Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease

<jats:sec><jats:title>Objective</jats:title><jats:p>To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS‐Aging) and age‐related diseases and to evaluate its contribution to cognitive impairment in the elderly.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University (St. Louis, MO). Relative neuron loss in the hippocampus of HS‐Aging was measured using unbiased stereological methods. Transactive response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy, a putative marker of HS‐Aging, was assessed. Clinical and cognitive data were analyzed using parametric statistical methods.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Ninety‐three cases had HS‐Aging (6.8%), 8 cases had “pure” HS‐Aging, and 37 cases had comorbid intermediate or high Alzheimer's disease neuropathological change (i/h ADNC). Relative neuron loss (ratio of neuron number in hippocampal subfield CA1 to the neuron number in parahippocampal gyrus) was 0.15 for HS‐Aging; this was significantly lower than 0.64 for i/h ADNC and 0.66 for control cases (Kruskal‐Wallis test, <jats:italic>p</jats:italic> < 0.0001; <jats:italic>p</jats:italic> = 0.0003, respectively). TDP‐43 proteinopathy was present in 92.4% of HS‐Aging cases, higher than that in i/h ADNC (52%) and control (25%) cases. Pure HS‐Aging cases were more likely to have cognitive impairment in the memory domain.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Relative neuron loss in the hippocampus compared to the parahippocampus gyrus may be useful in distinguishing HS‐Aging in the context of comorbid ADNC. HS‐Aging contributes to cognitive impairment, which phenotypically resembles AD dementia. TDP proteinopathy is a frequent comorbidity in HS‐Aging and may contribute to cognitive impairment to a modest degree. Ann Neurol 2018;84:749–761</jats:p></jats:sec>