Studies Take Aim at Groups at High Risk for Alzheimer's

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).