Abstract Hippocampal sclerosis of aging (HS) is an important degenerative pathology in the oldest old. It is present in up to a third of brain autopsy samples of those who die with dementia and has a stronger association with dementia than Alzheimer's disease neuropathology (ADNP) in this age group. Abnor- mal phosphorylation of TAR DNA binding protein of 43 kDa (TDP-43) is considered by some to be the underlying reason for HS. HS and TDP-43 proteinopathy can only be diagnosed at post-mortem as there are no available biomarkers. Currently, diagnosis of HS is dependent upon presence and de- gree of ADNP. This makes it impossible to study the relationship between these pathologies and their risk factors independently. Moreover, the increasing recognition of the relation between TDP-43 pa- thology and HS has necessitated elucidation of this relationship in the parent project. However, cur- rent national guidelines used for pathological assessment of brain samples in the parent project, only recommend a limited examination of brain for TDP-43 pathology. This might in turn lead to under- recognition of the extent of TDP-43 pathology. Given the fact that the oldest old are the fastest grow- ing segment of our population with the highest rate of dementia, there is a pressing need to improve the diagnosis of these important degenerative neuropathologies in this age group. In this supplement, we propose improving hippocampal sclerosis and TDP-43 neuropathological char- acterization by providing more detailed assessment of HS that are independent of ADNP and by ex- amining extra sections of the brain for presence of TDP-43 pathology. In Aim 1, we will examine the slides from 450 autopsied brains of the parent project to assign HS diagnosis solely based on the presence of disproportionate atrophy in HS relevant areas. We hypothesize that assigning HS diag- nosis independent of ADNP will lead to a significant increase in the number of those with HS diagno- sis. In Aim 2, We will examine an extra section of the brain from temporal lobe in 450 autopsied brains of the parent project to determine presence of abnormal TDP-43 pathology enabling more pre- cise recognition of TDP-43 pathology spread. We hypothesize determination of temporal lobe TDP-43 pathology load will lead to a significant increase in the number of cases with the most advanced stage of TDP-43 pathology. Completion of the proposed work will lead to a more robust identification of hippocampal sclerosis and its relationship to TDP-43 pathology. This is an important step towards better understanding of an important dementia related pathology in the fastest growing segment of population with highest rates of dementia.