Increased Genetic Protection Against Alzheimer's Disease in Centenarians.

Area of Science:

• Genetics
• Neuroscience
• Gerontology

Background:

• Alzheimer's disease (AD) poses a significant health challenge, particularly in aging populations.
• Understanding genetic factors contributing to longevity and AD resistance is crucial for developing effective interventions.
• The Apolipoprotein E (APOE) gene is a known risk factor for AD, but other genetic protective factors remain under investigation.

Purpose of the Study:

• To construct and validate an Alzheimer's disease polygenic protective score (AD PPS) excluding APOE variants.
• To investigate the association between AD PPS and extreme longevity across diverse populations.
• To examine the relationship between AD PPS, cognitive function, and mortality in centenarians.

Main Methods:

• Development of an AD PPS using established genetic variants associated with AD protection.
• Analysis of AD PPS in participants from five international studies of healthy aging and longevity.
• Comparison of AD PPS across different age groups, including centenarians, semi-supercentenarians, and supercentenarians.

Main Results:

• Centenarians demonstrated significantly higher AD PPS compared to individuals without familial longevity.
• Genetic protection against AD, as measured by AD PPS, increased with advancing age in centenarians.
• A higher AD PPS was associated with improved cognitive function and decreased mortality rates.

Conclusions:

• Individuals achieving extreme longevity possess substantial genetic protection against Alzheimer's disease.
• The AD PPS shows potential as a biomarker for cognitive aging and mortality risk.
• Findings suggest potential for therapeutic strategies targeting the genetic pathways identified by the AD PPS for broad applicability.