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

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. © 2025 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

• author: De Bruin, H. ; Groot, C. ; Hansson, O. ; Smith, R. ; Stomrud, E. ; Strandberg, O. ; Tideman, P. and Ossenkoppele, R.
• author collaboration: Alzheimer's Disease Neuroimaging Initiative (ADNI)
• organization: MultiPark: Multidisciplinary research on neurodegenerative diseases; Clinical Memory Research (research group); LU Profile Area: Proactive Ageing; Regeneration in Movement Disorders (research group); Neurology, Lund; MR Physics (research group)
• publishing date: 2025
• type: Contribution to journal
• publication status: published
• subject: Neurology
• keywords: atypical Alzheimer's disease, connectivity, fMRI, heterogeneity, PET, tau, apolipoprotein E, florquinitau f 18, flortaucipir f 18, izaflortaucipir f 18, tau protein, tracer, aged, Alzheimer disease, aphasia, Article, autopsy, BOLD signal, brain analysis, brain cortex atrophy, brain region, cerebrospinal fluid, cognition, cohort analysis, controlled study, corticobasal degeneration, cross-sectional study, default mode network, dorsal attention network, echo planar imaging, female, follow up, frontoparietal network, functional connectivity, functional magnetic resonance imaging, gray matter, human, image quality, language network, logopenic progressive aphasia, longitudinal study, major clinical study, male, Mini Mental State Examination, multicenter study, nerve degeneration, neuroimaging, nuclear magnetic resonance imaging, paired helical filament, personalized medicine, phenotype, positron emission tomography, probability, sensitivity analysis, standardized uptake value ratio, T1 weighted imaging, temporal lobe, ventral attention network, visual network, white matter
• in: Brain
• volume: 148
• issue: 11
• pages: 20 pages
• publisher: Oxford University Press
• external identifiers: scopus:105021027110; pmid:40810361
• ISSN: 0006-8950
• DOI: 10.1093/brain/awaf279
• language: English
• LU publication?: yes
• id: 9d39d532-2140-435b-8183-654fc8d846fd
• date added to LUP: 2026-03-26 12:48:05
• date last changed: 2026-03-27 03:05:08