TY - JOUR
T1 - Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease
AU - Zheng, Lukai
AU - Rubinski, Anna
AU - Denecke, Jannis
AU - Luan, Ying
AU - Smith, Ruben
AU - Strandberg, Olof
AU - Stomrud, Erik
AU - Ossenkoppele, Rik
AU - Svaldi, Diana Otero
AU - Higgins, Ixavier Alonzo
AU - Shcherbinin, Sergey
AU - Pontecorvo, Michael J.
AU - Hansson, Oskar
AU - Franzmeier, Nicolai
AU - Ewers, Michael
N1 - Funding Information: The F‐flortaucipir tracer was licensed by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company. I.A.H., D.O.S., S.S., and M.J.P. are employees of Eli Lilly and Company. M.E., N.F., and O.H. have received research funding from Eli Lilly and Company. The other authors report no conflicts of interests. 18 Publisher Copyright: © 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2023
Y1 - 2023
N2 - Objective: We aimed to test whether region-specific factors, including spatial expression patterns of the tau-encoding gene MAPT and regional levels of amyloid positron emission tomography (PET), enhance connectivity-based modeling of the spatial variability in tau-PET deposition in the Alzheimer disease (AD) spectrum. Methods: We included 685 participants (395 amyloid-positive participants within AD spectrum and 290 amyloid-negative controls) with tau-PET and amyloid-PET from 3 studies (Alzheimer's Disease Neuroimaging Initiative, 18F-AV-1451-A05, and BioFINDER-1). Resting-state functional magnetic resonance imaging was obtained in healthy controls (n = 1,000) from the Human Connectome Project, and MAPT gene expression from the Allen Human Brain Atlas. Based on a brain-parcellation atlas superimposed onto all modalities, we obtained region of interest (ROI)-to-ROI functional connectivity, ROI-level PET values, and MAPT gene expression. In stepwise regression analyses, we tested connectivity, MAPT gene expression, and amyloid-PET as predictors of group-averaged and individual tau-PET ROI values in amyloid-positive participants. Results: Connectivity alone explained 21.8 to 39.2% (range across 3 studies) of the variance in tau-PET ROI values averaged across amyloid-positive participants. Stepwise addition of MAPT gene expression and amyloid-PET increased the proportion of explained variance to 30.2 to 46.0% and 45.0 to 49.9%, respectively. Similarly, for the prediction of patient-level tau-PET ROI values, combining all 3 predictors significantly improved the variability explained (mean adjusted R2 range across studies = 0.118–0.148, 0.156–0.196, and 0.251–0.333 for connectivity alone, connectivity plus MAPT expression, and all 3 modalities combined, respectively). Interpretation: Across 3 study samples, combining the functional connectome and molecular properties substantially enhanced the explanatory power compared to single modalities, providing a valuable tool to explain regional susceptibility to tau deposition in AD. ANN NEUROL 2023.
AB - Objective: We aimed to test whether region-specific factors, including spatial expression patterns of the tau-encoding gene MAPT and regional levels of amyloid positron emission tomography (PET), enhance connectivity-based modeling of the spatial variability in tau-PET deposition in the Alzheimer disease (AD) spectrum. Methods: We included 685 participants (395 amyloid-positive participants within AD spectrum and 290 amyloid-negative controls) with tau-PET and amyloid-PET from 3 studies (Alzheimer's Disease Neuroimaging Initiative, 18F-AV-1451-A05, and BioFINDER-1). Resting-state functional magnetic resonance imaging was obtained in healthy controls (n = 1,000) from the Human Connectome Project, and MAPT gene expression from the Allen Human Brain Atlas. Based on a brain-parcellation atlas superimposed onto all modalities, we obtained region of interest (ROI)-to-ROI functional connectivity, ROI-level PET values, and MAPT gene expression. In stepwise regression analyses, we tested connectivity, MAPT gene expression, and amyloid-PET as predictors of group-averaged and individual tau-PET ROI values in amyloid-positive participants. Results: Connectivity alone explained 21.8 to 39.2% (range across 3 studies) of the variance in tau-PET ROI values averaged across amyloid-positive participants. Stepwise addition of MAPT gene expression and amyloid-PET increased the proportion of explained variance to 30.2 to 46.0% and 45.0 to 49.9%, respectively. Similarly, for the prediction of patient-level tau-PET ROI values, combining all 3 predictors significantly improved the variability explained (mean adjusted R2 range across studies = 0.118–0.148, 0.156–0.196, and 0.251–0.333 for connectivity alone, connectivity plus MAPT expression, and all 3 modalities combined, respectively). Interpretation: Across 3 study samples, combining the functional connectome and molecular properties substantially enhanced the explanatory power compared to single modalities, providing a valuable tool to explain regional susceptibility to tau deposition in AD. ANN NEUROL 2023.
UR - http://www.scopus.com/inward/record.url?scp=85174600957&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ana.26818
DO - https://doi.org/10.1002/ana.26818
M3 - Article
C2 - 37837382
SN - 0364-5134
JO - Annals of neurology
JF - Annals of neurology
ER -