Connectivity, Pathology, and <scp>ApoE4</scp> Interactions Predict Longitudinal Tau Spatial Progression and Memory

Tau pathology spread into neocortex indicates a transition from healthy aging to Alzheimer's disease (AD). Connectivity between tau epicenters and later accumulating regions of cortex has been proposed as a mechanism of tau spread, but how this relationship changes with greater AD pathology burden or genotype is not understood. We investigated tau accumulation in two key regions, precuneus and inferior temporal cortex, using resting state functional connectivity (rsFC) and longitudinal PET imaging from a multicohort sample of cognitively unimpaired older adults. We examined how baseline tau PET, Aβ PET, and ApoE4 genotype status interact with rsFC between hippocampus and these downstream regions to predict rate of tau accumulation in neocortex. We found that the 3-way interaction between connectivity, baseline tau, and baseline Aβ or ApoE4 status was associated with neocortical tau accumulation in precuneus and inferior temporal cortex. In addition, baseline tau, Aβ, and ApoE4 status also moderated the association between connectivity and rate of memory decline. Together, these results suggest that the extent and distribution of future tau accumulation may be predicted by the interaction of baseline connectivity, AD pathology, and genetic risk.