At least four shortcomings have been identified in the 2019 LATE-NC guidelines: (1) anatomic regions for sampling were recommended, but the implications of TDP-43 immunopositivity in subregions were not precisely defined; (2) it was not clear how additional information on genetic findings and other pathologies should be incorporated into reports of LATE-NC; (3) there was minimal guidance on how to separate LATE-NC from other TDP-43 proteinopathies; and (4) some cases with TDP-43 pathology in aging could not be readily classified into LATE-NC stages. Here, TARDBP is linked to proteostasis deficiencies.