Caroline Cassels

July 26, 2011

July 26, 2011 (Paris, France) — Interim results from a new study of individuals with a rare and aggressive form of Alzheimer's disease (AD), which strikes patients in the prime of life, offers the first glimmer of hope for prevention and treatment trials in this population and may ultimately have major clinical implications for the most common form of the disease.

The first results from the Dominant Inherited Alzheimer's Disease (DIAN) study, a multicenter international study of autosomal dominant AD, indicate that measurable, biochemical, and imaging markers can be detected up to 20 years before symptoms appear.

Presented here at the Alzheimer's Association International Conference 2011, baseline data show that cognitively normal individuals who are mutation carriers (MCs), and therefore destined to develop AD in their 40s, 30s, and sometime even in their 20s, have lower levels of β-amyloid 42 (Aβ-42) and elevated levels of tau and phosphorylated tau (p-tau) compared with their non–mutation-carrying siblings as determined by imaging and cerebrospinal fluid and blood testing.

Furthermore, among asymptomatic MCs at baseline, DIAN investigators were able to detect cognitive changes on clinical testing.

"We evaluate these individuals clinically, and they have no [cognitive] abnormalities whatsoever that we can detect. But when you look at the mutation carriers — and they are only 33 or 34 years of age — they are already performing worse than their noncarrier siblings," principal investigator John C. Morris, MD, Washington University School of Medicine, St. Louis Missouri, and director of the Knight Alzheimer's Disease Research Center, told reporters attending a press briefing here.

Dr. John C. Morris

"So already there is a memory change, and this appears to occur about 13 years before we would expect dementia symptoms to appear," he added.

Autosomal dominant AD is caused by a mutation in 1 of 3 genes — APP, PSEN1, PSEN2 — and accounts for about 1% of all AD cases worldwide. Each child of an affected parent has a 50/50 chance of inheriting that mutation. Offspring who are noncarriers (NCs), said Dr. Morris, have no more risk than anyone else for AD. But MCs have a 100% risk of developing the disease at roughly the same age as their parent, said Dr. Morris.

Research with MCs is important to detect brain changes that may develop before the dementia stage of AD, he added. However, families with the mutation are so rare that no single center has sufficient numbers of subjects to conduct definitive studies.

As a result, the DIAN study includes 11 academic centers — 7 in the United States, 3 in the United Kingdom, and 1 in Australia.

Established in 2008, the study's aim is to collect biomarker data in individuals 18 years and older with a family history of autosomal dominant AD and shed light on the pathological chronology of AD before symptoms begin.

Detecting AD in its earliest stages, said Dr. Morris, likely offers the best opportunity to stop the disease in its tracks.

"The major reason to know that the brain is changing and ultimately will culminate in dementia is because this gives us the opportunity to intervene therapeutically before dementia symptoms appear," said Dr. Morris.

With no disease-modifying agents currently available, Dr. Morris acknowledged that research efforts have been less than successful. This is likely because therapeutic trials intervene too late in the disease course to be effective.

"I would venture to say that no single drug will be truly effective in treating individuals who are already demented, but [with DIAN] we have an opportunity to test a single drug aimed at one of the biomarker changes in presymptomatic Alzheimer's, and in this way we could prevent the appearance of dementia. This is an opportunity that DIAN is particularly well suited to support," said Dr. Morris.

Early Changes

The study protocol requires participants to undergo extensive testing in a 4-day DIAN battery that includes clinical assessment with the Clinical Dementia Rating and a cognitive battery that includes the Mini-Mental State Examination and standard and novel psychometric measures that include plasma and CSF assays for Aβ-42 and tau, structural and functional magnetic resonance imaging, and positron emission tomography with Pittsburgh compound B (PiB).

The frequency of longitudinal follow-up is indexed to individual participants' age in relation to the age at onset of symptoms in their parent.

Baseline data in the first 128 subjects revealed participants had a mean age of 37 years at study entry and that 51% are MCs. The mean age at which their parent began experiencing symptoms is 45.8 years. A total of 84 subjects (n = 45 MCs, n = 39 NCs) are asymptomatic. Among symptomatic participants (n = 44) the mean age of symptom onset is 46.1 years. Approximately one-third of participants were symptomatic.

