Scientists find genetic variant helps delay early-onset Alzheimer’s Disease

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A scientific journey that began with one extraordinary patient is now making significant progress.

In 2019, researchers from Mass Eye and Ear and Massachusetts General Hospital (MGH) reported a case of a woman who did not show signs of cognitive impairment until her late 70s, despite her family’s high genetic risk for early-onset Alzheimer’s disease.

This woman had two copies of a rare APOE3 gene variant called Christchurch (APOE3Ch).

Now, the research team has found that even having one copy of this Christchurch variant can delay the onset of Alzheimer’s disease. This discovery comes from studying 27 more family members who carry just one copy of the variant and showed delayed disease onset.

The study, published in The New England Journal of Medicine, provides the first evidence that one copy of the Christchurch variant offers some protection against Alzheimer’s disease, although not as much as two copies.

“This finding is encouraging because it suggests we might be able to delay cognitive decline and dementia in older individuals,” said Dr. Yakeel T. Quiroz, a clinical neuropsychologist at MGH. “We hope to use this knowledge to develop effective treatments for dementia prevention.”

Dr. Quiroz and her team at MGH, along with Dr. Joseph Arboleda-Velasquez from Mass Eye and Ear, have been working with colleagues in Colombia. They are part of the MGH Colombia-Boston (COLBOS) biomarker study, examining the largest known family group with a genetic variant called the “Paisa” mutation (Presenilin-1 E280A). This mutation causes early-onset Alzheimer’s disease. About 1,200 of the 6,000 blood relatives in this family carry the mutation.

People with the Paisa mutation typically develop mild cognitive impairment in their 40s, dementia in their 50s, and die in their 60s. The researchers discovered that family members with one copy of the Christchurch variant started showing cognitive impairment later, around age 52 on average, compared to age 47 in those without the variant. They also developed dementia about four years later.

Brain scans of two individuals showed lower levels of tau (a protein linked to Alzheimer’s) and better metabolic activity in areas usually affected by the disease. Autopsy samples from four deceased individuals revealed less damage in blood vessels, which seems important for the protective effects of the APOE3 Christchurch variant.

Although the study was limited to a small number of people from a single family, the findings are promising. The team hopes to conduct further studies with larger and more diverse groups to understand the protective effects of the Christchurch variant better.

Dr. Quiroz emphasized the importance of the commitment shown by the Colombian patients and their families, which has been crucial for this research. “We are now focused on understanding brain resilience in family members who carry one copy of the Christchurch variant through MRI scans, cognitive evaluations, and blood sample analysis.”

The research team’s work aims to pave the way for new treatments inspired by these genetic findings, potentially offering hope for those at risk of Alzheimer’s disease.

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