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The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E (\n                    <jats:italic>APOE<\/jats:italic>\n                    ) \u03b54 is known to influence the spread of pathological protein in several neurodegenerative diseases, raising the possibility that it also modulates the pathological distribution of TDP-43 inclusions in ALS. We investigated this hypothesis in a cohort of 145 autopsy-confirmed sporadic ALS cases. ALS-associated TDP-43 pathology was classified into two subtypes: type 1 \u2013 largely restricted to motor regions \u2013 and type 2 \u2013 characterized by widespread cortical involvement.\n                    <jats:italic>APOE<\/jats:italic>\n                    genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-\u03b2 and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54, temporal clinical parameters, Alzheimer\u2019s disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model.\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE \u03b54 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-\u03b2 and tau pathology, while also reproducing the canonical cascade linking\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 to amyloid-\u03b2 and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer\u2019s disease pathology. Incorporation of\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03029-y","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:50:14Z","timestamp":1778874614000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["APOE \u03b54 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis"],"prefix":"10.1007","volume":"151","author":[{"given":"Yuya","family":"Hatano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asa","family":"Nakahara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Tada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiyoshi","family":"Kakita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Onodera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiko","family":"Ishihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"3029_CR1","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3109\/17482960802566824","volume":"10","author":"A Chi\u00f2","year":"2009","unstructured":"Chi\u00f2 A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E et al (2009) Prognostic factors in ALS: a critical review. 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