Among asymptomatic MCs and NCs early findings showed there were significant differences between the 2 groups in memory performance, brain amyloid burden as detected by PiB and CSF tau and Aβ-42 levels.

Dr. Anne Fagan

According to Anne Fagan, PhD, professor of neurology, Washington University Medical School, and biomarker core director of DIAN, said initial findings from plasma and CSF markers in the study cohort are consistent with biomarker evidence in sporadic, late-onset AD, specifically, low Aβ-42, high tau, p-tau levels, and high tau to Aβ-42 ratios.

"In general, we see what we consider to be the Alzheimer's disease CSF pattern in these mutation carries," said Dr. Fagan.

"Importantly," she added, "these changes can be detected many years prior to the appearance of cognitive symptoms. We have some people that have this profile 30 years before their estimated age of onset.

"Not only are we characterizing changes in these fluid biomarker levels in these autosomal dominant familial AD cases, we believe they can provide very important insight into the time course of pathology that's taking place in these individuals prior to the onset of clinical symptoms and that this information is really important in being able to design future clinical trials," said Dr. Fagan.

Clinical Trials Announcement

Preliminary imaging findings show increased amyloid deposition and increased brain atrophy, characteristic of late-onset AD. However, the imaging findings revealed distinct differences in regional distribution of Aβ-42 in the DIAN cohort vs late-onset disease.

Another notable difference between autosomal dominant AD and late-onset disease is that those with inherited AD have extra manifestations of motor symptoms.

Dr. Randall Bateman

"But the things that we define Alzheimer's disease by — early onset of memory loss — the slow progressive changes that ultimately affect one's ability to conduct activities of daily living and to take care of oneself and others — these are the same between the 2 diseases," said Randall Bateman, MD, assistant professor of neurology and associate director of DIAN.

According to Dr. Bateman the DIAN study and findings provide "the most extensive data on brain structural and pathologic biomarkers, blood and CSF biomarkers, and cognitive and clinical measures in preclinical and symptomatic early-onset autosomal dominant Alzheimer's disease" and represents a unique opportunity for prevention trials.

In the press briefing Dr. Bateman announced that the US Food and Drug Administration and the European Medicines Agency support prevention trials in this patient population and that 11 compounds have been nominated by the pharmaceutical industry for use in these studies and are currently under consideration by the DIAN clinical trials committee.

Although he would not reveal which compounds are under consideration, he disclosed that the majority are antiamyloid agents, most of which have previously been tested in humans.

The first trials are expected to begin in early 2012.

Historical Precedent

Dr. Bateman noted there is a successful historical model in cardiovascular disease for this approach to AD. He noted that coenzyme A reductase inhibitor trials were first conducted in individuals with a rare genetic form of hypercholesterolemia, which led to myocardial infarctions and stroke in very young individuals.

Dr. Ralph Nixon

Proof of efficacy in this rare patient group was "subsequently shown to have benefit for millions of people around the world," said Dr. Bateman.

Commenting on the DIAN trial, Ralph Nixon, MD, professor of psychiatry and cell biology at the New York University School of Medicine, New York City, and the vice-chairman of Alzheimer's Association Medical Scientific Advisory Council, said DIAN marks "a very exciting and new style of collaborative multinational research.

"But I think the most important message is that from this study we now have validation that it really is possible to detect changes at an early stage and that we are going to enhance the chances of administering therapies that will be more effective," said Dr. Nixon.

"This kind of project is exactly the sort of thing that the Alzheimer's Association has been trying to encourage in recent years. It underscores the importance of early detection so that we can be in a position to treat these individuals when therapies are available. I think this is also a mission to accelerate this type of research that is represented by DIAN, and so we are very happy to hear these positive and validating results," he added.

The study is supported by the National Institutes of Health National Institute on Aging. Dr. Morris, Dr. Fagan, Dr. Bateman, and Dr. Nixon have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2011: Featured Research Session F4-02. Presented July 20, 2011.

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