from risperidone to placebo, compared with the continuation group. Relapse occurred in 48% of the switched patients, compared with 15% of those who continued risperidone (HR, 4.33)

"There were no significant interactions predicting who would relapse, even in the baseline measures of psychosis or cognition," said Dr. Devanand, codirector of the memory disorders center and codirector of the late life depression clinic at the New York State Psychiatric Institute, New York.

There were no significant between-group differences in adverse events, he said. There were three deaths in the run-in phase and three in the randomization phase (two on risperidone and one in placebo), but Dr. Devanand said that the sample size wasn’t large enough to draw any conclusions about mortality risks.

He pointed out several factors that could have affected the study’s outcome. "This is a discontinuation trial, so the sample was an enriched population," he said. "This might mean that relapse is more likely in patients who have previously responded to a drug."

Dr. Devanand disclosed financial relationships with Eli Lilly, Novartis, Bristol-Myers Squibb, and Sanofi Aventis. Janssen Pharmaceuticals supplied the risperidone used in the study but had no input in the data compilation. The study was supported by the National Institutes of Health and the National Institute on Aging.

VANCOUVER, B.C.  – When Alzheimer’s disease patients who took risperidone for psychoses discontinued the drug, they were more than four times more likely to relapse than were those who continued treatment in a randomized, placebo-controlled trial.

The ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial suggests that at least some patients might benefit from a longer course of antipsychotic treatment, Dr. Davangere Devanand said at the Alzheimer’s Association International Conference 2012.

The ADAD trial began with a 16-week, open label phase in which 180 patients with dementia and psychotic symptoms or agitation and aggression received a flexible dose of risperidone. At the end of that period, 110 responders were randomized to one of three 32-week arms: continued risperidone treatment; placebo for 32 weeks; or risperidone for 16 weeks followed by 16 weeks of placebo.

The mean daily dose was small, at 0.97 mg. The primary outcome was relapse to psychotic symptoms. At the end of the run-in period, the average total Neuropsychiatric Inventory score had decreased from 36 to 9.

In the first half of the randomization period, 60% of those on placebo relapsed, compared with 33% of those who continued the drug (hazard ratio, 1.97).

The second 16-week period evaluated the change in those who switched from risperidone to placebo, compared with the continuation group. Relapse occurred in 48% of the switched patients, compared with 15% of those who continued risperidone (HR, 4.33)

"There were no significant interactions predicting who would relapse, even in the baseline measures of psychosis or cognition," said Dr. Devanand, codirector of the memory disorders center and codirector of the late life depression clinic at the New York State Psychiatric Institute, New York.

There were no significant between-group differences in adverse events, he said. There were three deaths in the run-in phase and three in the randomization phase (two on risperidone and one in placebo), but Dr. Devanand said that the sample size wasn’t large enough to draw any conclusions about mortality risks.

He pointed out several factors that could have affected the study’s outcome. "This is a discontinuation trial, so the sample was an enriched population," he said. "This might mean that relapse is more likely in patients who have previously responded to a drug."

Dr. Devanand disclosed financial relationships with Eli Lilly, Novartis, Bristol-Myers Squibb, and Sanofi Aventis. Janssen Pharmaceuticals supplied the risperidone used in the study but had no input in the data compilation. The study was supported by the National Institutes of Health and the National Institute on Aging.

VANCOUVER, B.C.  – When Alzheimer’s disease patients who took risperidone for psychoses discontinued the drug, they were more than four times more likely to relapse than were those who continued treatment in a randomized, placebo-controlled trial.

The ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial suggests that at least some patients might benefit from a longer course of antipsychotic treatment, Dr. Davangere Devanand said at the Alzheimer’s Association International Conference 2012.

The ADAD trial began with a 16-week, open label phase in which 180 patients with dementia and psychotic symptoms or agitation and aggression received a flexible dose of risperidone. At the end of that period, 110 responders were randomized to one of three 32-week arms: continued risperidone treatment; placebo for 32 weeks; or risperidone for 16 weeks followed by 16 weeks of placebo.

The mean daily dose was small, at 0.97 mg. The primary outcome was relapse to psychotic symptoms. At the end of the run-in period, the average total Neuropsychiatric Inventory score had decreased from 36 to 9.

In the first half of the randomization period, 60% of those on placebo relapsed, compared with 33% of those who continued the drug (hazard ratio, 1.97).

The second 16-week period evaluated the change in those who switched from risperidone to placebo, compared with the continuation group. Relapse occurred in 48% of the switched patients, compared with 15% of those who continued risperidone (HR, 4.33)

"There were no significant interactions predicting who would relapse, even in the baseline measures of psychosis or cognition," said Dr. Devanand, codirector of the memory disorders center and codirector of the late life depression clinic at the New York State Psychiatric Institute, New York.

There were no significant between-group differences in adverse events, he said. There were three deaths in the run-in phase and three in the randomization phase (two on risperidone and one in placebo), but Dr. Devanand said that the sample size wasn’t large enough to draw any conclusions about mortality risks.

He pointed out several factors that could have affected the study’s outcome. "This is a discontinuation trial, so the sample was an enriched population," he said. "This might mean that relapse is more likely in patients who have previously responded to a drug."

Dr. Devanand disclosed financial relationships with Eli Lilly, Novartis, Bristol-Myers Squibb, and Sanofi Aventis. Janssen Pharmaceuticals supplied the risperidone used in the study but had no input in the data compilation. The study was supported by the National Institutes of Health and the National Institute on Aging.

VANCOUVER, B.C. – An investigational drug has shown promise in improving memory and cognition in patients with mild to moderate Alzheimer’s disease in a 6-month, randomized, placebo-controlled trial that was presented at the Alzheimer’s Association International Conference 2012.

The fact that the patients were still continuing to improve on statistically significant measurements of those aspects of the disease provided a hint, at least, that the drug EVP-6124, an alpha-7 nicotinic acetylcholine receptor partial agonist, could change the course of Alzheimer’s.

But it’s too soon to place any long-term bets, Dr. Dana Hilt said in an interview.

"This is being investigated as a procognitive and symptomatic drug," said Dr. Hilt, senior vice president of clinical development and chief medical officer of EnVivo Pharmaceuticals, which funded the trial. "It certainly appears to improve cognition in a clinically beneficial way at 6 months. But if the curves continue to diverge, is it possible that something more fundamental could be going on? Could this be maintained at 12 months? That’s what we need to know."

Dr. Paul S. Aisen, director of the Alzheimer's Disease Cooperative Study and a professor of neurosciences at the University of California, San Diego, said that EVP-6124’s phase II data looked very good.

"Reviewing the results, I would consider this to be a solidly positive trial," he said in an interview. "While we cannot rely on a relatively small phase II trial to accurately indicate the size of a treatment effect, the consistency of the findings here are encouraging. If efficacy is confirmed in additional trials, this may prove to be an important therapeutic option."

The study group comprised 409 patients who were randomized to one of three drug doses (0.3 mg, 1 mg, or 2 mg daily), or to placebo.

