Researchers are studying people who avoid dementia despite high genetic risk, finding rare gene variants that may protect against Alzheimer's disease.
By Hermes Vector
Some people avoid dementia despite age or genes that put them at high risk. Geneticist Henne Holstege wanted to study these individuals, but for five years all her grant applications were rejected. She launched her project in 2013.
Researchers are increasingly convinced that understanding resilience to dementia is as interesting as studying the genetics of high risk. The brain appears to have defence mechanisms against the toxic proteins that cause Alzheimer's, and scientists hope to exploit them.
"Nature has already done the experiment for us: certain gene variants protect us from Alzheimer's and they do so safely," says neuroscientist Guojun Bu from the Hong Kong University of Science and Technology. "Learning how they do this could guide us to new therapies."
The APOE gene is the most important genetic determinant of late-onset Alzheimer's disease. Three main alleles exist: APOE3 is the most common variant, APOE4 is the greatest genetic risk factor known, and APOE2 can delay onset of Alzheimer's by a decade when a person has two copies. Only about 1% of the population has two copies of APOE2.
A dozen or so rare gene variants have been verified as likely contributors to Alzheimer's resilience, though the strength of evidence varies. Three extremely rare variants of APOE3 have been found in people who seem to escape Alzheimer's, and one variant of APOE4 seems to neutralize the risk usually carried by that form.
One rare APOE3 variant, known as the Christchurch variant, affects the receptor-binding region of the ApoE protein and is thought to bind less strongly to receptors, making tau less likely to spread. The other two rare APOE3 variants influence the lipid-binding section, probably making the protein less sticky and less likely to clump and form plaques.
Greicius's team has found a rare protective variant known as W276C in a population of people with Native American ancestry, which has not been seen in other cohorts. "There's an incredible amount of power in ancestrally diverse data sets that we miss completely when we myopically focus on European ancestry," says Michael Greicius, a geneticist at Stanford University in California.
Protective gene variants could help illuminate how Alzheimer's emerges and worsens, and potentially how to treat it. Scientists are studying how these variants affect disease biology by mutating genes in mice or cell cultures and examining donated brain tissue.
Sources
This article was drafted with AI assistance and checked against the sources above. Company claims are reported as claims. Cover image is AI-generated.
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