Subicular degeneration occurs in amyotrophic lateral sclerosis (ALS) patients. However, it was unknown whether microscopic subicular degeneration could be observed as macroscopic changes and whether these changes were associated with the transactive-response DNA binding protein 43 kDa (TDP-43) pathology. Topographic differences between subicular degeneration caused by ALS and Alzheimer disease (AD) had also not been characterized. Here we investigated the subiculum and related areas in autopsied brains from 3 ALS and 3 AD patients. Macroscopic subicular thinning and corresponding astrocytosis were pronounced in ALS compared to AD. This thinning was frequently accompanied by TDP-43 pathology in the transentorhinal cortex and nucleus accumbens. The preferential susceptibility of the perforant pathway to TDP-43 deposition may be an underlying cause of subicular thinning in ALS.