Half of the group were on stable doses of donepezil (Aricept) or rivastigmine (Exelon) and half were not taking any acetylcholinesterase inhibitor (AChEI), at least at the time of the trial, Dr. Hilt said. "Some of them had never taken an AChEI, and some had taken them in the past but were now off, for a number of reasons," including insurance coverage and lack of efficacy.

The subjects’ mean MMSE (Mini-Mental State Exam) at baseline score was 20, but the range was wide, from 12 to 29; the mean score on the CDR (Clinical Dementia Rating) scale was 6.

The primary end points were changes in the ADAS Cog-13 (Alzheimer’s Disease Assessment Scale Cognitive-13) and the CDR sum of boxes scores. Additional prespecified end points were the ADAS Cog-11 and composite measures of cognition and memory.

In each finding, Dr. Hilt noted effect size as well as statistical significance. Effect size is important in clinical trials because it suggests clinical efficacy better than statistical findings, he said in an interview.

"The effect size of approved drugs is somewhere around 0.15-0.28. In terms of clinical change, an effect size of 0.2 is something a trained clinician could detect. And effect size of 0.4 is something the next-door neighbor could detect."

During the first month of the study, the lower-dose groups and the placebo groups all improved their ADAS Cog-13 scores, a finding consistent with a placebo effect often seen in such studies. Interestingly, the 2-mg group remained at baseline for the first 4 months of the trial; after 4 months, cognition scores increased rapidly and outstripped all of the other groups. By the end of the study, the 2-mg group had a mean improvement of 1.5 points over baseline, whereas the placebo group had dropped below baseline, giving a total group separation of 2.2 points (P = .0189; effect size 0.39). This effect size is higher than the 0.28 estimated for high doses of donepezil, rivastigmine, or memantine (Namenda), Dr. Hilt said.

At the end of the treatment period, the curves were still diverging, suggesting that longer treatment might confer more benefit.

On the CDR sum of boxes, the 2-mg dose also performed significantly better than placebo. Again, there was the early upward trend for all groups, including placebo. But after 4 months, the placebo group and the active groups of 0.3 mg and 1 mg began losing those gains. The 2-mg group maintained its gain (P = .0253; effect size 0.31).

Findings on the secondary end points were similarly encouraging, although all were not statistically significant, Dr. Hilt said.

On the ADAS Cog-11, those taking the 2-mg dose faired significantly better than did those in any of the other groups. By the end of the study period, the lower-dose groups and placebo group had declined below baseline to the same degree. The 2-mg group had improved significantly and was still on an upward trend (P = .0151; effect size 0.34).

The ADCS-ADL (Alzheimer's Disease Cooperative Study Activities of Daily Living) scale showed the pattern of early improvement observed with other scales. The 2-mg group maintained its gains, but the between-group difference was not significant at the end of the study (P = .0925; effect size 0.20). Nor was there a significant 24-month difference in the MMSE (P = 0.0955; effect size 0.21).

A composite measure of cognition that included word recall on the ADAS-Cog, word recognition, word association, and orientation significantly favored the 2-mg group (P = .0037; effect size 0.42), as did a composite measure of memory (P = 0.0088; effect size 0.37).

Besides being richly distributed in the hippocampus and frontal cortex, alpha-7 nicotinic acetylcholine receptors are found in many other tissues, including the gut and skeletal muscles. A compound that attaches nonselectively could be loaded with adverse effects, including cardiovascular changes and unpleasant GI reactions. These adverse effects have proved difficult to overcome, and in fact are one reason that a number of nicotinic acetylcholine receptor studies have been discontinued.

"A number of companies tried to develop these, but at high dose levels that had indiscriminate stimulation of the receptors," Dr. Hilt said. "When you give a neurotransmitter to affect receptors in the brain, you have to live with the consequences of stimulating that receptor everywhere. The way we have dealt with this is to use a drug with a very long half-life, in very low concentrations."

The long half-life allows the drug to build up slowly, and keeps levels at a steady concentration without extreme peaks or nadirs. "It turns out this receptor is very finicky. Too high a level overstimulates it and too low a level doesn’t stimulate it at all. I’m convinced this is the major trouble with some of these other drugs."

Adverse events in the trial were mild gastrointestinal issues, including nausea and constipation. No patients of the active-drug study groups withdrew because of an adverse effect. The rate of adverse events in the 2-mg group also varied by baseline medication status, with more among those already taking an AChEI at baseline than among those not on the drugs (64% vs. 42%). Similar differences in adverse events rates occurred in the other treatment groups, although the rates were lower than in the 2-mg group. These differences reflect the expected problems with AChEI drugs, with the additional increase due to EVP-6124, Dr. Hilt said.

All told, there were 23 serious adverse events in the study: 4 in the placebo group, and 19 in the active groups. The investigators deemed that only two were treatment related; two additional events were considered possibly related to treatment.

Dr. Hilt said that EnVivo plans to go forward with a phase III trial early next year.

Dr. Aisen serves as a consultant to Eisai, Pfizer, Novartis, and other companies. He also receives research support from Pfizer and others.

VANCOUVER, B.C. – An investigational drug has shown promise in improving memory and cognition in patients with mild to moderate Alzheimer’s disease in a 6-month, randomized, placebo-controlled trial that was presented at the Alzheimer’s Association International Conference 2012.

The fact that the patients were still continuing to improve on statistically significant measurements of those aspects of the disease provided a hint, at least, that the drug EVP-6124, an alpha-7 nicotinic acetylcholine receptor partial agonist, could change the course of Alzheimer’s.

But it’s too soon to place any long-term bets, Dr. Dana Hilt said in an interview.

"This is being investigated as a procognitive and symptomatic drug," said Dr. Hilt, senior vice president of clinical development and chief medical officer of EnVivo Pharmaceuticals, which funded the trial. "It certainly appears to improve cognition in a clinically beneficial way at 6 months. But if the curves continue to diverge, is it possible that something more fundamental could be going on? Could this be maintained at 12 months? That’s what we need to know."

Dr. Paul S. Aisen, director of the Alzheimer's Disease Cooperative Study and a professor of neurosciences at the University of California, San Diego, said that EVP-6124’s phase II data looked very good.

"Reviewing the results, I would consider this to be a solidly positive trial," he said in an interview. "While we cannot rely on a relatively small phase II trial to accurately indicate the size of a treatment effect, the consistency of the findings here are encouraging. If efficacy is confirmed in additional trials, this may prove to be an important therapeutic option."

The study group comprised 409 patients who were randomized to one of three drug doses (0.3 mg, 1 mg, or 2 mg daily), or to placebo.

Half of the group were on stable doses of donepezil (Aricept) or rivastigmine (Exelon) and half were not taking any acetylcholinesterase inhibitor (AChEI), at least at the time of the trial, Dr. Hilt said. "Some of them had never taken an AChEI, and some had taken them in the past but were now off, for a number of reasons," including insurance coverage and lack of efficacy.

The subjects’ mean MMSE (Mini-Mental State Exam) at baseline score was 20, but the range was wide, from 12 to 29; the mean score on the CDR (Clinical Dementia Rating) scale was 6.

