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.