Amyloid-dependent and amyloid-independent effects of Tau in individuals without dementia.

Objective: To investigate the relationship between the topography of amyloid-β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia.

Methods: We evaluated 154 individuals who were assessed with amyloid-β PET with [ F]AZD4694, tau-PET with [ F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid-β PET with [ F]Florbetapir, tau-PET with [ F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel-wise linear regressions between amyloid-PET, tau-PET, and their interaction with cognitive function, correcting for age, sex, and years of education.

Results: In both cohorts, we observed that tau-PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR-SoB) scores independently of local amyloid-PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau-PET and clinical function were dependent on local amyloid-PET (FWE corrected at p < 0.001).

Interpretation: In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid-β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid-β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau's relationship with cognitive dysfunction was dependent on local amyloid-β concentrations. Our results provide evidence that amyloid-β in Alzheimer's disease influences cognition by potentiating the deleterious effects of tau pathology.