The primary end points were changes in the ADAS Cog-13 (Alzheimer’s Disease Assessment Scale Cognitive-13) and the CDR sum of boxes scores. Additional prespecified end points were the ADAS Cog-11 and composite measures of cognition and memory.

In each finding, Dr. Hilt noted effect size as well as statistical significance. Effect size is important in clinical trials because it suggests clinical efficacy better than statistical findings, he said in an interview.

"The effect size of approved drugs is somewhere around 0.15-0.28. In terms of clinical change, an effect size of 0.2 is something a trained clinician could detect. And effect size of 0.4 is something the next-door neighbor could detect."

During the first month of the study, the lower-dose groups and the placebo groups all improved their ADAS Cog-13 scores, a finding consistent with a placebo effect often seen in such studies. Interestingly, the 2-mg group remained at baseline for the first 4 months of the trial; after 4 months, cognition scores increased rapidly and outstripped all of the other groups. By the end of the study, the 2-mg group had a mean improvement of 1.5 points over baseline, whereas the placebo group had dropped below baseline, giving a total group separation of 2.2 points (P = .0189; effect size 0.39). This effect size is higher than the 0.28 estimated for high doses of donepezil, rivastigmine, or memantine (Namenda), Dr. Hilt said.

At the end of the treatment period, the curves were still diverging, suggesting that longer treatment might confer more benefit.

On the CDR sum of boxes, the 2-mg dose also performed significantly better than placebo. Again, there was the early upward trend for all groups, including placebo. But after 4 months, the placebo group and the active groups of 0.3 mg and 1 mg began losing those gains. The 2-mg group maintained its gain (P = .0253; effect size 0.31).

Findings on the secondary end points were similarly encouraging, although all were not statistically significant, Dr. Hilt said.

On the ADAS Cog-11, those taking the 2-mg dose faired significantly better than did those in any of the other groups. By the end of the study period, the lower-dose groups and placebo group had declined below baseline to the same degree. The 2-mg group had improved significantly and was still on an upward trend (P = .0151; effect size 0.34).

The ADCS-ADL (Alzheimer's Disease Cooperative Study Activities of Daily Living) scale showed the pattern of early improvement observed with other scales. The 2-mg group maintained its gains, but the between-group difference was not significant at the end of the study (P = .0925; effect size 0.20). Nor was there a significant 24-month difference in the MMSE (P = 0.0955; effect size 0.21).

A composite measure of cognition that included word recall on the ADAS-Cog, word recognition, word association, and orientation significantly favored the 2-mg group (P = .0037; effect size 0.42), as did a composite measure of memory (P = 0.0088; effect size 0.37).

Besides being richly distributed in the hippocampus and frontal cortex, alpha-7 nicotinic acetylcholine receptors are found in many other tissues, including the gut and skeletal muscles. A compound that attaches nonselectively could be loaded with adverse effects, including cardiovascular changes and unpleasant GI reactions. These adverse effects have proved difficult to overcome, and in fact are one reason that a number of nicotinic acetylcholine receptor studies have been discontinued.

"A number of companies tried to develop these, but at high dose levels that had indiscriminate stimulation of the receptors," Dr. Hilt said. "When you give a neurotransmitter to affect receptors in the brain, you have to live with the consequences of stimulating that receptor everywhere. The way we have dealt with this is to use a drug with a very long half-life, in very low concentrations."

The long half-life allows the drug to build up slowly, and keeps levels at a steady concentration without extreme peaks or nadirs. "It turns out this receptor is very finicky. Too high a level overstimulates it and too low a level doesn’t stimulate it at all. I’m convinced this is the major trouble with some of these other drugs."

Adverse events in the trial were mild gastrointestinal issues, including nausea and constipation. No patients of the active-drug study groups withdrew because of an adverse effect. The rate of adverse events in the 2-mg group also varied by baseline medication status, with more among those already taking an AChEI at baseline than among those not on the drugs (64% vs. 42%). Similar differences in adverse events rates occurred in the other treatment groups, although the rates were lower than in the 2-mg group. These differences reflect the expected problems with AChEI drugs, with the additional increase due to EVP-6124, Dr. Hilt said.

All told, there were 23 serious adverse events in the study: 4 in the placebo group, and 19 in the active groups. The investigators deemed that only two were treatment related; two additional events were considered possibly related to treatment.

Dr. Hilt said that EnVivo plans to go forward with a phase III trial early next year.

Dr. Aisen serves as a consultant to Eisai, Pfizer, Novartis, and other companies. He also receives research support from Pfizer and others.

VANCOUVER, B.C. – An investigational drug has shown promise in improving memory and cognition in patients with mild to moderate Alzheimer’s disease in a 6-month, randomized, placebo-controlled trial that was presented at the Alzheimer’s Association International Conference 2012.

The fact that the patients were still continuing to improve on statistically significant measurements of those aspects of the disease provided a hint, at least, that the drug EVP-6124, an alpha-7 nicotinic acetylcholine receptor partial agonist, could change the course of Alzheimer’s.

But it’s too soon to place any long-term bets, Dr. Dana Hilt said in an interview.

"This is being investigated as a procognitive and symptomatic drug," said Dr. Hilt, senior vice president of clinical development and chief medical officer of EnVivo Pharmaceuticals, which funded the trial. "It certainly appears to improve cognition in a clinically beneficial way at 6 months. But if the curves continue to diverge, is it possible that something more fundamental could be going on? Could this be maintained at 12 months? That’s what we need to know."

Dr. Paul S. Aisen, director of the Alzheimer's Disease Cooperative Study and a professor of neurosciences at the University of California, San Diego, said that EVP-6124’s phase II data looked very good.

"Reviewing the results, I would consider this to be a solidly positive trial," he said in an interview. "While we cannot rely on a relatively small phase II trial to accurately indicate the size of a treatment effect, the consistency of the findings here are encouraging. If efficacy is confirmed in additional trials, this may prove to be an important therapeutic option."

The study group comprised 409 patients who were randomized to one of three drug doses (0.3 mg, 1 mg, or 2 mg daily), or to placebo.

Half of the group were on stable doses of donepezil (Aricept) or rivastigmine (Exelon) and half were not taking any acetylcholinesterase inhibitor (AChEI), at least at the time of the trial, Dr. Hilt said. "Some of them had never taken an AChEI, and some had taken them in the past but were now off, for a number of reasons," including insurance coverage and lack of efficacy.

The subjects’ mean MMSE (Mini-Mental State Exam) at baseline score was 20, but the range was wide, from 12 to 29; the mean score on the CDR (Clinical Dementia Rating) scale was 6.

The primary end points were changes in the ADAS Cog-13 (Alzheimer’s Disease Assessment Scale Cognitive-13) and the CDR sum of boxes scores. Additional prespecified end points were the ADAS Cog-11 and composite measures of cognition and memory.

In each finding, Dr. Hilt noted effect size as well as statistical significance. Effect size is important in clinical trials because it suggests clinical efficacy better than statistical findings, he said in an interview.

"The effect size of approved drugs is somewhere around 0.15-0.28. In terms of clinical change, an effect size of 0.2 is something a trained clinician could detect. And effect size of 0.4 is something the next-door neighbor could detect."

