De Bruin, Hannah; Groot, Colin; Barthel, Henryk; Bischof, Gérard N; Blazhenets, Ganna; Boellaard, Ronald; Boon, Baayla DC; ... Ossenkoppele, Rik; + view all De Bruin, Hannah; Groot, Colin; Barthel, Henryk; Bischof, Gérard N; Blazhenets, Ganna; Boellaard, Ronald; Boon, Baayla DC; Brendel, Matthias; Cash, David M; Coath, William; Day, Gregory S; Dickerson, Bradford C; Doering, Elena; Drzezga, Alexander; van Dyck, Christopher H; van Eimeren, Thilo; van der Flier, Wiesje M; Fredericks, Carolyn A; Fryer, Tim D; van de Giessen, Elsmarieke; Gordon, Brian A; Graff-Radford, Jonathan; Grinberg, Lea T; Hansson, Oskar; Hobbs, Diana A; Hoenig, Merle C; Höglinger, Günter; Irwin, David J; Jones, P Simon; Josephs, Keith A; Katsumi, Yuta; La Joie, Renaud; Lee, Edward B; Levin, Johannes; Malpetti, Maura; McGinnis, Scott M; Mecca, Adam P; Mohanty, Rosaleena; Nasrallah, Ilya M; O'Brien, John T; O'Dell, Ryan S; Palleis, Carla; Perneczky, Robert; Phillips, Jeffrey S; Putcha, Deepti; Rabinovici, Gil D; Rahmouni, Nesrine; Rosa-Neto, Pedro; Rowe, James B; Rullmann, Michael; Sabri, Osama; Saur, Dorothee; Schildan, Andreas; Schott, Jonathan M; Schroeter, Matthias L; Seeley, William W; Servaes, Stijn; Sintini, Irene; Smith, Ruben; Spina, Salvatore; Stevenson, Jenna; Stomrud, Erik; Strandberg, Olof; Therriault, Joseph; Tideman, Pontus; Touroutoglou, Alexandra; Trainer, Anne E; Visser, Denise; Wekselman, Fattin; Weston, Philip SJ; Whitwell, Jennifer L; Wolk, David A; Yong, Keir; Pijnenburg, Yolande AL; Franzmeier, Nicolai; Ossenkoppele, Rik; - view fewer (2025) Connectivity as a universal predictor of tau progression in atypical Alzheimer's disease. Brain , Article awaf279. 10.1093/brain/awaf279. (In press).

Preview

Text awaf279.pdf - Accepted Version Download (2MB) | Preview

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.

Download activity - last month

Export as JSONCSVXML

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item