August 14, 2012

Alzheimer's Prevention: Can a Mutation-Afflicted Extended Family in Colombia Show the Way?

Two years ago, as this blog was getting started, I saw an article by Pam Belluck in the New York Times that captured my imagination. It told the story of an extended family – 5,000 strong -- in Colombia, South America… a family in which many members developed early-onset Alzheimer’s disease. The article began this way:
At frighteningly young ages, in their 40s, four of Laura Cuartas’s children began forgetting and falling apart, assaulted by what people here have long called La Bobera, the foolishness. It is a condition attributed, in hushed rumors, to everything from touching a mysterious tree to the revenge of a wronged priest.
Since all our efforts so far to treat Alzheimer’s -- in people already suffering from the disease – had pretty much come to naught, it seemed like a goldmine for scientists to find this family group plagued by an inherited genetic mutation that caused the debilitating dementia by middle age. Could researchers tap this troubled gene pool and figure a way to PREVENT the disease altogether, in a population known in advance to be acutely susceptible? The possibilities seemed fascinating, and encouraging.

Last fall, the New York Times updated its story. The new, large, and novel study to assess the possibility of preventing the disease was underway. Family members had begun travelling from their homes around Medellin, Colombia, to the Banner Alzheimer’s Institute in Phoenix, AZ, for PET scans to determine the presence of amyloid plaques, those tell-tale protein accumulations that typically accompany AD, and are thought to play a causative role.

The Mutation Target: Presenilin 1
If science could prevent Alzheimer’s before it began ravaging the brain, then this extended family group – all with the very same rare genetic mutation, presenilin 1, which triggers the early onset -- provided the perfect unit for investigation. Researchers knew AD would strike this group, and the subjects – before their genetic mutations kicked in – gave the scientists relatively healthy, young, undamaged brains to study. If plaques indeed caused AD, and if researchers could create and administer a drug to prevent their accumulation in the brain, medicine might take a giant step forward.

Study partners from the National Institutes of Health, biotech giant Genentech, and the Banner Alzheimer’s Institute created their methodology. About 100 people who carry the presenilin 1 mutation would receive the drug therapy. About 100 mutation carriers would receive a placebo. And about 100 non-carriers would also receive the placebo. Most participants have chosen not to know their mutation status, a fact that helps keep results "clean." The study also includes a small group of Americans whose families have shown a predisposition toward AD.

The Attack Drug: Crenezumab
A final piece in the study was selecting the drug therapy. Scientists decided to use crenezumab, described on the Genentech site as a “humanized monoclonal antibody… designed to bind to amyloid beta (Abeta), the main constituent of amyloid plaque in the brains of patients with Alzheimer’s disease.” Quite simply, the drug is designed to prevent the plaques from forming in the brain.

I’m excited to learn the outcome of this study, one of the most interesting I’ve encountered in my research. It shifts the current paradigm from reversing the symptoms of Alzheimer’s in people already afflicted to preventing the disease in healthy people likely to develop the dementia. And the study – if all the pieces fall into place – might just prove once and for all the role played by amyloid plaques in the development of the disease.

Don't hold your breath. It's a five-year trial, so we won't have results anytime soon. The $100M study was funded by NIH, the Banner Alzheimer's Institute, and Genentech -- which holds the license to crenezumab, and is poised to profit enormously if the study plays out in a positive way. Given the potential magnitude of the study’s outcome, Genentech has announced it plans to share all its findings, hoping that transparency will lead to additional research, and perhaps therapies, down the road. 

If you’d like to learn more about this trial – and see a series of brief videos featuring Genentech EVP Richard Scheller – check this page from Genentech's site.

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