Yu et al.1 investigated the association of TMEM106B variants with TAR-DNA binding protein 43 (TDP-43) pathology in elderly individuals without frontotemporal lobar degeneration (FTLD-TDP). They also examined whether these associations were independent of comorbid pathologic processes, such as Alzheimer disease (AD) and hippocampal sclerosis (HS). The results confirmed earlier findings that TMEM106B variants are an important TDP-43 pathology risk factor in FTLD-TDP, sporadic amyotrophic lateral sclerosis, AD, tangle predominant dementia, and Lewy body disease.2–4 The authors also reported a lack of association between TMEM106B variants and HS after adjusting for the presence of TDP-43 pathology. This likely reflects lack of specificity in the HS diagnostic criteria.
Evidence suggests that HS in the elderly is a degenerative process that can be distinguished from hippocampal neuronal loss associated with anoxic-ischemic injury or epilepsy by the presence of TDP-43 pathology.5 Grouping HS of the elderly with HS due to other etiologies confounds the results and weakens the TMEM106B association with HS of the elderly. Current evidence suggests the strongest genetic determinant of HS in the elderly is TMEM106B and more precise neuropathologic criteria for HS should be used when assessing genetic risk factors for HS.