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

doi:10.1093/brain/awaf279

. 2025 Aug 14:awaf279.

doi: 10.1093/brain/awaf279. Online ahead of print.

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

Hannah de Bruin^{1

2

3}, Colin Groot^{1

2

4}, Henryk Barthel⁵, Gérard N Bischof^{6

7}, Ganna Blazhenets⁸, Ronald Boellaard^{9

10}, Baayla D C Boon^{1

11}, Matthias Brendel^{12

13

14

15

16}, David M Cash^{17

18}, William Coath¹⁷, Gregory S Day¹¹, Bradford C Dickerson¹⁹, Elena Doering^{7

20}, Alexander Drzezga^{6

7

20}, Christopher H van Dyck^{21

22}, Thilo van Eimeren^{7

23}, Wiesje M van der Flier^{1

2}, Carolyn A Fredericks^{24

25}, Tim D Fryer^{26

27}, Elsmarieke van de Giessen^{9

10}, Brian A Gordon^{28

29}, Jonathan Graff-Radford³⁰, Lea T Grinberg^{8

31}, Oskar Hansson⁴, Diana A Hobbs^{28

29}, Merle C Hoenig^{6

7}, Günter Höglinger^{13

14

32}, David J Irwin^{33

34}, P Simon Jones²⁶, Keith A Josephs³⁰, Yuta Katsumi¹⁹, Renaud La Joie⁸, Edward B Lee^{35

36

37}, Johannes Levin^{13

14

32}, Maura Malpetti^{26

38}, Scott M McGinnis¹⁹, Adam P Mecca^{21

22}, Rosaleena Mohanty³⁹, Ilya M Nasrallah⁴⁰, John T O'Brien⁴¹, Ryan S O'Dell^{21

22}, Carla Palleis³², Robert Perneczky⁴², Jeffrey S Phillips^{33

34}, Deepti Putcha¹⁹, Gil D Rabinovici^{8

43}, Nesrine Rahmouni⁴⁴, Pedro Rosa-Neto⁴⁴, James B Rowe^{26

45}, Michael Rullmann⁵, Osama Sabri⁵, Dorothee Saur⁴⁶, Andreas Schildan⁵, Jonathan M Schott¹⁷, Matthias L Schroeter^{47

48}, William W Seeley^{8

31}, Stijn Servaes⁴⁴, Irene Sintini⁴⁹, Ruben Smith^{4

50}, Salvatore Spina⁸, Jenna Stevenson⁴⁴, Erik Stomrud^{4

50}, Olof Strandberg⁴, Joseph Therriault⁴⁴, Pontus Tideman^{4

50}, Alexandra Touroutoglou¹⁹, Anne E Trainer⁵¹, Denise Visser^{2

9

10}, Fattin Wekselman^{8

31}, Philip S J Weston^{17

18}, Jennifer L Whitwell⁴⁹, David A Wolk^{33

35

52}, Keir Yong¹⁷, Yolande A L Pijnenburg^{1

2}, Nicolai Franzmeier^{3

13

53}, Rik Ossenkoppele^{1

2

4}

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam 1081 HV, Netherlands.
² Amsterdam Neuroscience, Neurodegeneration, Amsterdam 1081 HV, The Netherlands.
³ Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich 81377, Germany.
⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund 221 00, Sweden.
⁵ Department of Nuclear Medicine, University of Leipzig, Leipzig 04109, Germany.
⁶ Research Center Jülich, Institute for Neuroscience and Medicine II, Molecular Organization of the Brain, Jülich 52428, Germany.
⁷ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Nuclear Medicine, Cologne 50923, Germany.
⁸ Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁹ Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam 1081 HV, The Netherlands.
¹⁰ Amsterdam Neuroscience, Brain Imaging, Amsterdam 1081 HV, The Netherlands.
¹¹ Mayo Clinic, Jacksonville, FL, 32224, USA.
¹² Department of Nuclear Medicine, LMU University Hospital, Munich 81377, Germany.
¹³ Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany.
¹⁴ German Center for Neurodegenerative Diseases (DZNE), Munich 81377, Germany.
¹⁵ German Cancer Consortium (DKTK), Partner Site Munich, a partnership between German Cancer Research Center (DKFZ) and LMU Munich, Munich 81377, Germany.
¹⁶ Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich 81377, Germany.
¹⁷ Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁸ UK Dementia Research Institute, UCL, London NW1 3BT, UK.
¹⁹ Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Bonn/Cologne 53127, Germany.
²¹ Alzheimer's Disease Research Unit, Yale University School of Medicine, One Church Street, 8th Floor, New Haven, CT, 06510, USA.
²² Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06510, USA.
²³ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne 50937, Germany.
²⁴ Yale University School of Medicine, New Haven, CT, 06510, USA.
²⁵ Department of Neurology, Yale New Haven Hospital, New Haven, CT, 06510, USA.
²⁶ Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge CB2 0QQ, UK.
²⁷ Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB2 0QQ, UK.
²⁸ Department of Radiology, Washington University in St Louis, St Louis, MO, 63130, USA.
²⁹ Knight Alzheimer's Disease Research Center, Washington University in St Louis, St Louis, MO, 63130, USA.
³⁰ Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
³¹ Department of Pathology, University of California, San Francisco, San Francisco, CA, 94143, USA.
³² Department of Neurology, LMU University Hospital, LMU Munich, Munich 81377, Germany.
³³ Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁴ Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁵ Institute on Aging, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁶ Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁷ Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁸ UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK.
³⁹ Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Karolinska Institutet, Huddinge 141 83, Sweden.
⁴⁰ Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁴¹ Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, UK.
⁴² Department of Psychiatry and Psychotherapy, LMU University Hospital, Munich 80336, Germany.
⁴³ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 94143, USA.
⁴⁴ McGill Centre for Studies in Aging, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada.
⁴⁵ Medical Research Council Cognition and Brain Sciences Unit, Cambridge CB2 7EF, UK.
⁴⁶ Department of Neurology, University of Leipzig, Leipzig 04103, Germany.
⁴⁷ Clinic for Cognitive Neurology, University of Leipzig, Leipzig 04103, Germany.
⁴⁸ Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103, Germany.
⁴⁹ Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
⁵⁰ Memory Clinic, Skåne University Hospital, Malmö 205 02, Sweden.
⁵¹ Clinical Neurosciences Imaging Center, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁵² Penn Memory Center, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁵³ University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Psychiatry and Neurochemistry, Gothenburg 413 90, Sweden.

