Connectivity as a universal predictor of tau progression in atypical Alzheimer’s disease

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (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), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we 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 modelling 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 brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

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Journal
Brain
Published
2025-08-08
DOI
https://doi.org/10.1093/brain/awaf279
Citations
4
Primary Topic
Functional Brain Connectivity Studies
Type
article
Field-Weighted Citation Impact
5.72

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article

Connectivity as a universal predictor of tau progression in atypical Alzheimer’s disease

Alexandra Touroutoglou, Gérard N. Bischof, Lea T. Grinberg, Elena Doering et al.
4 citations
Brain
Functional Brain Connectivity Studies
5.72
article

Connectivity as a universal predictor of tau progression in atypical Alzheimer’s disease

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

Abstract

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (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), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we 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 modelling 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 brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

BrainVol. 148(11)
Yale New Haven Hospital (US), Mayo Clinic (US), Harvard University (US), Leipzig University of Applied Sciences (DE), Forschungszentrum Jülich (DE), German Cancer Research Center (DE), University of California, San Francisco (US), Lund University (SE), MRC Cognition and Brain Sciences Unit (GB), Washington University in St. Louis (US), University of Cambridge (GB), German Center for Neurodegenerative Diseases (DE), Jacksonville College (US), McGill University Health Centre (CA), WinnMed (US), Cambridge University Hospitals NHS Foundation Trust (GB), Karolinska Institutet (SE), LMU Klinikum (DE), Yale University (US), Massachusetts General Hospital (US), Cambridge School (PT), Bridge University (SS), University Memory and Aging Center (US), Amsterdam Neuroscience (NL), Institute for Neurodegenerative Disorders (US), Munich Cluster for Systems Neurology (DE), Pennsylvania Academic Library Consortium (US), Centre de Coopération Universitaire Franco-Bavarois (DE), Mayo Clinic in Arizona (US), University Hospital Leipzig (DE), UK Dementia Research Institute (GB), Penn Center for AIDS Research (US), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Jülich Aachen Research Alliance (DE), Institute on Aging (US), Skåne University Hospital (SE), NIHR Queen Square Dementia Biomedical Research Unit (GB), Mayo Clinic in Florida (US), University Hospital Cologne (DE), Imaging Center (US), University College London (GB), McGill University (CA), University of San Francisco (US), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Medical Research Council (GB), Leipzig University (DE)
Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Sanofi, Biogen, Teva Pharmaceutical Industries, University of Pennsylvania, Alzheimer's Disease Neuroimaging Initiative, Cure Alzheimer's Fund, McGill University, Astex Pharmaceuticals, University of Oxford, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Lunds Universitet, Lundbeckfonden, Eisai, Novo Nordisk, Ludwig-Maximilians-Universität München, Alzheimerfonden, Stichting Dioraphte, Alzheimer Nederland, Siemens Healthineers, H. Lundbeck A/S, Genentech, University of California, San Francisco, Avid Radiopharmaceuticals, Bayer Vital
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