Utility of Polygenic Risk Scores in Families with Exceptional Longevity

Area of Science:

• Genetics
• Neuroscience
• Epidemiology

Background:

• Polygenic risk scores (PRS) are utilized to estimate individual disease susceptibility, including for Alzheimer's disease (AD).
• This research investigates PRS utility within a cohort characterized by healthy aging and reduced AD incidence.

Purpose of the Study:

• To evaluate the predictive power of PRS for AD risk in a cohort of families with a history of healthy aging.
• To assess the association between PRS and AD biomarkers in this specific population.

Main Methods:

• Utilized whole genome sequencing (WGS) data from US Longitudinal Study of Aging participants evaluated for AD.
• Calculated PRS using a published weighted formula based on SNPs significantly associated with AD.
• Employed mixed-effects models to analyze PRS association with AD risk and biomarkers (Aβ42, Aβ40, NfL, GFAP), adjusting for confounders and familial relatedness.

Main Results:

• Polygenic risk scores demonstrated limited predictive capacity for AD in the healthy aging cohort.
• Allele frequencies for single nucleotide polymorphisms (SNPs) used in PRS differed between this cohort and the general population.
• No significant associations were found between PRS and AD biomarkers, potentially due to a low number of SNPs associated with biomarkers.

Conclusions:

• Population ascertainment is critical for interpreting PRS results accurately.
• PRS derived from general population data may be insufficient for populations with inherently reduced disease risk, such as those with familial healthy aging.
• Genetic risk variants used in PRS may necessitate population-specific adjustments for effective disease risk prediction.