Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Polygenic scores of Core 1 Alzheimer's disease biomarkers predict early cognitive and pathological change.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Xu Yuexuan, Qiao Min, Gunasekaran Tamil I, Gu Yian, Reyes-Dumeyer Dolly, Piriz Angel, Sanchez Danurys, Soriano Belisa, Franco Yahaira, Coronado Zoraida Dominguez, Recio Patricia, Mejia Diones Rivera, Medrano Martin, Lantigua Rafael A, Honig Lawrence, Wilson Rachael, Manly Jennifer J, Brickman Adam M, Engelman Corinne D, Johnson Sterling, Asthana Sanjay, Vardarajan Badri, Mayeux Richard
Аннотация
INTRODUCTION: Core 1 biomarkers, such as amyloid positron emission tomography, 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 was to determine whether genetic regulators of Core 1 biomarker levels predicted AD pathology better than genetic regulators of clinical AD.
METHODS: Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. 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 PGSs in both populations.
DISCUSSION: The Core 1 PGSs 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 non-Hispanic White 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.
METHODS: Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. 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 PGSs in both populations.
DISCUSSION: The Core 1 PGSs 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 non-Hispanic White 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.