Unique Patients Gear Up for Alzheimer's Prevention Trials

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report.