Alzheimer's Pathology May Appear 20 Years Before Symptoms

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.

BARCELONA – The pathologic changes of Alzheimer’s disease may begin as early as 20 years before the expected onset of disease, at least in people whose families carry a high-risk gene, preliminary data from a 6-year longitudinal study suggested.

These first findings from the Dominantly Inherited Alzheimer Network (DIAN) study, a 6-year, cross-sectional, longitudinal study indicate that the use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein may allow researchers to select enriched pools of subjects for the testing of potential drug treatments, and, someday, allow clinicians to target patients with incipient disease for preventive treatment, Dr. John Morris said at the International Conference on Alzheimer’s and Parkinson’s Diseases.

"I have not yet had sufficient sample size or follow-up to predict this completely," said Dr. Morris, DIAN’s principal investigator. "However, I think there are data both from Europe and the U.S. showing that low beta-amyloid 42 [Abeta 42] and high tau in the cerebrospinal fluid together will reach a hazard ratio of 5.2 for becoming demented within 3-4 years. We are just beginning to get these same data for amyloid imaging and the hazard ratio is about the same."

Dr. Morris, professor of neurology at Washington University, St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with a known autosomal-dominant Alzheimer’s gene. Currently, three of those genes are known: amyloid precursor protein (APP), presenilin 1, and presenilin 2. He expects that about half the group will carry one of the mutations, while the other half will be unaffected siblings, who will serve as controls. The study involves 10 research institutions in the United States, United Kingdom, and Australia.

Each participant will undergo genetic analysis and the same periodic assessments, including cognitive and clinical testing; brain imaging with Pittsburgh imaging compound B, which binds to Abeta 42 plaques; ¹⁸fluorodeoxyglucose positron emission tomography; MRI; and lumbar punctures to test levels of Abeta 42 and tau. If subjects die during the study, their brains will be autopsied.

"The goals are to try and determine when the pathologic process begins in asymptomatic mutation carriers," Dr. Morris said. "We know, based on the parent’s age of onset, approximately when these carriers will become symptomatic. We want to see the changes, the rates of these changes, and determine to what extent the changes resemble those seen in sporadic Alzheimer’s."

As of last fall, DIAN had collected 106 volunteers, Dr. Morris said. About 70% of those are asymptomatic carriers, with an average age of 37 years, although that varies from 19 to 56 years. The average age of parental onset of dementia symptoms is 47 years, "so we have these folks an average of 10 years before their expected age of onset."

The presenilin 1 mutation is the most common in the group, occurring in 75%; presenilin 2 is present in 10%, and the APP mutation, in 15%.

Comparing the carriers with the noncarriers, the study’s "very preliminary" data indicate that cognitive decline begins as early as 10 years before the expected onset of symptoms, while neuropathologic changes start up to 20 years before.

But scores on the Mini-Mental State Exam (MMSE) for noncarrier siblings of these volunteers "have remained very clearly at 30," which is a normal score, Dr. Morrison said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale (pdf) sum of boxes (CDR-SOB), another test used to identify Alzheimer’s-related cognitive changes.

This was not the case "for carriers, in whom we begin to see declines in the MMSE and the CDR about 10 years before the expected age of onset," Dr. Morris said.

The cerebrospinal fluid biomarkers followed a similar pattern. A decrease in spinal fluid Abeta 42 suggests that the protein is aggregating somewhere else in the body – probably in the characteristic brain plaques. These changes could be seen in carriers 20 years before the expected age of onset. Tau protein levels in the cerebrospinal fluid (CSF) of carriers begin to rise around 20 years before the onset of symptoms, "with a clear acceleration at the time they are changing from asymptomatic to symptomatic," he said.

However, noncarriers have stable levels of both proteins in the CSF at the same ages.

Imaging in the precuneus and caudate with Pittsburgh imaging compound B shows no Abeta 42 accumulation in noncarriers, but in carriers, the protein begins to appear in those regions about the same time that the CSF biomarkers start to change – 20 years before the expected appearance of symptomatic disease.

If these findings can be confirmed, they prove the existence of a long prodromal stage in subjects who are genetically destined to develop Alzheimer’s disease. This has several important applications in both drug research and potential treatment, Dr. Morris noted.

First, the neuropsychological testing scores currently in use, which define normal cognitive function, may be incorrect, because they could be based on cohorts that included individuals who had already experienced cognitive decline, but still fell within the "normal" range.

To illustrate this problem, Dr. Morris referred to the cognitive testing of two subjects. One began with cognitive functioning at the mean of normal, while the other began at 2 standard deviations above the mean. Over a period of years, the first person remained stable at the mean, while the second declined to the mean – showing that this subject was experiencing significant cognitive decline on an individual basis, while still being considered cognitively normal. The patient quickly developed mild cognitive impairment and then Alzheimer’s disease.

"This interferes with the ability to detect very early stages of symptomatic Alzheimer’s based on neuropsychological testing, because the test norms are contaminated by the inclusion of subjects who may have preclinical disease," Dr. Morris said.

Comparative testing or the report of a close companion could detect change in a high-functioning individual, but the majority of people never undergo neuropsychological testing unless a problem is suspected.

Biomarkers, on the other hand, appear to predict decline very objectively. "People [with altered biomarkers] should be considered the real treatment target so we are not focusing all of our efforts on curing people who already have the symptoms of Alzheimer’s dementia, but rather on trying to prevent those symptoms from appearing," Dr. Morris said.

"I would hope I’m wrong about this, but I would say it’s possible that amyloid monotherapies used after the symptomatic stage has begun will not be effective," he said. "At the point when we can make the diagnosis, when symptoms begin, up to 60% of the neurons in layer 2 of the entorhinal cortex are already lost; we are treating a damaged brain. Ideally, we need to treat when the lesions are just beginning, when an intervention might be effective."

DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he had received research grant funding from multiple drug companies.