An ounce of prevention

Alzheimer's Prevention Initiative launches two clinical trials that will apply biomarkers to test the efficacy of pre-symptomatic treatments

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PHOENIX—A group of Alzheimer'sdisease researchers is taking the road less traveled in this growingacademic and commercial field, spearheading a dedicated effort to"launch the era of Alzheimer's prevention research"—beforeanother generation of patients is lost.

The effort, called the Alzheimer'sPrevention Initiative (API), aims to test potential Alzheimer'streatments and identify new biomarkers that could lead to earlier andmore accurate diagnoses for Alzheimer's patients. Once that goal isachieved, the API then hopes to use these much-needed gains toeventually bring to market disease-delaying or prevention therapies.

The initiative initially grew out ofefforts at the Banner Alzheimer's Institute (BAI), a nonprofit,collaborative research center in Phoenix that is working onevaluating pre-symptomatic Alzheimer's treatments and providingevidence to the U.S. Food and Drug Administration (FDA) to helpassess the potential impact of these new therapies.

BAI's stated goals and mission—whichit acknowledges are ambitious, but affirms are achievable—arethreefold: to end Alzheimer's without losing a generation; toestablish a new standard of care for patients and families; and toforge collaborative models in biomedical research. The institute'spursuit of the latter goal involves brain imaging studies, genomicsand clinical trials.

The API's current work on clinicaltrials has made headlines lately—notably, in the Washington Postand New York Times—putting the initiative and BAI on the mapof cutting-edge Alzheimer's research.

Specifically, the API plans to launchtwo trials by 2012 that will evaluate pre-symptomatic Alzheimer'sdisease treatments and surrogate biomarker development. In bothstudies, the subjects will have completed genetic testing prior toparticipating in biomarker-driven trials of therapeutic agents aimedat delaying or preventing the onset of symptomatic Alzheimer's.

In one study, researchers will study5,000 young to middle-aged adult relatives of a large, extendedfamily in Antioquia, Colombia, about 1,000 of whom are estimated tocarry a PS1 mutation known to cause early-onset Alzheimer's atabout age 48. To date, more than 2,000 family members and 400 PS1mutation carriers have had genetic testing, including more than 100cognitively normal mutation carriers over the age of 40.

The other study will involve about50,000 U.S. citizens aged 60 to 80 who carry two copies of the riskgene ApoE4. These individuals are at especially high risk forlate-onset Alzheimer's and have an average age of dementia onset atabout 68 years.

Leading this effort are Dr. EricReiman, executive director of BAI and the institute's leadresearcher, and Dr. Pierre Tariot, associate director of BAI anddirector of the institute's Memory Disorders Center. Both men areinternationally recognized for pioneering contributions to the fieldsof brain imaging, behavioral neuroscience and Alzheimer's diseaseresearch, and have each authored hundreds of scientific publications.

"We and others have shown how brainimaging and other biomarker techniques can be used to detect andtrack Alzheimer's before the onset of symptoms in people who are atrisk for the disorder," says Reiman, who also serves as theclinical director of the Neurogenomics Division at the TranslationalGenomics Research Institute, or TGen. "Biomarkers have high valuefrom a research standpoint, but until you embed them in clinicaltrials, you don't know if they will change in response totreatment. We need to have more humility about how these biomarkerswork and embed them in clinical trials to help the field and developthe tools we need."

Tariot, who is also board-certified ininternal medicine and geriatric psychiatry, points out that with theskyrocketing number of people living to older ages, there is anurgent need to find effective pre-symptomatic treatments and alsohelp avert an overwhelming financial crisis. In addition, there are anumber of suggested—but unproven—"healthy lifestyle"interventions that might reduce a person's chance of developingAlzheimer's symptoms that should be tested, he says.

Most notably, Tariot says, the trialswill enable researchers to evaluate promising experimental therapiesthat have the potential to slow down, stop or prevent Alzheimer'sfrom developing in the first place. While he is obviously unable tospecify if any compounds in development have been selected or namecompanies that are working with the API, Tariot notes: "Consensusis mounting that these treatments may need to be started before theonset of symptoms for them to have their most pronounced benefit. Assufficient safety data is obtained, these new agents can then bestudied in cognitively normal people who are at the highest imminentrisk for symptomatic Alzheimer's, before the onset of symptoms."

Once regulatory agencies are able tosupport the use of surrogate endpoints to allow accelerated approvalof pre-symptomatic Alzheimer's treatments, Reiman says, "Thiswould help provide the incentives needed for sponsors to invest inmany different prevention trials at the same time, and find one thatworks without losing a generation."

The API has many partners, includingthe National Institutes of Health, the Alzheimer's DiseaseNeuroimaging Initiative, the Alzheimer's Disease Cooperative Study,the Dominantly Inherited Alzheimer's Network, the Alzheimer'sAssociation, Prevent Alzheimer's Disease 2010, ACT-AD, LeadersEngaged on Alzheimer's Disease and several other privatefoundations and advocacy groups—in addition to the FDA and otherregulatory agencies.

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