APOE and amyotrophic lateral sclerosis: Apolipoprotein E ε4 (APOE4), the most common genetic risk factor for AD, has an increased frequency of TDP-43 pathology,40 and reactive astrocytes carrying the APOE4 risk allele have been reported in ALS.41 Glial cell inclusions of TDP-43 appear characteristic of most ALS cases and can be sporadic or associated with C9orf72, TARDBP, or optineurin (OPTN) mutations.42