Lesion‐network Mapping of Tau Accumulation is Predictive of Domain‐specific Cognitive Deficits in Alzheimer’s Disease

Fibrillar tau gradually progresses in the brain during the course of Alzheimer’s disease (AD). However, the contribution of tau accumulation in a given brain region to decline in different cognitive domains and thus phenotypic heterogeneity in AD remains unclear. Here, we leveraged the functional connectome to link the locality of tau accumulation to domain-specific cognitive impairment.In the current study, we mapped regional tau-PET accumulation onto the normative functional connectome. Subsequently, we cross-validated in two samples of AD-patients the associations between the tau-connectivity profiles and cognitive domains (episodic memory, executive function, or language). Lastly, we tested the effect of local tau-PET accumulation on the domain-specific tau-lesion networks and cognition.We identified cognitive-domain-specific tau-lesion networks, where closer topological proximity of tau-PET locations to a network was predictive of worse impairment in that domain. Higher tau-PET was associated with decreased domain-specific network connectivity, and the decrease in connectivity was associated with lower domain-specific cognition.The tau locations’ connectivity profile explained domain-specific cognitive impairment, where disrupted connectivity may underlie the effect of tau on cognitive impairment.