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Luan, Y.* ; Zheng, L.* ; Denecke, J.* ; Dehsarvi, A.* ; Roemer-Cassiano, S.N.* ; Dewenter, A.* ; Steward, A.* ; Shcherbinin, S.* ; Svaldi, D.O.* ; Kotari, V.* ; Higgins, I.A.* ; Pontecorvo, M.J.* ; Valentim, C.* ; Schnabel, J.A. ; Casale, F.P. ; Dyrba, M.* ; Teipel, S.* ; Franzmeier, N.* ; Ewers, M.*

Multimodal spatial gradients to explain regional susceptibility to fibrillar tau in Alzheimer's disease.

Alzheimers Dement. 21:e70170 (2025)

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INTRODUCTION: In Alzheimer's disease (AD), fibrillar tau gradually progresses from initial seed to larger brain area. However, those brain properties underlying the region-dependent susceptibility to tau accumulation remain unclear. METHODS: We constructed multimodal spatial gradients to characterize molecular properties and connectomic architecture. A predictive model for regional tau deposition was developed by integrating embeddings in the principal gradients of global connectome gradients with gene expression, neurotransmitters, myelin, and amyloid-beta. The model was trained on amyloid-beta-positive participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated in independent datasets. RESULTS: The combination of gradients explained up to 77.7% of cross-sectional and 77.3% of longitudinal inter-regional variance of tau deposition. Gene set enrichment analysis of a major gene expression gradient points to synaptic transmission to confer increased susceptibility to tau. DISCUSSION: Our findings reveal a spatially heterogeneous molecular landscape shaping regional susceptibility to tau deposition, presenting a powerful system-level explanatory model of tau pathology in AD. HIGHLIGHTS: Spatial gradients of fundamental molecular brain properties associated with tau pathology. The explanatory power showed high consistency across studies. Genetic analyses suggested that synapse expression plays a vital role in tau accumulation.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Alzheimer's Disease ; Functional Connectivity ; Gene Expression ; Multimodal Gradients ; Neurotransmitters ; Predictive Model ; Tau Positron Emission Tomography; Human Brain; Propagation; Pathology; Expression; Release; Cortex; Memory; Atlas

ISSN (print) / ISBN 1552-5260

e-ISSN 1552-5279

Journal Alzheimer's & Dementia

Quellenangaben Volume: 21, Issue: 5, Article Number: e70170

Publisher Elsevier

Publishing Place New York, NY [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Machine Learning in Biomed Imaging (IML)

Grants National Institute of Biomedical Imaging, and Bioengineering
NIA NIH HHS