Journal Article

DZNE-2026-01112

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pathway-specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease.

Valentim, C. ; Denecke, J. ; Frerich, S. ; Betthauser, T. J. ; Li, Y. ; Ahmadi, R. ; Franzmeier, N. ; Initiative, A. D. N. (Collaboration Author) ; Malik, R. ; Ewers, M. (Last author)DZNE*

2026
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/alz.71939

Abstract: 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.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.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.Genetic variation in transport pathways modulates amyloid-driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Female (MeSH) ; Positron-Emission Tomography (MeSH) ; Genetic Risk Score (MeSH) ; tau Proteins: metabolism (MeSH) ; Genome-Wide Association Study (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Brain: metabolism (MeSH) ; Brain: diagnostic imaging (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Cross-Sectional Studies (MeSH) ; Aged, 80 and over (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Alzheimer's disease ; amyloid chronicity ; pathway analysis ; polygenic risk score ; positron emission tomography imaging ; tau Proteins ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Wiley ; Essential Science Indicators ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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