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

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 (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. Conclusions. Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes.