Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) phenotypes might result from differences in selective vulnerability. Evidence from preclinical models suggests that tau pathology has cell-to-cell propagation properties. Therefore, here, we tested the cell-to-cell propagation framework in the amnestic, visuospatial, language, and behavioral/dysexecutive phenotypes of AD. We report that each AD phenotype is associated with a distinct network-specific pattern of tau aggregation, where tau aggregation is concentrated in brain network hubs. In all AD phenotypes, regional tau load could be predicted by connectivity patterns of the human brain. Furthermore, regions with greater connectivity displayed similar rates of longitudinal tau accumulation in an independent cohort. Connectivity-based tau deposition was not restricted to a specific vulnerable network but was rather a general property of brain organization, linking selective vulnerability and transneuronal spreading models of neurodegeneration. Together, this study indicates that intrinsic brain connectivity provides a framework for tau aggregation across diverse phenotypic manifestations of AD.

Associations between different tau-PET patterns and longitudinal atrophy in the Alzheimer’s disease continuum: biological and methodological perspectives from disease heterogeneity

“…Compared to previous studies describing cortical predominant subtypes in tau-PET (occipital-dominant/visual variant, left hemisphere-dominant/language variant, etc.) [ 16 , 30 , 31 ], the cortical predominant pattern in our sample is reflective of an amnestic phenotype. In this study, we describe heterogeneity in terms of tau-PET patterns and not subtypes .…”

“…We have previously identified tau-PET subtypes in AD dementia using this approach and reported how this method relates to other discrete-scale operationalizations [ 15 ]. Since a cortical predominant pattern can be heterogeneous in itself [ 16 , 30 , 31 ], we further investigated the contribution of different cortical regions (frontal, parietal, temporal, and occipital) to this pattern [ 30 ].…”

A robust core architecture of functional brain networks supports topological resilience and cognitive performance in middle- and old-aged adults

“…These targeted attacks are similar to types of pathological lesions that commonly occur in neurodegenerative diseases ( 19 ). In the context of Alzheimer’s disease, this similarity is likely driven by connectivity-based tau deposition with a preference for functional network hubs ( 20 ). Furthermore, connectivity in healthy states is more resilient to targeted attacks than in diseased states ( 21 – 23 ).…”

Untitled

“…Finally, it is important to emphasize that staging systems involve dimensionality reduction. Despite the fact that atypical clinical variants of AD largely conform to the Braak system, some information about the spatial distribution of tau in atypical AD [8] is lost when only considering an individual's tau stage.…”