During the first month of the study, the lower-dose groups and the placebo groups all improved their ADAS Cog-13 scores, a finding consistent with a placebo effect often seen in such studies. Interestingly, the 2-mg group remained at baseline for the first 4 months of the trial; after 4 months, cognition scores increased rapidly and outstripped all of the other groups. By the end of the study, the 2-mg group had a mean improvement of 1.5 points over baseline, whereas the placebo group had dropped below baseline, giving a total group separation of 2.2 points (P = .0189; effect size 0.39). This effect size is higher than the 0.28 estimated for high doses of donepezil, rivastigmine, or memantine (Namenda), Dr. Hilt said.

At the end of the treatment period, the curves were still diverging, suggesting that longer treatment might confer more benefit.

On the CDR sum of boxes, the 2-mg dose also performed significantly better than placebo. Again, there was the early upward trend for all groups, including placebo. But after 4 months, the placebo group and the active groups of 0.3 mg and 1 mg began losing those gains. The 2-mg group maintained its gain (P = .0253; effect size 0.31).

Findings on the secondary end points were similarly encouraging, although all were not statistically significant, Dr. Hilt said.

On the ADAS Cog-11, those taking the 2-mg dose faired significantly better than did those in any of the other groups. By the end of the study period, the lower-dose groups and placebo group had declined below baseline to the same degree. The 2-mg group had improved significantly and was still on an upward trend (P = .0151; effect size 0.34).

The ADCS-ADL (Alzheimer's Disease Cooperative Study Activities of Daily Living) scale showed the pattern of early improvement observed with other scales. The 2-mg group maintained its gains, but the between-group difference was not significant at the end of the study (P = .0925; effect size 0.20). Nor was there a significant 24-month difference in the MMSE (P = 0.0955; effect size 0.21).

A composite measure of cognition that included word recall on the ADAS-Cog, word recognition, word association, and orientation significantly favored the 2-mg group (P = .0037; effect size 0.42), as did a composite measure of memory (P = 0.0088; effect size 0.37).

Besides being richly distributed in the hippocampus and frontal cortex, alpha-7 nicotinic acetylcholine receptors are found in many other tissues, including the gut and skeletal muscles. A compound that attaches nonselectively could be loaded with adverse effects, including cardiovascular changes and unpleasant GI reactions. These adverse effects have proved difficult to overcome, and in fact are one reason that a number of nicotinic acetylcholine receptor studies have been discontinued.

"A number of companies tried to develop these, but at high dose levels that had indiscriminate stimulation of the receptors," Dr. Hilt said. "When you give a neurotransmitter to affect receptors in the brain, you have to live with the consequences of stimulating that receptor everywhere. The way we have dealt with this is to use a drug with a very long half-life, in very low concentrations."

The long half-life allows the drug to build up slowly, and keeps levels at a steady concentration without extreme peaks or nadirs. "It turns out this receptor is very finicky. Too high a level overstimulates it and too low a level doesn’t stimulate it at all. I’m convinced this is the major trouble with some of these other drugs."

Adverse events in the trial were mild gastrointestinal issues, including nausea and constipation. No patients of the active-drug study groups withdrew because of an adverse effect. The rate of adverse events in the 2-mg group also varied by baseline medication status, with more among those already taking an AChEI at baseline than among those not on the drugs (64% vs. 42%). Similar differences in adverse events rates occurred in the other treatment groups, although the rates were lower than in the 2-mg group. These differences reflect the expected problems with AChEI drugs, with the additional increase due to EVP-6124, Dr. Hilt said.

All told, there were 23 serious adverse events in the study: 4 in the placebo group, and 19 in the active groups. The investigators deemed that only two were treatment related; two additional events were considered possibly related to treatment.

Dr. Hilt said that EnVivo plans to go forward with a phase III trial early next year.

Dr. Aisen serves as a consultant to Eisai, Pfizer, Novartis, and other companies. He also receives research support from Pfizer and others.

VANCOUVER, B.C. – Medical foods and supplements designed to support neural health and function may soon expand treatment options for common forms of dementia based on the results of two studies.

One study found that a cocktail of compounds designed to support synapse formation and function improved memory in patients with mild Alzheimer’s disease. The other found that oral citicoline, a substrate for acetylcholine synthesis that inhibits neurodegeneration, yielded better memory than no treatment in patients with mild cognitive impairment (MCI) due to vascular causes.

Susan London/IMNG Medical Media

The findings may signal the start of an era in which Alzheimer’s disease and other dementias are managed with a multimodality approach involving a variety of pharmacologic and nonpharmacologic strategies, according to Maria Carrillo, Ph.D., senior director of medical and scientific relations for the Alzheimer’s Association. "We need to continue to be open to different therapeutic avenues and approaches," she commented while moderating a press briefing at the Alzheimer’s Association International Conference 2012, where the data were first presented.

Souvenaid for Mild Alzheimer’s Disease

Susan London/IMNG Medical Media

In the first trial, known as Souvenir II, researchers led by Dr. Philip Scheltens of the VU University Medical Center in Amsterdam studied 259 patients from multiple centers in Europe who had mild Alzheimer’s disease, with a Mini-Mental State Examination (MMSE) score of 25 or greater.

Patients were randomized evenly to receive Souvenaid (125 mL orally once a day) or a control drink for the first 24 weeks. Souvenaid contains a special formulation of omega-3 and -6 fatty acids, choline, phospholipids, B vitamins, and antioxidants designed to promote the formation and function of synapses, he explained.

"Synapse dysfunction is ... critical to causing symptoms in Alzheimer’s disease. It’s not the amyloid load that causes memory problems – it’s the loss of synapses and the loss of neurons that do so," he noted. In a subsequent 24-week extension period, all patients received Souvenaid.

Rates of serious adverse events did not differ between groups, and there were no new safety signals during the extension period, Dr. Scheltens reported.

Compliance was uniformly high in both groups during both periods, ranging from 93% to 97%. "People really liked [Souvenaid] and stayed on the product the whole time," he said. "There are two flavors: strawberry and vanilla. It’s like a drinkable yogurt. ... It tastes very, very good, and that’s why the compliance was so high. Although the amount of fish oil in it is equivalent to three or four herrings, you would be surprised that it doesn’t smell at all like fish or taste like fish."

At 24 weeks, patients in the Souvenaid group had a significantly greater improvement from baseline in z scores for the Neuropsychological Test Battery memory domain (P = .023) and marginally better total composite scores (P = .053), as recently published (J. Alzheimers Dis. 2012;31:225-36).

In additional results, there was a significant improvement between 24 and 48 weeks in the z score for the memory domain of the Neuropsychological Test Battery among both patients who started and continued on Souvenaid (P = .025) and patients who started on the control drink and switched to Souvenaid (P = .009).

"The memory actually even improved further; there was no ceiling effect on memory," Dr. Scheltens commented. "So the mild patients could even improve further."

The effect size in the study was 0.21, "exactly on the order of the cholinesterase inhibitors," he pointed out. "But the risk-benefit ratio is much better, because there are no side effects and people can take it as long as they want."

