Rare Mutation In Alzheimer’s Disease Gene Could Inform Future Therapies

Published: Friday, November 8, 2019 - 10:47am
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A rare mutation in a gene associated with Alzheimer's disease could reduce or delay its effects, even in a population known for its high risk.

The research, which appears in the journal Nature Medicine, could contribute to the development of gene or drug therapies.

It's a tale of two mutations.

One, a mutation in the PSEN1 gene, is the most common cause of familial Alzheimer's disease, a rare form of the illness that is entirely passed down through genetics. In one unusual extended family in Columbia, it means 1,200 of 6,000 members will almost certainly develop Alzheimer's disease in their 40s.

The other, a mutation in two APOE genes associated with Alzheimer's disease, appears to have slowed or blunted the first mutation's harmful effects, enabling one woman whose brain had accumulated amyloid plaques almost from birth to reach her 70s before symptom onset.

If the researchers are correct, the second mutation, dubbed "Christchurch," slowed or blunted the harmful effects of the first.

Co-author Dr. Eric Reiman of Banner Alzheimer's Institute said the patient showed more than a mere reduction in amyloid plaques.

"She also had a low measurements of other elements of Alzheimer's disease, known as tau tangles, and measurements that reflect the loss of brain cells," he said.

APOE genes come in three slightly different versions, or alleles, each associated with Alzheimer's disease outcomes: APOE3 is the baseline; APOE2 correlates with a lower risk of Alzheimer's disease and older age of symptom onset; APOE4 is linked to a higher risk and younger onset age.

The PSEN1 mutation skews that calculus toward early onset and family inheritance, although scientists still debate the mechanism by which it does so.

The woman in the study had the PSEN1 mutation, as well as two copies of the Christchurch mutation in her APOE3 genes.

The researchers believe the Christchurch mutation might have resisted the effects of the PSEN1 mutation by slowing neurodegeneration and limiting the buildup of tau protein tangles, a chief marker of Alzheimer's disease.

Reiman acknowledged the study's limitations, including its reliance on a single subject and a medical history necessarily based in part on anecdotal accounts, and said further independent studies are called for.

"On the other hand, it tells us how valuable every research participant who participates in this study is, and the impact that they continue to make every day," he said.

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