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We aimed to characterize features of early HS to refine the understanding of its role within combined pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010mortem cognitive and magnetic resonance imaging (MRI) data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two\u2010level assessment along the hippocampal longitudinal axis revealed an anterior\u2010posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The definition of hippocampal sclerosis of aging (HS) is currently limited to an end\u2010stage pathological fingerprint.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We characterize early HS histological features to define a complete staging system.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The proposed staging displays a parallel but not identical progression to limbic\u2010predominant age\u2010related TAR DNA\u2010binding protein 43 (TDP\u201043) encephalopathy (LATE).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The proposed staging\nalso reflects the expected demographic and cognitive differences associated with HS.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In vivo magnetic resonance imaging (MRI) showed focal hippocampal gray matter loss as a function of HS staging.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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