"We think this may offer a new approach, a dietary management approach, if you like, in people with very early Alzheimer’s disease," Dr. Scheltens concluded. "We are continuing the [research] program because we think it is worthwhile to pursue this in a rigorous, scientifically oriented way. The targeted patient population will be the mild to very mild Alzheimer’s disease patients."

He said it’s unlikely that combining individual dietary supplements could achieve the benefit seen with Souvenaid. Studies of various individual components have shown "they basically don’t work. Only the particular combination of all these nutrients is needed and is necessary to build up the membrane of the synapse. So it’s just not something you can do at home – throw a little bit of this, a little bit of that in a tube. It is the specific combination and the ratio between the [components of the] combination that actually works."

Assuming Souvenaid makes it to the market, it will be classified as a medical food. "That means it has to be prescribed by a doctor and it needs to be delivered by a pharmacist. It is not over the counter," Dr. Scheltens noted. He expects that the product will first be launched in Europe, as the manufacturer is located there.

Citicoline for Vascular MCI

In the second trial, known as IDEALE, Dr. Pietro Gareri, a geriatrician with the Ambulatory Center for Dementia in Catanzaro, Italy, and his colleagues enrolled 349 patients in Italy at least 65 years of age who had evidence of vascular lesions on neuroradiologic imaging, and either an MMSE score of at least 21 or subjective memory complaints. (Those with probable Alzheimer’s disease were excluded.)

The patients were assigned in a 3:1 ratio to open-label treatment with citicoline (500 mg twice a day) or a control condition (no treatment).

"Citicoline has a number of different properties," Dr. Gareri explained. "For example, it inhibits apoptosis associated with cerebral ischemia. And it’s able to inhibit several models of neurodegeneration. It’s able to potentiate neuroplasticity. And it is a natural precursor of phospholipid synthesis."

Trial results showed a nonsignificant increase in MMSE scores over 6 months in the citicoline group (from 22.4 to 22.9), compared with a decrease in scores in the control group (from 21.5 to 19.6). Scores differed significantly between groups at 3 months and at 6 months.

Both groups had improvements in functional dependence, as assessed from activities of daily living and instrumental activities of daily living, with no significant between-group difference.

There was a trend toward better Geriatric Depression Scale scores with citicoline (P = .06). "This was not a surprise, because citicoline increases noradrenaline and dopamine levels in the central nervous system," Dr. Gareri commented. None of the patients experienced adverse events.

"Definitively, this study shows that citicoline is effective and safe. Therefore it can be recommended in vascular mild cognitive impairment," he concluded.

Neither Dr. Scheltens nor Dr. Gareri disclosed any relevant conflicts of interest.

VANCOUVER, B.C. – Medical foods and supplements designed to support neural health and function may soon expand treatment options for common forms of dementia based on the results of two studies.

One study found that a cocktail of compounds designed to support synapse formation and function improved memory in patients with mild Alzheimer’s disease. The other found that oral citicoline, a substrate for acetylcholine synthesis that inhibits neurodegeneration, yielded better memory than no treatment in patients with mild cognitive impairment (MCI) due to vascular causes.

Susan London/IMNG Medical Media

The findings may signal the start of an era in which Alzheimer’s disease and other dementias are managed with a multimodality approach involving a variety of pharmacologic and nonpharmacologic strategies, according to Maria Carrillo, Ph.D., senior director of medical and scientific relations for the Alzheimer’s Association. "We need to continue to be open to different therapeutic avenues and approaches," she commented while moderating a press briefing at the Alzheimer’s Association International Conference 2012, where the data were first presented.

Souvenaid for Mild Alzheimer’s Disease

Susan London/IMNG Medical Media

In the first trial, known as Souvenir II, researchers led by Dr. Philip Scheltens of the VU University Medical Center in Amsterdam studied 259 patients from multiple centers in Europe who had mild Alzheimer’s disease, with a Mini-Mental State Examination (MMSE) score of 25 or greater.

Patients were randomized evenly to receive Souvenaid (125 mL orally once a day) or a control drink for the first 24 weeks. Souvenaid contains a special formulation of omega-3 and -6 fatty acids, choline, phospholipids, B vitamins, and antioxidants designed to promote the formation and function of synapses, he explained.

"Synapse dysfunction is ... critical to causing symptoms in Alzheimer’s disease. It’s not the amyloid load that causes memory problems – it’s the loss of synapses and the loss of neurons that do so," he noted. In a subsequent 24-week extension period, all patients received Souvenaid.

Rates of serious adverse events did not differ between groups, and there were no new safety signals during the extension period, Dr. Scheltens reported.

Compliance was uniformly high in both groups during both periods, ranging from 93% to 97%. "People really liked [Souvenaid] and stayed on the product the whole time," he said. "There are two flavors: strawberry and vanilla. It’s like a drinkable yogurt. ... It tastes very, very good, and that’s why the compliance was so high. Although the amount of fish oil in it is equivalent to three or four herrings, you would be surprised that it doesn’t smell at all like fish or taste like fish."

At 24 weeks, patients in the Souvenaid group had a significantly greater improvement from baseline in z scores for the Neuropsychological Test Battery memory domain (P = .023) and marginally better total composite scores (P = .053), as recently published (J. Alzheimers Dis. 2012;31:225-36).

In additional results, there was a significant improvement between 24 and 48 weeks in the z score for the memory domain of the Neuropsychological Test Battery among both patients who started and continued on Souvenaid (P = .025) and patients who started on the control drink and switched to Souvenaid (P = .009).

"The memory actually even improved further; there was no ceiling effect on memory," Dr. Scheltens commented. "So the mild patients could even improve further."

The effect size in the study was 0.21, "exactly on the order of the cholinesterase inhibitors," he pointed out. "But the risk-benefit ratio is much better, because there are no side effects and people can take it as long as they want."

"We think this may offer a new approach, a dietary management approach, if you like, in people with very early Alzheimer’s disease," Dr. Scheltens concluded. "We are continuing the [research] program because we think it is worthwhile to pursue this in a rigorous, scientifically oriented way. The targeted patient population will be the mild to very mild Alzheimer’s disease patients."

He said it’s unlikely that combining individual dietary supplements could achieve the benefit seen with Souvenaid. Studies of various individual components have shown "they basically don’t work. Only the particular combination of all these nutrients is needed and is necessary to build up the membrane of the synapse. So it’s just not something you can do at home – throw a little bit of this, a little bit of that in a tube. It is the specific combination and the ratio between the [components of the] combination that actually works."

Assuming Souvenaid makes it to the market, it will be classified as a medical food. "That means it has to be prescribed by a doctor and it needs to be delivered by a pharmacist. It is not over the counter," Dr. Scheltens noted. He expects that the product will first be launched in Europe, as the manufacturer is located there.

Citicoline for Vascular MCI

In the second trial, known as IDEALE, Dr. Pietro Gareri, a geriatrician with the Ambulatory Center for Dementia in Catanzaro, Italy, and his colleagues enrolled 349 patients in Italy at least 65 years of age who had evidence of vascular lesions on neuroradiologic imaging, and either an MMSE score of at least 21 or subjective memory complaints. (Those with probable Alzheimer’s disease were excluded.)

