Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease

Abstract

ObjectiveWe 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.MethodsWe 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.ResultsConnectivity 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).InterpretationAcross 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 2024;95:274–287