Heterogeneous tau patterns in atypical AD are explained by connectivity‐associated tau progression

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

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Journal
Alzheimer s & Dementia
Published
2025-12-01
DOI
https://doi.org/10.1002/alz70856_104871
Primary Topic
Dementia and Cognitive Impairment Research
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article
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article

Heterogeneous tau patterns in atypical AD are explained by connectivity‐associated tau progression

Alexandra Touroutoglou, Gérard N. Bischof, Lea T. Grinberg, Elena Doering et al.
Alzheimer s & Dementia
Dementia and Cognitive Impairment Research
article

Heterogeneous tau patterns in atypical AD are explained by connectivity‐associated tau progression

Alexandra Touroutoglou, Gérard N. Bischof, Lea T. Grinberg, Elena Doering, Maura Malpetti, Tim D. Fryer, Ilya M. Nasrallah, Robert Perneczky, Michael Rullmann, Nesrine Rahmouni, Renaud La Joie, Philip SJ. Weston, Carolyn Fredericks, Rik Ossenkoppele, Erik Stomrud, James Benedict Rowe, Salvatore Spina, Denise Visser, O'Brien John Tiernan, Ronald Boellaard, Pontus Tideman, Olof T. Strandberg, Jeffrey S. Phillips, Johannes Levin, Carla Palleis, Osama Sabri, David A. Wolk, Deepti Putcha, Irene Sintini, William Coath, Dorothee Saur, Diana A. Hobbs, Thilo van Eimeren, Anne Trainer, Yuta Katsumi, Ganna Blazhenets, Alexander Drzezga, Nicolai Franzmeier, Adam P. Mecca, Andreas Schildan, Rosaleena Mohanty, Fattin Wekselman, Merle C. Hönig, Colin Groot, Yolande A.L. Pijnenburg, Oskar H. Hansson, Hannah de Bruin, Jonathan Graff Radford, Jenna Stevenson, Keir X X Yong, Henryk Barthel, Brad C. Dickerson, Baayla D.C. Boon, Ryan S O'Dell, Elsmarieke van de Giessen, Pedro Rosa‐Neto, Stijn Servaes, Günter U Höglinger, Jennifer L. Whitwell, Matthias Brendel, Christopher H van Dyck, Gregory S Day, Joseph Therriault, Eddie B. Lee, Matthias L Schroeter, David M Cash, P Simon Jones, Brian A. Gordon, David J. Irwin, Scott M McGinnis, Alzheimer's Disease Neuroimaging Initiative (ADNI), Ruben Smith, Keith A. Josephs, William W. Seeley, Wiesje M. van der Flier, Jonathan M Schott, Gil D. Rabinovici
article en

Abstract

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

Alzheimer s & DementiaVol. 21(S2)
University of Southern California (US), Harvard University (US), Forschungszentrum Jülich (DE), University of California, San Francisco (US), University of Cologne (DE), Lund University (SE), MRC Cognition and Brain Sciences Unit (GB), Washington University in St. Louis (US), University of Cambridge (GB), Jacksonville College (US), McGill University Health Centre (CA), WinnMed (US), Karolinska Institutet (SE), LMU Klinikum (DE), Yale University (US), Massachusetts General Hospital (US), University Memory and Aging Center (US), Amsterdam Neuroscience (NL), Munich Cluster for Systems Neurology (DE), Mayo Clinic in Arizona (US), UK Dementia Research Institute (GB), Jülich Aachen Research Alliance (DE), Skåne University Hospital (SE), Mayo Clinic in Florida (US), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), University Hospital Cologne (DE), Imaging Center (US), University College London (GB), McGill University (CA), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Vrije Universiteit Amsterdam (NL), Medical Research Council (GB), Leipzig University (DE)
Openalex Percentile: Top 29%
Dementia and Cognitive Impairment Research
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