The patients were assigned in a 3:1 ratio to open-label treatment with citicoline (500 mg twice a day) or a control condition (no treatment).

"Citicoline has a number of different properties," Dr. Gareri explained. "For example, it inhibits apoptosis associated with cerebral ischemia. And it’s able to inhibit several models of neurodegeneration. It’s able to potentiate neuroplasticity. And it is a natural precursor of phospholipid synthesis."

Trial results showed a nonsignificant increase in MMSE scores over 6 months in the citicoline group (from 22.4 to 22.9), compared with a decrease in scores in the control group (from 21.5 to 19.6). Scores differed significantly between groups at 3 months and at 6 months.

Both groups had improvements in functional dependence, as assessed from activities of daily living and instrumental activities of daily living, with no significant between-group difference.

There was a trend toward better Geriatric Depression Scale scores with citicoline (P = .06). "This was not a surprise, because citicoline increases noradrenaline and dopamine levels in the central nervous system," Dr. Gareri commented. None of the patients experienced adverse events.

"Definitively, this study shows that citicoline is effective and safe. Therefore it can be recommended in vascular mild cognitive impairment," he concluded.

Neither Dr. Scheltens nor Dr. Gareri disclosed any relevant conflicts of interest.

VANCOUVER, B.C. – Medical foods and supplements designed to support neural health and function may soon expand treatment options for common forms of dementia based on the results of two studies.

One study found that a cocktail of compounds designed to support synapse formation and function improved memory in patients with mild Alzheimer’s disease. The other found that oral citicoline, a substrate for acetylcholine synthesis that inhibits neurodegeneration, yielded better memory than no treatment in patients with mild cognitive impairment (MCI) due to vascular causes.

Susan London/IMNG Medical Media

The findings may signal the start of an era in which Alzheimer’s disease and other dementias are managed with a multimodality approach involving a variety of pharmacologic and nonpharmacologic strategies, according to Maria Carrillo, Ph.D., senior director of medical and scientific relations for the Alzheimer’s Association. "We need to continue to be open to different therapeutic avenues and approaches," she commented while moderating a press briefing at the Alzheimer’s Association International Conference 2012, where the data were first presented.

Souvenaid for Mild Alzheimer’s Disease

Susan London/IMNG Medical Media

In the first trial, known as Souvenir II, researchers led by Dr. Philip Scheltens of the VU University Medical Center in Amsterdam studied 259 patients from multiple centers in Europe who had mild Alzheimer’s disease, with a Mini-Mental State Examination (MMSE) score of 25 or greater.

Patients were randomized evenly to receive Souvenaid (125 mL orally once a day) or a control drink for the first 24 weeks. Souvenaid contains a special formulation of omega-3 and -6 fatty acids, choline, phospholipids, B vitamins, and antioxidants designed to promote the formation and function of synapses, he explained.

"Synapse dysfunction is ... critical to causing symptoms in Alzheimer’s disease. It’s not the amyloid load that causes memory problems – it’s the loss of synapses and the loss of neurons that do so," he noted. In a subsequent 24-week extension period, all patients received Souvenaid.

Rates of serious adverse events did not differ between groups, and there were no new safety signals during the extension period, Dr. Scheltens reported.

Compliance was uniformly high in both groups during both periods, ranging from 93% to 97%. "People really liked [Souvenaid] and stayed on the product the whole time," he said. "There are two flavors: strawberry and vanilla. It’s like a drinkable yogurt. ... It tastes very, very good, and that’s why the compliance was so high. Although the amount of fish oil in it is equivalent to three or four herrings, you would be surprised that it doesn’t smell at all like fish or taste like fish."

At 24 weeks, patients in the Souvenaid group had a significantly greater improvement from baseline in z scores for the Neuropsychological Test Battery memory domain (P = .023) and marginally better total composite scores (P = .053), as recently published (J. Alzheimers Dis. 2012;31:225-36).

In additional results, there was a significant improvement between 24 and 48 weeks in the z score for the memory domain of the Neuropsychological Test Battery among both patients who started and continued on Souvenaid (P = .025) and patients who started on the control drink and switched to Souvenaid (P = .009).

"The memory actually even improved further; there was no ceiling effect on memory," Dr. Scheltens commented. "So the mild patients could even improve further."

The effect size in the study was 0.21, "exactly on the order of the cholinesterase inhibitors," he pointed out. "But the risk-benefit ratio is much better, because there are no side effects and people can take it as long as they want."

"We think this may offer a new approach, a dietary management approach, if you like, in people with very early Alzheimer’s disease," Dr. Scheltens concluded. "We are continuing the [research] program because we think it is worthwhile to pursue this in a rigorous, scientifically oriented way. The targeted patient population will be the mild to very mild Alzheimer’s disease patients."

He said it’s unlikely that combining individual dietary supplements could achieve the benefit seen with Souvenaid. Studies of various individual components have shown "they basically don’t work. Only the particular combination of all these nutrients is needed and is necessary to build up the membrane of the synapse. So it’s just not something you can do at home – throw a little bit of this, a little bit of that in a tube. It is the specific combination and the ratio between the [components of the] combination that actually works."

Assuming Souvenaid makes it to the market, it will be classified as a medical food. "That means it has to be prescribed by a doctor and it needs to be delivered by a pharmacist. It is not over the counter," Dr. Scheltens noted. He expects that the product will first be launched in Europe, as the manufacturer is located there.

Citicoline for Vascular MCI

In the second trial, known as IDEALE, Dr. Pietro Gareri, a geriatrician with the Ambulatory Center for Dementia in Catanzaro, Italy, and his colleagues enrolled 349 patients in Italy at least 65 years of age who had evidence of vascular lesions on neuroradiologic imaging, and either an MMSE score of at least 21 or subjective memory complaints. (Those with probable Alzheimer’s disease were excluded.)

The patients were assigned in a 3:1 ratio to open-label treatment with citicoline (500 mg twice a day) or a control condition (no treatment).

"Citicoline has a number of different properties," Dr. Gareri explained. "For example, it inhibits apoptosis associated with cerebral ischemia. And it’s able to inhibit several models of neurodegeneration. It’s able to potentiate neuroplasticity. And it is a natural precursor of phospholipid synthesis."

Trial results showed a nonsignificant increase in MMSE scores over 6 months in the citicoline group (from 22.4 to 22.9), compared with a decrease in scores in the control group (from 21.5 to 19.6). Scores differed significantly between groups at 3 months and at 6 months.

Both groups had improvements in functional dependence, as assessed from activities of daily living and instrumental activities of daily living, with no significant between-group difference.

There was a trend toward better Geriatric Depression Scale scores with citicoline (P = .06). "This was not a surprise, because citicoline increases noradrenaline and dopamine levels in the central nervous system," Dr. Gareri commented. None of the patients experienced adverse events.

"Definitively, this study shows that citicoline is effective and safe. Therefore it can be recommended in vascular mild cognitive impairment," he concluded.

Neither Dr. Scheltens nor Dr. Gareri disclosed any relevant conflicts of interest.

