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July 26, 2012
An Alzheimer's Update: Amyloid Lives?
There's a good state-of-the-field post over at Chemiotics on Alzheimer's, in the wake of the bapineuzumab news the other day.
Of particular interest is the recent finding by deCODE and Genentech researchers that there's a mutation in the Alzheimer's precursor protein (APP) that actually seems to be protective against the disease. There are several APP mutations that are known to bring on amyloid-driven Alzheimer's at much earlier ages, but seeing one that goes the other way does lend more support to the idea that amyloid really is a causative agent:
The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without suffering major cognitive decline, such as memory loss. They also perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.
For Stefánsson, this suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. “Pathologists have always suspected that there was a substantial overlap between Alzheimer’s disease and normal age-related changes,” says Stefánsson. A drug that mimics the effects of the mutation, he says, would have the potential both to slow cognitive decline and to prevent Alzheimer’s.
Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks — and the alteration is enough to reduce the enzyme’s efficiency.
The flip side of this news is that targeting beta-secretase has already been the subject of a huge amount of work in the drug industry. That's good, in that we're not exactly starting from scratch, but that's bad, since the lack of success so far shows you that it's not exactly an easy thing to do. But there are still plenty of people taking cracks at it - CoMentis and Astellas have a compound in development, as do Merck, Lilly, Takeda, and others. Here's hoping that something from this class finally works out, and that this latest result isn't a red herring from a small mutation population.
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