Hippocampal/medial temporal sclerosis is associated with clinical severity, regional TDP-43, and hippocampal atrophy in Alzheimer disease.

Alzheimer disease neuropathologic change (ADNC) does not fully explain clinical severity, suggesting important contributions from coexisting pathologies. We examined major co-pathologies in a multicenter autopsy cohort, focusing on hippocampal/medial temporal sclerosis (HS/MTL sclerosis), clinical severity, regional TDP-43 topography, clinical status near death, and gross hippocampal atrophy. We analyzed longitudinal clinical and neuropathology data from the National Alzheimer's Coordinating Center autopsy cohort. Form-specific definitions harmonized AD pathology, major co-pathologies, HS/MTL sclerosis, and regional TDP-43 findings across neuropathology versions 8-10. HS/MTL sclerosis was present in 13.0% of assessed AD cases and was associated with greater CDR® Dementia Staging Instrument sum-of-boxes severity in non-AD (odds ratio [OR], 4.93; 95% confidence interval [CI], 3.66-6.63) and AD strata (OR, 2.56; 95% CI, 2.15-3.04). In version 10, HS/MTL sclerosis was associated with higher regional TDP-43 topography (OR, 6.54; 95% CI, 3.88-11.02) and greater gross hippocampal atrophy (OR, 6.43; 95% CI, 4.97-8.32). Among AD cases assessed within 2 years of death, HS-negative participants had greater odds of non-dementia status than HS-positive participants (OR, 5.81; 95% CI, 2.80-12.06). HS/MTL sclerosis marked greater clinical severity in both AD and non-AD strata and co-occurred with regional TDP-43 involvement and hippocampal atrophy. Its absence identified a subset with intermediate/high AD pathology but no dementia near death. Clinical severity therefore cannot be inferred from ADNC alone.