VANCOUVER, B.C. – Intravenous immunoglobulin continues to slow the decline in cognitive and other functions seen in Alzheimer’s disease for at least 3 years, suggest data from an extended phase II randomized trial among 21 patients with mild to moderate disease.

Compared with their counterparts who started on a placebo and crossed over to intravenous immunoglobulin (IVIG) in the trial, patients who received the pooled antibody preparation continuously had significantly better scores on measures of cognitive, global, and daily function, and behavior, Dr. Norman Relkin reported at the Alzheimer’s Association International Conference 2012.

Susan London/IMNG Medical Media

Moreover, the subset of patients who received the optimal dose of IVIG for the entire 3-year period had little to no decline in these measures from baseline, suggesting that clinical progression of the disease had been effectively halted.

Adverse effects seen with IVIG were consistent with what was expected, given 30 years of experience with this agent in other diseases – mainly short-lived infusion-related reactions such as rash and fever, although a single patient did experience a stroke. The majority of patients received all planned infusions.

"By the results that we have shown here, we have established that IVIG is potentially a viable therapy for as long as 36 months and perhaps longer," Dr. Relkin commented in a press briefing. However, he cautioned, the number of patients studied was small, and IVIG is not currently approved to treat Alzheimer’s disease.

"My coinvestigators and I want to really emphasize that this work is investigational, and it’s not intended to promote the off-label use of this particular product to treat Alzheimer’s disease. This is a very important point because this agent is in limited supply, and the indications for which it is approved, some of them represent disorders in which patients can only survive by getting this particular product," he explained. "So we don’t want to bankrupt the available supplies by creating false hope or premature use of this product."

The promising results seen in the extended trial prompted initiation of the phase III Gammaglobulin Alzheimer Partnership (GAP) study, which has been further testing the optimal dose of IVIG against placebo. "The last patient should be through that study by December of this year, and we expect readout [of the results] by the middle of 2013," he said.

The patients enrolled in the phase II trial had mild to moderate Alzheimer’s disease, with a Mini-Mental State Examination score of 14-26. Those who had experienced myocardial infarction or stroke were generally excluded to reduce the risk of thromboembolic complications.

During the initial 6 months, patients received randomized double-blind treatment with placebo or various doses of IVIG (Gammagard). In a first extension out to 18 months, placebo patients were switched to IVIG and treatment became open-label. In a second extension out to 36 months, all patients were given the dose that had emerged as the optimal one (0.4 g/kg every 2 weeks).

Cognitive function was assessed with the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), global functioning with the Clinical Global Impression of Change (CGIC) scale, daily functioning from Activities of Daily Living (ADL), and behavior from the Neuropsychiatric Inventory (NPI).

Results at 6 months and at 18 months favored IVIG over placebo, according to Dr. Relkin, director of the memory disorders program at Weill Cornell Medical College, New York.

Results for the full 36 months, reported for the first time in a poster session at the meeting, showed that in a comparison of all patients given IVIG continuously in the trial (regardless of dose) with patients who had a delay because they started with placebo, the decline in the four main measures was slower in the former group, with significant differences at nearly all time points.

"Particularly if you look at the global measure and daily function measure, there is a bend in the curve of the group that got placebo, and that bend occurs when they were switched to the optimum dose," Dr. Relkin noted. "We think that’s important because it shows that even patients who are a little bit further along in the disease state can benefit."

In what he characterized as "the most striking finding," analyses restricted to the four patients who received the optimal dose of IVIG continuously showed virtually no decline in the four main measures over 36 months.

"To put this in perspective, when we see patients with Alzheimer’s disease in our clinic untreated, there is usually a measurable decline below baseline within 3-6 months. If we treat them with the currently available agents, they typically drop below their baseline between 6 and 12 months," he commented. "If we have a patient who goes out to 18 or 24 months without changing, we usually begin to doubt if they have Alzheimer’s disease. If we have two patients like that in our practice, we begin to doubt our own diagnostic prowess. To have four patients, all of whom received the same dose [and] are effectively unchanged after 3 years, is a remarkable result."

It is still too premature to conclude that IVIG had a disease-modifying effect, according to Dr. Relkin. "However, the shapes of those graphs are exactly what people model when they are predicting what a disease-modifying therapy would look like, which is that there is a divergence of slopes, which means that the curves widen as time goes on. I think we have to wait for the results of the phase III study before we can answer that question," he concluded.

Dr. Relkin disclosed that he receives research support from Baxter Healthcare, which supported the trial.

VANCOUVER, B.C. – Intravenous immunoglobulin continues to slow the decline in cognitive and other functions seen in Alzheimer’s disease for at least 3 years, suggest data from an extended phase II randomized trial among 21 patients with mild to moderate disease.

Compared with their counterparts who started on a placebo and crossed over to intravenous immunoglobulin (IVIG) in the trial, patients who received the pooled antibody preparation continuously had significantly better scores on measures of cognitive, global, and daily function, and behavior, Dr. Norman Relkin reported at the Alzheimer’s Association International Conference 2012.

Susan London/IMNG Medical Media

Moreover, the subset of patients who received the optimal dose of IVIG for the entire 3-year period had little to no decline in these measures from baseline, suggesting that clinical progression of the disease had been effectively halted.

Adverse effects seen with IVIG were consistent with what was expected, given 30 years of experience with this agent in other diseases – mainly short-lived infusion-related reactions such as rash and fever, although a single patient did experience a stroke. The majority of patients received all planned infusions.

"By the results that we have shown here, we have established that IVIG is potentially a viable therapy for as long as 36 months and perhaps longer," Dr. Relkin commented in a press briefing. However, he cautioned, the number of patients studied was small, and IVIG is not currently approved to treat Alzheimer’s disease.

"My coinvestigators and I want to really emphasize that this work is investigational, and it’s not intended to promote the off-label use of this particular product to treat Alzheimer’s disease. This is a very important point because this agent is in limited supply, and the indications for which it is approved, some of them represent disorders in which patients can only survive by getting this particular product," he explained. "So we don’t want to bankrupt the available supplies by creating false hope or premature use of this product."

The promising results seen in the extended trial prompted initiation of the phase III Gammaglobulin Alzheimer Partnership (GAP) study, which has been further testing the optimal dose of IVIG against placebo. "The last patient should be through that study by December of this year, and we expect readout [of the results] by the middle of 2013," he said.

The patients enrolled in the phase II trial had mild to moderate Alzheimer’s disease, with a Mini-Mental State Examination score of 14-26. Those who had experienced myocardial infarction or stroke were generally excluded to reduce the risk of thromboembolic complications.

During the initial 6 months, patients received randomized double-blind treatment with placebo or various doses of IVIG (Gammagard). In a first extension out to 18 months, placebo patients were switched to IVIG and treatment became open-label. In a second extension out to 36 months, all patients were given the dose that had emerged as the optimal one (0.4 g/kg every 2 weeks).

Cognitive function was assessed with the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), global functioning with the Clinical Global Impression of Change (CGIC) scale, daily functioning from Activities of Daily Living (ADL), and behavior from the Neuropsychiatric Inventory (NPI).

Results at 6 months and at 18 months favored IVIG over placebo, according to Dr. Relkin, director of the memory disorders program at Weill Cornell Medical College, New York.

