AbstractBackgroundHippocampal sclerosis of aging (HS) is characterized by neuronal loss and astrogliosis in subiculum and/or CA1 subfield of hippocampus. Using a novel quantitative approach, we studied the prevalence and localization of HS pathology in a well‐characterized oldest‐old cohort and examined its association with other neuropathologic changes and cognitive impairment.MethodsWe studied 409 consecutive autopsied participants of The 90+ Study with longitudinal assessments. In those with HS by traditional method (presence/absence), we used digitized hematoxylin and eosin and luxol fast blue hippocampal slides for further quantitative analysis. Using QuPath, we measured the length of each hippocampal subfield partitioned into three subregions (Figure1). We then calculated the proportion affected by HS for each subregion. Both traditional (presence/absence) and quantitative (subfield‐specific proportions) measures were used to study the relationship between HS and other neuropathologic changes and cognitive outcomes using regression models adjusted for sex, age at death, and education with all neuropathologic changes as covariates.ResultsHS was present in 11% of participants and was always focal, mostly affecting CA1 (89%), followed by subiculum (27%). Overlapping CA1/subiculum pathology was seen in 16% (Figure2). Left‐sided HS was more frequent (75%) than right‐sided (18%). Bilateral cases were the least frequent (7%). HS presence (traditional measure) was only associated with Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (OR = 3.45, p<0.001). Quantitative measures revealed that HS proportion in subiculum and CA1 was associated with arteriolosclerosis (t36 = 4.11, p = 0.001) and LATE (t35 = 2.98, p = 0.005). HS proportion in subiculum alone was inversely associated with microvascular lesions (t41 = ‐3.16, p = 0.003) (Table1). HS proportion in subiculum and CA1 was associated with dementia at death and impairment of memory, language, calculation, and orientation. HS proportion in subiculum was additionally associated with impaired executive function. HS traditional measure was only associated with impaired orientation (Table1).ConclusionBased on our novel quantitative analysis, HS pathology was always focal, mostly unilateral, and associated with dementia and impairment in major cognitive domains. We found associations between HS and vascular pathologies that were not detected using traditional measure. The associations of HS with dementia and impaired memory, language, and calculation, identified with our quantitative method, were not detected using traditional measure.