Polygenic Scores of Core-1 Alzheimer’s Disease Biomarkers Predict Early Cognitive and Pathological Change

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ABSTRACT BACKGROUND Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes leading to Alzheimer’s disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core-1 biomarkers remains unclear. The goal of this study is to determine whether genetic regulators of Core-1 biomarker levels predict AD pathology better than genetic regulators of clinical AD. METHODS Among 955 non-Hispanic white individuals, PGSs were built using GWAS of amyloid PET, plasma P-tau181, CSF P-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma P-tau181 and clinical AD GWAS. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts. RESULTS The Core-1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGS in both populations. DISCUSSION The Core-1 PGS show improved predictive value for AD-related plasma biomarkers and early cognitive changes. HIGHLIGHTS APOE -ε4 explained more variance in plasma P-tau217 than in plasma P-tau181. PGSs based on Core-1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in white non-Hispanic and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age. While the variance in P-tau181 and P-tau217 explained by individual Core-1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core-1 biomarkers may provide an opportunity for developing an integrative Core-1 PGS that more effectively predicts plasma P-tau181 and P-tau217 levels than AD-based PGS. RESEARCH IN CONTEXT SYSTEMATIC REVIEW Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes in Alzheimer’s disease (AD). The authors reviewed the literature on the association between core-1 biomarker-based polygenic scores (PGS) and plasma biomarkers using traditional sources (e.g., PubMed), meeting abstracts, and presentations. While several studies examined the association between PGS and plasma P-tau181 and P-tau217, most PGSs were based on AD genetic studies and performed poorly in predicting these biomarkers—especially in asymptomatic individuals. No studies have comprehensively assessed Core-1 biomarker-based PGSs in relation to P-tau181, P-tau217, other plasma biomarkers, and cognitive change. INTERPRETATION Our findings show that Core-1 biomarker-based PGSs outperform AD PGSs in predicting early changes in plasma P-tau181, P-tau217, other non-tau plasma biomarkers, and cognition in asymptomatic White and Caribbean Hispanic individuals. FUTURE DIRECTIONS The Core-1 PGS offers improved predictive value for AD-related plasma biomarkers and early cognitive changes. Future research should validate these findings using larger genome-wide association studies and explore integrated Core-1 PGSs for P-tau217 and P-tau181, especially as more Core-1 biomarker genetic data become available.

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