Results for the full 36 months, reported for the first time in a poster session at the meeting, showed that in a comparison of all patients given IVIG continuously in the trial (regardless of dose) with patients who had a delay because they started with placebo, the decline in the four main measures was slower in the former group, with significant differences at nearly all time points.

"Particularly if you look at the global measure and daily function measure, there is a bend in the curve of the group that got placebo, and that bend occurs when they were switched to the optimum dose," Dr. Relkin noted. "We think that’s important because it shows that even patients who are a little bit further along in the disease state can benefit."

In what he characterized as "the most striking finding," analyses restricted to the four patients who received the optimal dose of IVIG continuously showed virtually no decline in the four main measures over 36 months.

"To put this in perspective, when we see patients with Alzheimer’s disease in our clinic untreated, there is usually a measurable decline below baseline within 3-6 months. If we treat them with the currently available agents, they typically drop below their baseline between 6 and 12 months," he commented. "If we have a patient who goes out to 18 or 24 months without changing, we usually begin to doubt if they have Alzheimer’s disease. If we have two patients like that in our practice, we begin to doubt our own diagnostic prowess. To have four patients, all of whom received the same dose [and] are effectively unchanged after 3 years, is a remarkable result."

It is still too premature to conclude that IVIG had a disease-modifying effect, according to Dr. Relkin. "However, the shapes of those graphs are exactly what people model when they are predicting what a disease-modifying therapy would look like, which is that there is a divergence of slopes, which means that the curves widen as time goes on. I think we have to wait for the results of the phase III study before we can answer that question," he concluded.

Dr. Relkin disclosed that he receives research support from Baxter Healthcare, which supported the trial.

VANCOUVER, B.C. – Intravenous immunoglobulin continues to slow the decline in cognitive and other functions seen in Alzheimer’s disease for at least 3 years, suggest data from an extended phase II randomized trial among 21 patients with mild to moderate disease.

Compared with their counterparts who started on a placebo and crossed over to intravenous immunoglobulin (IVIG) in the trial, patients who received the pooled antibody preparation continuously had significantly better scores on measures of cognitive, global, and daily function, and behavior, Dr. Norman Relkin reported at the Alzheimer’s Association International Conference 2012.

Susan London/IMNG Medical Media

Moreover, the subset of patients who received the optimal dose of IVIG for the entire 3-year period had little to no decline in these measures from baseline, suggesting that clinical progression of the disease had been effectively halted.

Adverse effects seen with IVIG were consistent with what was expected, given 30 years of experience with this agent in other diseases – mainly short-lived infusion-related reactions such as rash and fever, although a single patient did experience a stroke. The majority of patients received all planned infusions.

"By the results that we have shown here, we have established that IVIG is potentially a viable therapy for as long as 36 months and perhaps longer," Dr. Relkin commented in a press briefing. However, he cautioned, the number of patients studied was small, and IVIG is not currently approved to treat Alzheimer’s disease.

"My coinvestigators and I want to really emphasize that this work is investigational, and it’s not intended to promote the off-label use of this particular product to treat Alzheimer’s disease. This is a very important point because this agent is in limited supply, and the indications for which it is approved, some of them represent disorders in which patients can only survive by getting this particular product," he explained. "So we don’t want to bankrupt the available supplies by creating false hope or premature use of this product."

The promising results seen in the extended trial prompted initiation of the phase III Gammaglobulin Alzheimer Partnership (GAP) study, which has been further testing the optimal dose of IVIG against placebo. "The last patient should be through that study by December of this year, and we expect readout [of the results] by the middle of 2013," he said.

The patients enrolled in the phase II trial had mild to moderate Alzheimer’s disease, with a Mini-Mental State Examination score of 14-26. Those who had experienced myocardial infarction or stroke were generally excluded to reduce the risk of thromboembolic complications.

During the initial 6 months, patients received randomized double-blind treatment with placebo or various doses of IVIG (Gammagard). In a first extension out to 18 months, placebo patients were switched to IVIG and treatment became open-label. In a second extension out to 36 months, all patients were given the dose that had emerged as the optimal one (0.4 g/kg every 2 weeks).

Cognitive function was assessed with the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), global functioning with the Clinical Global Impression of Change (CGIC) scale, daily functioning from Activities of Daily Living (ADL), and behavior from the Neuropsychiatric Inventory (NPI).

Results at 6 months and at 18 months favored IVIG over placebo, according to Dr. Relkin, director of the memory disorders program at Weill Cornell Medical College, New York.

Results for the full 36 months, reported for the first time in a poster session at the meeting, showed that in a comparison of all patients given IVIG continuously in the trial (regardless of dose) with patients who had a delay because they started with placebo, the decline in the four main measures was slower in the former group, with significant differences at nearly all time points.

"Particularly if you look at the global measure and daily function measure, there is a bend in the curve of the group that got placebo, and that bend occurs when they were switched to the optimum dose," Dr. Relkin noted. "We think that’s important because it shows that even patients who are a little bit further along in the disease state can benefit."

In what he characterized as "the most striking finding," analyses restricted to the four patients who received the optimal dose of IVIG continuously showed virtually no decline in the four main measures over 36 months.

"To put this in perspective, when we see patients with Alzheimer’s disease in our clinic untreated, there is usually a measurable decline below baseline within 3-6 months. If we treat them with the currently available agents, they typically drop below their baseline between 6 and 12 months," he commented. "If we have a patient who goes out to 18 or 24 months without changing, we usually begin to doubt if they have Alzheimer’s disease. If we have two patients like that in our practice, we begin to doubt our own diagnostic prowess. To have four patients, all of whom received the same dose [and] are effectively unchanged after 3 years, is a remarkable result."

It is still too premature to conclude that IVIG had a disease-modifying effect, according to Dr. Relkin. "However, the shapes of those graphs are exactly what people model when they are predicting what a disease-modifying therapy would look like, which is that there is a divergence of slopes, which means that the curves widen as time goes on. I think we have to wait for the results of the phase III study before we can answer that question," he concluded.

Dr. Relkin disclosed that he receives research support from Baxter Healthcare, which supported the trial.

Reversible medical conditions such as hypothyroidism and vitamin deficiency could be the cause of mild cognitive impairment in up to 17% of patients with symptoms, according to a study by Dr. Gregory Jicha and colleagues at the University of Kentucky, Lexington.

Dr. Jicha suggested that primary care physicians test for the conditions in patients who may be showing signs of memory decline.

Reversible medical conditions such as hypothyroidism and vitamin deficiency could be the cause of mild cognitive impairment in up to 17% of patients with symptoms, according to a study by Dr. Gregory Jicha and colleagues at the University of Kentucky, Lexington.

Dr. Jicha suggested that primary care physicians test for the conditions in patients who may be showing signs of memory decline.

Reversible medical conditions such as hypothyroidism and vitamin deficiency could be the cause of mild cognitive impairment in up to 17% of patients with symptoms, according to a study by Dr. Gregory Jicha and colleagues at the University of Kentucky, Lexington.

Dr. Jicha suggested that primary care physicians test for the conditions in patients who may be showing signs of memory decline.