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

• DOI: 10.1038/s41467-025-56469-7
• Publication Date: 2025-02-21T15:23:22Z
• Authors: Danielle F. Browne; Denis S. Smirnov; David G. Coughlin; Iris Peng; Heidi G. Standke; Yongya Kim; Donald P. Pizzo; Alexandra Unapanta; Thea Andreasson; Annie Hiniker; Allison Kraus
• Keywords: Tauopathy; Tau protein; Neocortex

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for diagnosis 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 species equally pathogenic raises question whether unidentified modifications augment seeding activity neurodegeneration AD. We investigated how biochemical relate to clinicopathological outcomes a cohort 38 patients Braak-matched AD neuropathologic change (ADNC) or primary age-related tauopathy (PART), 3R/4R identical filament core structure ADNC but little no Aβ deposition. comprehensively measured histologic density, using real-time quaking induced conversion (RT-QuIC) amplification assays, select post-translational (PTMs) (i.e. pT217, pS202/T205, & C-terminal epitopes) hippocampus neocortex. Even cases without overt neocortical neuropathology, substantial hippocampal occurred both PART predicted region-specific performance longitudinal decline. Notably, PTM profiles were associated neuritic plaque density differentiated Our data indicate meaningfully disease trajectory, potentially explaining more severe dysfunction observed late-stage versus PART. Abnormal, misfolded proteins found Tauopathies, suggesting pathogenic. Here, authors show modification two tauopathies.