Pathway‐specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease
6 affiliations
- 1Institute for Stroke and Dementia Research University Hospital Ludwig Maximilian University Munich Germany
- 2Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA
- 3Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA
- 4Munich Cluster for Systems Neurology (SyNergy) Munich Germany
- 5Department of Psychiatry and Neurochemistry The Sahlgrenska Academy Institute of Neuroscience and Physiology, University of Gothenburg Mölndal and Gothenburg Sweden
- 6German Center for Neurodegenerative Diseases (DZNE) Munich Germany
Abstract
BACKGROUND: Genome‐wide association studies (GWASs) identified multiple genetic variants associated with Alzheimer's disease (AD) risk, yet the biological pathways linking these to amyloid and tau pathology remain unclear.
METHODS: We conducted a meta‐analysis of recent GWASs to identify independent genome‐wide significant single nucleotide polymorphisms which were mapped via gene‐set enrichment to derive pathway‐specific polygenic risk scores (pPRSs). Analyses included 441 amyloid‐positive participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 224 with longitudinal tau positron emission tomography [PET]) and 250 amyloid‐positive participants from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study (113 with longitudinal tau PET). Robust linear regressions tested cross‐sectional and longitudinal pPRS‐by‐amyloid chronicity interactions on tau PET.
RESULTS: Four pPRSs were identified including adaptive immune response, leukocyte activation, transport, and intracellular signaling. Only the transport pPRS strengthened amyloid–tau coupling cross‐sectionally across all Braak stages in ADNI (p < 0.05) and at Braak I in A4 (p < 0.05), with stronger effects observed in females; in ADNI, these associations persisted longitudinally only at the higher Braak stages.
DISCUSSION: Genetic variation in transport pathways modulates amyloid‐driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.
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BibTeX
@article{valentim2026pathwayspecific,
title = {{Pathway‐specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease}},
author = {Carolina Valentim and Jannis Denecke and Simon Frerich and Tobey J. Betthauser and Yuanxi Li and Reihaneh Ahmadi and Nicolai Franzmeier and Alzheimer's Disease Neuroimaging Initiative (ADNI) and Rainer Malik and Michael Ewers},
journal = {Alzheimer's \& Dementia},
year = {2026},
month = oct,
doi = {10.1002/alz.71939},
url = {https://doi.org/10.1002/alz.71939},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pathway‐specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease
AU - Carolina Valentim
AU - Jannis Denecke
AU - Simon Frerich
AU - Tobey J. Betthauser
AU - Yuanxi Li
AU - Reihaneh Ahmadi
AU - Nicolai Franzmeier
AU - Alzheimer's Disease Neuroimaging Initiative (ADNI)
AU - Rainer Malik
AU - Michael Ewers
PY - 2026
DA - 2026/10/27
JO - Alzheimer's & Dementia
DO - 10.1002/alz.71939
UR - https://doi.org/10.1002/alz.71939
AB - BACKGROUND: Genome‐wide association studies (GWASs) identified multiple genetic variants associated with Alzheimer's disease (AD) risk, yet the biological pathways linking these to amyloid and tau pathology remain unclear. METHODS: We conducted a meta‐analysis of recent GWASs to identify independent genome‐wide significant single nucleotide polymorphisms which were mapped via gene‐set enrichment to derive pathway‐specific polygenic risk scores (pPRSs). Analyses included 441 amyloid‐positive participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 224 with longitudinal tau positron emission tomography [PET]) and 250 amyloid‐positive participants from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study (113 with longitudinal tau PET). Robust linear regressions tested cross‐sectional and longitudinal pPRS‐by‐amyloid chronicity interactions on tau PET. RESULTS: Four pPRSs were identified including adaptive immune response, leukocyte activation, transport, and intracellular signaling. Only the transport pPRS strengthened amyloid–tau coupling cross‐sectionally across all Braak stages in ADNI (p < 0.05) and at Braak I in A4 (p < 0.05), with stronger effects observed in females; in ADNI, these associations persisted longitudinally only at the higher Braak stages. DISCUSSION: Genetic variation in transport pathways modulates amyloid‐driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.
SN - 1552-5260
SN - 1552-5279
ER -