Lucky guys. Among healthy elderly, the top Alzheimer’s risk gene is more dangerous to women than to men.

Lucky guys. Among healthy elderly, the top Alzheimer’s risk gene is more dangerous to women than to men.


Gene Mutation Protects Against Alzheimer's

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 β 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 β amyloid. Previously, researchers have identified more than 30 mutations to APP, none of them good. Several of these changes increase β 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 β 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 β 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."