Gene Mutation Protects Against Alzheimer's

by Greg Miller 
July 11, 2012
Science
http://news.sciencemag.org/sciencenow/2012/07/gene-mutation-protects-against-a.html

A rare mutation that alters a single letter of the
genetic code protects people from the memory-robbing
dementia of Alzheimer's disease, according to a new
study. The DNA change may inhibit the buildup of ß
amyloid, the protein fragment that accumulates in the
hallmark plaques that form in the brains of Alzheimer's
patients. Other researchers say the findings are
intriguing but not hugely surprising. They fit well, in
fact, with current thinking about Alzheimer's disease.

The newly identified mutation affects a gene called APP,
which encodes a protein that gets broken down into
pieces, including ß amyloid. Previously, researchers
have identified more than 30 mutations to APP, none of
them good. Several of these changes increase ß amyloid
formation and cause a devastating inherited form of
Alzheimer's that afflicts people in their 30s and 40s-
much earlier than the far more common "late-onset" form
of Alzheimer's that typically strikes people their 70s
and 80s.

The new mutation appears to do the opposite. Researchers
led by Kari Stefansson at deCODE genetics in Reykjavik
scanned whole-genome data from 1795 Icelanders for
variations in APP that protect against Alzheimer's. One
particular variant stood out: a switch of a single
nucleotide at one position in the APP gene. Among people
85 or older, those who had this mutation were 7.5 times
less likely to have Alzheimer's disease than were those
who did not have it. Additional experiments with
cultured cells suggested that the mutation interferes
with one of the enzymes that breaks down the APP protein
and causes a 40% reduction in ß amyloid formation,
Stefansson and colleagues report online today in Nature.

A naturally occurring variant in a different gene, the
so-called APOE2 allele, has been previously shown to
protect against Alzheimer's disease, but Stefansson says
the new variant, while rarer, confers much greater
protection. It may also protect against memory loss and
other cognitive declines even in people who don't
develop Alzheimer's disease. When the researchers
examined cognitive test results from thousands of people
in Icelandic nursing homes, they found that those with
the APP mutation tended to fare better through their 80s
and 90s than did those without it.

The findings bolster the predominant hypothesis that
amyloid accumulation is the primary culprit in
Alzheimer's disease, says Alison Goate, a geneticist who
studies Alzheimer's disease at Washington University in
St. Louis. "We've always had evidence that genetic
variants that increase amyloid ß increase risk for
disease, but showing the opposite I think really
provides strong support for the idea that this is
central to the disease mechanism."

The amyloid hypothesis has been called into question in
recent years as clinical trials with drugs and
antibodies intended to reduce amyloid buildup in the
brain have yielded disappointing results. But many
researchers now think those trials failed because they
started too late-after too much irreversible damage had
been done to the brain. The big question now is whether
these drugs could be effective if given much earlier.
Clinical trials scheduled to begin later this year will
test this idea by giving anti-amyloid drugs to people
genetically predisposed to early-onset Alzheimer's
disease before they develop symptoms.

In light of those upcoming trials, the new work is
encouraging in that it supports the idea that the early-
and late-onset forms of Alzheimer's involve the same
mechanisms, says Gerard Schellenberg, a molecular
geneticist at the University of Pennsylvania. "This
study makes it seem more likely that if they find
something [that prevents early-onset Alzheimer's],
there's a good chance it will also work for late-onset
disease."

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