Despite Alzheimer’s running in her family, a Colombian woman was able to sidestep the disease thanks to a unique genetic quirk.
Reporting in the journal, Nature Medicine, Harvard Medical School researchers and other scientists highlighted a family with a history of early-onset Alzheimer’s. One female member of the clan remarkably avoided symptoms until her 70s. The researchers said her case is unusual because most of the family members developed cognitive issues much earlier due to a specific genetic mutation known as PSEN1 E280A.
Mutations Matter
The PSEN1 gene plays a crucial role in Alzheimer’s disease. It encodes a protein that is part of the gamma-secretase complex, responsible for cutting other proteins into smaller pieces. One of these proteins is the amyloid precursor protein (APP). When PSEN1 functions correctly, it helps produce amyloid-beta, a protein fragment.
However, mutations in PSEN1 can lead to the production of abnormal amyloid-beta, which clumps together to form plaques in the brain that are the hallmark of Alzheimer’s and believed to contribute to the disease’s progression. The E280A mutation carried by this is known to lead to an overproduction of a harmful form of amyloid-beta that accelerates the onset of Alzheimer’s symptoms.
So how did the woman avoid the fate of so many of her relatives? Another rare genetic mutation known as APOE3 Christchurch held the answer.
The APOE family of genes control production of apolipoproteins, which transport lipids in blood that can affect brain health. The APOE2 variant has shown a protective against Alzheimer’s dementia, while the APOE4 variant has been associated with a higher risk for the disease. Research suggests that a third variant, APOE3, is agnostic, with either reduced or increased risk for Alzheimer’s.
APOE3 Christchurch is a different variant entirely. This mutation appears to alter the function of the APOE protein, conferring a strong protective effect and potentially slowing the disease’s progression or at least reducing its severity.
PET scans showed that the woman’s brain maintained normal glucose metabolism in areas typically affected by Alzheimer’s, despite carrying the PSEN1 mutation. Her MRI scans also indicated normal hippocampal volume, a key brain region often diminished in Alzheimer’s patients. Furthermore, her blood tests revealed low levels of a marker associated with brain damage, suggesting limited neurodegeneration.
These findings imply that the APOE3 Christchurch mutation might protect against Alzheimer’s by reducing tau pathology and neurodegeneration, even in the presence of significant amyloid plaques.
An Alzheimer’s Game Changer
“This is a ground-breaking case for Alzheimer’s disease and has already opened new paths for treatment and prevention, which we’re currently pursuing with some collaborators. This work is now bringing light into some of the mechanisms of resistance to Alzheimer’s disease” investigator Yakeel T. Quiroz told the Harvard Gazette. Quiroz is director of the Multicultural Alzheimer Prevention Program (MAPP) at Mass General, an associate professor of psychology at Harvard Medical School, and Paul B. and Sandra M. Edgerley MGH Research Scholar 2020-2025.
This case could indeed have a significant impact on Alzheimer’s research. Results suggest that certain genetic mutations might offer protection against the disease’s typical progression, even in the presence of other high-risk factors. Understanding how the APOE3 Christchurch mutation alters Alzheimer’s development could lead to new therapeutic approaches by shifting the focus towards genetic factors and their interactions in disease management. It also opens possibilities for targeted treatments that mimic the protective effects of this rare mutation.
“It is seldom that we have nice surprises while studying familial Alzheimer’s disease brains. This case showed an amazingly clear protected phenotype. I am sure our molecular and pathologic findings will at least suggest some avenues of research and elicit hope for a successful treatment against this disorder.” says co-first author Diego Sepulveda-Falla, research lead at University Medical Center Hamburg-Eppendorf in Hamburg, Germany.
Further Reading:
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