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 TDP43 topography, clinical status near death, and gross hippocampal atrophy. We analyzed longitudinal clinical and neuropathology data from the National Alzheimers Coordinating Center autopsy cohort. Form specific definitions harmonized AD pathology, major co-pathologies, HS/MTL sclerosis, and regional TDP43 findings across neuropathology versions 8 to10. 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 to 6.63) and AD strata (OR, 2.56; 95% CI, 2.15 to 3.04). In version 10, HS/MTL sclerosis was associated with higher regional TDP43 topography (OR, 6.54; 95% CI, 3.88 to11.02) and greater gross hippocampal atrophy (OR, 6.43; 95% CI, 4.97 to 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 to 12.06). HS/MTL sclerosis marked greater clinical severity in both AD and non-AD strata and co-occurred with regional TDP43 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.