In severe ADNC, hippocampi with comorbid LATE-NC and hippocampal sclerosis have substantially more astrocytosis than those with LATE-NC or hippocampal sclerosis alone.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-A) pathologies are found together at autopsy in ∼20% of elderly demented persons. Although astrocytosis is known to occur in neurodegenerative diseases, it is currently unknown how the severity of astrocytosis is correlated with the common combinations of pathologies in aging brains. To address this knowledge gap, we analyzed a convenience sample of autopsied subjects from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. The subjects were stratified into 5 groups (n = 51 total): pure ADNC, ADNC + LATE-NC, ADNC + HS-A, ADNC + LATE-NC + HS-A, and low-pathology controls. Following GFAP immunostaining and digital slide scanning with a ScanScope, we measured GFAP-immunoreactive astrocytosis. The severities of GFAP-immunoreactive astrocytosis in hippocampal subfield CA1 and subiculum were compared between groups. The group with ADNC + LATE-NC + HS-A had the most astrocytosis as operationalized by either any GFAP+ or strong GFAP+ immunoreactivity in both CA1 and subiculum. In comparison to that pathologic combination, ADNC + HS or ADNC + LATE-NC alone showed lower astrocytosis. Pure ADNC had only marginally increased astrocytosis in CA1 and subiculum, in comparison to low-pathology controls. We conclude that there appeared to be pathogenetic synergy such that ADNC + LATE-NC + HS-A cases had relatively high levels of astrocytosis in the hippocampal formation.