Early Alzheimer’s Disease with frequent neuritic plaques harbors neocortical tau seeds distinct from primary age-related tauopathy

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for the diagnosis of Alzheimer's Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all tau species are equally pathogenic and raises the question of whether unidentified tau modifications augment tau seeding activity and neurodegeneration in AD. We investigated how biochemical modifications of tau relate to clinicopathological outcomes in a cohort of 38 patients with Braak-matched AD neuropathologic change (ADNC) or primary age-related tauopathy (PART), a 3R/4R tauopathy with identical tau filament core structure to ADNC but with little to no Aβ deposition. We comprehensively measured tau histologic density, seeding activity using real-time quaking induced conversion (RT-QuIC) seed amplification assays, and select post-translational modifications (PTMs) (i.e. pT217, pS202/T205, & C-terminal epitopes) in hippocampus and neocortex. Even in cases without overt neocortical tau neuropathology, substantial hippocampal and neocortical tau seeding occurred in both PART and ADNC and predicted region-specific cognitive performance and longitudinal decline. Notably, tau seeding and PTM profiles were associated with Aβ neuritic plaque density and differentiated ADNC from PART in neocortex. Our data indicate that tau seed modifications meaningfully relate to disease trajectory, potentially explaining the more severe cognitive dysfunction observed in late-stage AD versus PART.