PMID: 40810361
DOI: 10.1093/brain/awaf279

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

Hannah de Bruin et al. Brain. 2025.

. 2025 Aug 14:awaf279.

doi: 10.1093/brain/awaf279. Online ahead of print.

Authors

Affiliations

¹ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam 1081 HV, Netherlands.
² Amsterdam Neuroscience, Neurodegeneration, Amsterdam 1081 HV, The Netherlands.
³ Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich 81377, Germany.
⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund 221 00, Sweden.
⁵ Department of Nuclear Medicine, University of Leipzig, Leipzig 04109, Germany.
⁶ Research Center Jülich, Institute for Neuroscience and Medicine II, Molecular Organization of the Brain, Jülich 52428, Germany.
⁷ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Nuclear Medicine, Cologne 50923, Germany.
⁸ Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁹ Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam 1081 HV, The Netherlands.
¹⁰ Amsterdam Neuroscience, Brain Imaging, Amsterdam 1081 HV, The Netherlands.
¹¹ Mayo Clinic, Jacksonville, FL, 32224, USA.
¹² Department of Nuclear Medicine, LMU University Hospital, Munich 81377, Germany.
¹³ Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany.
¹⁴ German Center for Neurodegenerative Diseases (DZNE), Munich 81377, Germany.
¹⁵ German Cancer Consortium (DKTK), Partner Site Munich, a partnership between German Cancer Research Center (DKFZ) and LMU Munich, Munich 81377, Germany.
¹⁶ Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich 81377, Germany.
¹⁷ Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁸ UK Dementia Research Institute, UCL, London NW1 3BT, UK.
¹⁹ Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Bonn/Cologne 53127, Germany.
²¹ Alzheimer's Disease Research Unit, Yale University School of Medicine, One Church Street, 8th Floor, New Haven, CT, 06510, USA.
²² Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06510, USA.
²³ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne 50937, Germany.
²⁴ Yale University School of Medicine, New Haven, CT, 06510, USA.
²⁵ Department of Neurology, Yale New Haven Hospital, New Haven, CT, 06510, USA.
²⁶ Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge CB2 0QQ, UK.
²⁷ Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB2 0QQ, UK.
²⁸ Department of Radiology, Washington University in St Louis, St Louis, MO, 63130, USA.
²⁹ Knight Alzheimer's Disease Research Center, Washington University in St Louis, St Louis, MO, 63130, USA.
³⁰ Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
³¹ Department of Pathology, University of California, San Francisco, San Francisco, CA, 94143, USA.
³² Department of Neurology, LMU University Hospital, LMU Munich, Munich 81377, Germany.
³³ Department of Neurology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁴ Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁵ Institute on Aging, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁶ Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁷ Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³⁸ UK Dementia Research Institute at the University of Cambridge, Cambridge CB2 0AH, UK.
³⁹ Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Karolinska Institutet, Huddinge 141 83, Sweden.
⁴⁰ Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁴¹ Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, UK.
⁴² Department of Psychiatry and Psychotherapy, LMU University Hospital, Munich 80336, Germany.
⁴³ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 94143, USA.
⁴⁴ McGill Centre for Studies in Aging, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada.
⁴⁵ Medical Research Council Cognition and Brain Sciences Unit, Cambridge CB2 7EF, UK.
⁴⁶ Department of Neurology, University of Leipzig, Leipzig 04103, Germany.
⁴⁷ Clinic for Cognitive Neurology, University of Leipzig, Leipzig 04103, Germany.
⁴⁸ Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig 04103, Germany.
⁴⁹ Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
⁵⁰ Memory Clinic, Skåne University Hospital, Malmö 205 02, Sweden.
⁵¹ Clinical Neurosciences Imaging Center, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁵² Penn Memory Center, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁵³ University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Psychiatry and Neurochemistry, Gothenburg 413 90, Sweden.

PMID: 40810361
DOI: 10.1093/brain/awaf279

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 epicenters. 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, multicenter 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 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 brain regions with stronger resting-state fMRI-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 epicenters (i.e., the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicenters (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 epicenters 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 epicenters and accumulation epicenters 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 epicenters, 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 endpoints in clinical trials.

Keywords: PET; atypical Alzheimer’s disease; connectivity; fMRI; heterogeneity; tau.

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

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

Authors

Affiliations

Abstract

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