Introduction: Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. Methods:We studied 159 brain donations from the multimodal Vallecas Alzheimer's Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data.Results: Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anteriorposterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. Discussion:The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS.

IntroductionHippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically‐defined features is unknown. We investigated pre‐mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia‐associated pathologies.MethodsWe analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow‐up and post‐mortem neuropathological evaluation, including HS assessment in the hippocampal head and body.ResultsSignificant HS‐associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy.DiscussionHS‐associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD.HIGHLIGHTS Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre‐mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.