Internal Medicine News
March 21, 2011
By Michele G. Sullivan
Studies that use Alzheimer’s disease biomarkers to predict the clinical benefit of investigational treatments in families with autosomal-dominant mutations that cause early-onset disease could prove to be the saving grace for researchers who have seen one treatment after another fail in trials of symptomatic patients.
Two research projects – the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer Network (DIAN) – hope to provide biomarker evidence that companies can use to test promising presymptomatic treatments without having to conduct costly long-term trials in individuals who might not develop symptoms for many years.
“In order to approve a treatment based on biomarker, the regulatory agencies said: ‘Show us with demonstrably effective, clinically proven treatments that the treatments’ effects on the biomarker predict a clinical benefit.’ Well that sounds like a Catch-22. If we had clinically proven prevention therapies, what do we need a biomarker for?” said Dr. Eric Reiman, who is leading the API with Dr. Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix.
“So, in the last few years, we’ve modified our approach to not only help provide the scientific means to evaluate the range of promising presymptomatic treatments as rapidly as possible, but to help provide the financial incentives – that is, the accelerated regulatory approval pathway needed to encourage everybody to go out and start studying their promising prevention therapies and everybody using biomarkers.”
The API is raising funds from philanthropic organizations, industry, and federal grants to study presymptomatic anti-amyloid treatments in people who are at high imminent risk for developing symptoms of Alzheimer’s disease (AD), based on their genetic background and age.
Fortunately, the largest extended family of individuals in the world who carry an autosomal-dominant mutation in the presenilin 1 (PS1) gene – about 5,000 people – live in and around Medellín, Colombia; about one-third of them have the PS1 mutation. Because mutation carriers are destined to develop symptoms of AD, typically around 45 years of age, the risk-to-benefit ratio for treatment in this population is different from the ratio for other individuals at lower risk for AD, said Dr. Reiman, executive director of the Banner Alzheimer’s Institute and director of the Arizona Alzheimer’s Consortium.
In collaboration with Colombian neurologist Dr. Francisco Lopera, who brought the extended family to the attention of researchers, the API is enrolling about 2,000 members of this extended family who are within 10 years of their expected age of onset in a prevention trial. Investigators are currently obtaining baseline data with cognitive tests; volumetric MRI; 18fluorodeoxyglucose and amyloid PET imaging; and cerebrospinal fluid measurements of beta-amyloid 42 (Abeta 42), tau, and total tau, he said.
In the trial, about 150 PS1 carriers will receive an anti-amyloid treatment and about 150 noncarriers will get a placebo. The anti-amyloid treatment to be given in the trial has not yet been determined, according to Dr. Reiman.
“We’ll be pretty unique in having the adequate sample size to show not just the biomarker effects, but within 3 or 4 years, the clinical effect as they’re close to their age of onset,” he said in an interview.
Dr. Reiman added that “if there’s no effect on the biomarkers after 2 years in the right direction, [we will] declare futility and give these people at highest imminent risk access to the next most promising treatment. If however, they do budge in the right direction, [we will] continue to follow them a little bit longer to see if it slows even subtle memory decline. And if it does, I have a feeling that may be enough evidence for regulatory agencies to consider using biomarkers under their accelerated approval mechanism in other [Alzheimer’s disease] populations.”
A second study in the United States will create a national registry of 20,000-50,000 people to gather a large number of people with one or two copies of the apolipoprotein E (APOE) e4 gene, which substantially increases an individual’s risk for late-onset Alzheimer’s disease. About 400 homozygous (and possibly heterozygous) APOE e4 carriers, who begin to have symptoms at a mean age of 68 years, will be enrolled in a prevention trial with of an anti-amyloid treatment; this therapy might not be the same as the one used in the trial of PS1 carriers, Dr. Reiman said.
Investigators are hoping to start one or both studies in 2012.
Study results from DIAN will be complementary to those from the API in many ways. DIAN is a 6-year, cross-sectional, longitudinal study of families who carry an autosomal dominant mutation in one of the three genes that affect amyloid processing: amyloid precursor protein (APP), PS1, and presenilin 2 (PS2).
Preliminary findings from the first analysis of DIAN indicate that the pathologic changes of AD might begin as early as 20 years before the expected onset of disease in mutation carriers.
The use of PET and cerebrospinal fluid biomarkers of beta-amyloid and tau protein in these individuals might 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 in Barcelona.
“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 in St. Louis, said the DIAN study hopes to recruit 400 subjects who are the children of a parent with one of the gene mutations. 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 compound B, which binds to Abeta 42 plaques; 18fluorodeoxyglucose PET; MRI; and lumbar punctures to test cerebrospinal fluid 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 PS1 mutation is the most common in the group, occurring in 75%; PS2 is present in 10%, and the APP mutation, in 15%.
About 90% of DIAN participants do not know whether they are a carrier of one of the mutations or not, and most do not want to know their status, Dr. Morris said in an interview. If DIAN researchers decide to conduct a clinical trial of an anti-amyloid treatment in the participants who carry a mutation, they will have to figure out a way to ensure that noncarriers receive a placebo without revealing mutation status to participants who do not want to know – and thereby not risk potential harm to the noncarriers from the treatment.
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. Morris said. The noncarriers also had normal scores on the Clinical Dementia Rating Scale 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 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 AD. 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, might 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 two 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 AD.
“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.
DIAN is funded by a multiple-year research grant from the National Institute on Aging. Dr. Morris declared that he has served as a consultant, received speaking honoraria, and served as an investigator in industry-sponsored clinical trials from multiple drug companies. Dr. Reiman said he has no relevant personal financial disclosures.
Jeff Evans contributed to this report.