AI Insight
This study analyzed polygenic risk scores (PRS) from 1,752 different methods across four genetic ancestry groups, examining over 11,000 Alzheimer's disease cases and 19,000 controls aged 65 and older. Researchers found that individuals with extremely high PRS values showed significantly increased Alzheimer's disease risk across all ancestries tested, with notably strong associations in European and African ancestry groups where zero controls appeared among those with the most extreme scores. Importantly, 38% of individuals with extreme PRS were not carriers of the APOE ε4 variant, suggesting that extreme polygenic risk can identify high-risk individuals independently of this well-known genetic risk factor.
Why it matters
This research could enable earlier identification of individuals at very high risk for Alzheimer's disease before symptoms appear, potentially allowing for preventive interventions or closer monitoring. The finding that extreme polygenic risk operates independently of APOE ε4 status expands the population that could benefit from genetic risk stratification beyond traditional high-risk groups.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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=2.3068×10^-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 {varepsilon}4 carriers. Conclusions. Rare subsets of individuals at the most extreme PRS thresholds have markedly elevated AD enrichment across ancestries and APOE diplotypes.
Source: Rare extreme polygenic risk scores strongly indicate Alzheimer's disease risk