Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk

BackgroundAlzheimers 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. MethodsUsing 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. ResultsIndividuals in the extreme upper PRS tail were significantly enriched for AD in all ancestries: Admixed American (Padj=0.02727), African (Padj=0.004827), East Asian (Padj=0.02824), and European (Padj=2.3068x10-13). 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 {varepsilon}4 carriers. ConclusionsRare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes. Data AvailabilityAll data are available through the ADSP, which is managed by The National Institute on Aging Genetics of Alzheimers Disease Data Storage Site (NIAGADS).