medRxiv : the preprint server for health sciences · 2026
Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk.
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Ward Elizabeth L, Nelson Peter T, Katsumata Yuriko, Fardo David W, Jicha Gregory A, Alzheimer’s Disease Neuroimaging Initiative, Miller Justin B
Аннотация
BACKGROUND: Alzheimer's disease (AD) pathology often accumulates years before memory loss, creating a need to identify high-risk individuals presymptomatically. Polygenic risk scores (PRS) stratify AD risk, but individual-level predictions remain uncertain. Extreme PRS may identify high-risk individuals independent of APOE .
METHODS: Using GenoPred, extreme tails of 1,752 PRS methods were evaluated across four genetic ancestries using 11,200 autopsy- or clinically-defined AD cases and 19,321 controls (age ≥65) from the AD Sequencing Project (ADSP) Release 5.
RESULTS: Individuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American ( P adj =0.02727), African ( P adj =0.004827), East Asian ( P adj =0.02824), and European ( P adj =2.3068×10 -13 ). No controls were observed among the 42 European- and 12 African-ancestry individuals with extreme PRS. Extreme PRS spanned APOE diplotypes; 38% occurred in non- APOE ε4 carriers.
CONCLUSIONS: Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes.
DATA AVAILABILITY: All data are available through the ADSP, which is managed by The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS).
METHODS: Using GenoPred, extreme tails of 1,752 PRS methods were evaluated across four genetic ancestries using 11,200 autopsy- or clinically-defined AD cases and 19,321 controls (age ≥65) from the AD Sequencing Project (ADSP) Release 5.
RESULTS: Individuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American ( P adj =0.02727), African ( P adj =0.004827), East Asian ( P adj =0.02824), and European ( P adj =2.3068×10 -13 ). No controls were observed among the 42 European- and 12 African-ancestry individuals with extreme PRS. Extreme PRS spanned APOE diplotypes; 38% occurred in non- APOE ε4 carriers.
CONCLUSIONS: Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes.
DATA AVAILABILITY: All data are available through the ADSP, which is managed by The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS).