Abstract
Typical Alzheimer disease (AD) features an amnestic syndrome that reflects the progression of pathology through specific neural networks. However, a subset of patients exhibits atypical onset with prominent language, behavioral, or visuospatial deficits that are not explained by current neuropathological staging schemes. Astrogliopathy featuring tau inclusions with thorn-shaped and granular fuzzy morphologies is common in the aging brain and collectively known as aging-related tau astrogliopathy (ARTAG). Prior studies have identified tau-positive thorn-shaped astrocytes in the white matter that associate with a primary progressive aphasia phenotype in an AD cohort. However, a possible contribution of ARTAG copathology to AD clinical heterogeneity has yet to be systematically examined. To investigate whether ARTAG pathology contributes to atypical presentations, we mapped the presence and density of ARTAG subtypes throughout cortical and subcortical regions in a well-characterized cohort of AD cases enriched for atypical presentations. In our cohort, ARTAG pathology is frequent and correlates with older age and higher Braak stage. ARTAG subtypes exhibit distinct distribution patterns with subpial and subependymal deposition occurring in the amygdala, while white and grey matter astrocytic deposition are distributed throughout cortical regions. However, ARTAG pathology is equally prevalent in cases with typical and atypical clinical presentations.