Polygenic scores of Core 1 Alzheimer's disease biomarkers predict early cognitive and pathological change

Yuexuan Xu; Min Qiao; Tamil I Gunasekaran; Yian Gu; Dolly Reyes-Dumeyer; Angel Piriz; Danurys Sanchez; Belisa Soriano; Yahaira Franco; Zoraida Dominguez Coronado; Patricia Recio; Diones Rivera Mejia; Martin Medrano; Rafael A Lantigua; Lawrence Honig; Rachael Wilson; Jennifer J Manly; Adam M Brickman; Corinne D Engelman; Sterling Johnson; Sanjay Asthana; Badri Vardarajan; Richard Mayeux

doi:10.1002/alz.70937

Polygenic scores of Core 1 Alzheimer's disease biomarkers predict early cognitive and pathological change

Alzheimers Dement. 2025 Nov;21(11):e70937. doi: 10.1002/alz.70937.

Authors

Yuexuan Xu^{1

2}, Min Qiao^{1

2}, Tamil I Gunasekaran^{1

2}, Yian Gu^{1

2

3}, Dolly Reyes-Dumeyer^{1

2}, Angel Piriz¹, Danurys Sanchez¹, Belisa Soriano⁴, Yahaira Franco⁵, Zoraida Dominguez Coronado⁶, Patricia Recio⁷, Diones Rivera Mejia^{4

7}, Martin Medrano⁸, Rafael A Lantigua^{1

9}, Lawrence Honig^{1

2

3}, Rachael Wilson^{10

11}, Jennifer J Manly^{1

2

3}, Adam M Brickman^{1

2

3}, Corinne D Engelman¹², Sterling Johnson^{10

11}, Sanjay Asthana^{10

11}, Badri Vardarajan^{1

2}, Richard Mayeux^{1

2

3}

Affiliations

¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
² G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
³ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, New York, USA.
⁴ Universidad Pedro Henríquez Urena, Santo Domingo, Dominican Republic.
⁵ Clinica Corominas, Santiago, Dominican Republic.
⁶ Clínica Gregorio Hernandez, Puerto Plata, Dominican Republic.
⁷ CEDIMAT, Santo Domingo, Dominican Republic.
⁸ Pontificia Universidad Catolica Madre y Maestra (PUCMM), Santiago, Dominican Republic.
⁹ Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, New York, USA.
¹⁰ Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹¹ Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹² Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Abstract

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.

Keywords: APOE; cognition; plasma biomarker; polygenic score; preclinical; p‐tau217.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Biomarkers* / blood
Biomarkers* / cerebrospinal fluid
Cognition
Female
Genome-Wide Association Study
Humans
Male
Middle Aged
Multifactorial Inheritance* / genetics
Positron-Emission Tomography
White / genetics
tau Proteins* / blood
tau Proteins* / cerebrospinal fluid

Substances

Biomarkers
tau Proteins

Abstract

MeSH terms

Substances

Grants and funding