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Basic Science and Pathogenesis
Oluwatosin A Olayinka1,2, John J Farrell2,3,4,5, Congcong Zhu2,3,4
1Boston University Bioinformatics Program, Boston, MA, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
This study reveals that rare variants (RVs) significantly impact Alzheimer's disease (AD) risk, even in individuals with low polygenic risk scores (PRS). Stratifying by PRS enhances the discovery of novel AD-associated RVs and low-frequency variants (LVs).
Area of Science:
- Genetics
- Neuroscience
- Computational Biology
Background:
- Polygenic risk scores (PRS) typically use common variants to estimate genetic risk for diseases like Alzheimer's disease (AD).
- Rare variants (RVs), while not included in standard PRS, are known to contribute significantly to AD pathogenesis.
- This study aimed to leverage PRS to identify novel associations with RVs in AD.
Purpose of the Study:
- To investigate the association of rare variants (RVs) with Alzheimer's disease (AD) risk.
- To determine if stratifying individuals by polygenic risk score (PRS) enhances the discovery of AD-associated RVs and low-frequency variants (LVs).
- To explore RVs with opposing effects to an individual's genetic background risk.
Main Methods:
- Calculated PRS for non-Hispanic white (NHW) samples (n=11,409) from the Alzheimer's Disease Sequencing Project (ADSP) R4 dataset.
- Classified participants into high (n=5,442) and low (n=5,967) PRS groups based on the median.
- Analyzed 11,485,531 low-frequency variants (LVs) and RVs (MAC>5) for association with AD in each PRS group separately using regression models.
Main Results:
- Identified genome-wide significant associations for RVs and LVs with AD in both low and high PRS groups.
- Observed disproportionate enrichment of risk variants in the low PRS group and protective variants in the high PRS group.
- Discovered specific RVs and LVs associated with increased or decreased AD risk within distinct PRS strata, with no association in the opposite stratum.
Conclusions:
- Stratifying individuals by common variant-based PRS improves the detection of RV and LV associations with AD.
- An individual's PRS may not accurately reflect their overall genetic relative risk for AD.
- The study identified unique RVs that confer risk opposite to the individual's genetic background, offering new research avenues.
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