What does this research mean for the field?

The APOE ε4 allele promotes a widespread cortical distribution of TDP-43 pathology in sporadic amyotrophic lateral sclerosis, independent of classical Alzheimer's disease amyloid-β and tau pathologies. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aims to examine how APOE ε4 genotype affects the distribution of TDP-43 pathology in sporadic ALS.

May 17, 2026Acta Neuropathologica0 citationsOpen Access

APOE ε4 influences the widespread TDP-43 pathological subtype in sporadic amyotrophic lateral sclerosis

YHYuya HatanoNiigata University Medical and Dental Hospital ANAsa NakaharaNiigata University MTMari TadaNiigata University

Key Points

The study aims to examine how APOE ε4 genotype affects the distribution of TDP-43 pathology in sporadic ALS.
Cohort of 145 autopsy-confirmed sporadic ALS cases analyzed for TDP-43 pathology subtypes.
Genotyping for APOE and rare ALS-associated variants via exome sequencing and neuropathological evaluation.
Employed structural equation modeling and random forest models to determine relationships between APOE ε4 and TDP-43 subtypes.
APOE ε4 carriers showed a significant increase in type 2 TDP-43 pathology compared to non-carriers.
Bayesian structural equation modeling confirmed direct association of APOE ε4 with widespread type 2 TDP-43 pathology, independent of amyloid-β and tau.
Rare variants in ALS-associated genes did not significantly influence TDP-43 subtype distribution.

Abstract

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, most sporadic cases exhibiting TAR DNA-binding protein 43 (TDP-43) pathology. The anatomical distribution of TDP-43 pathology varies among patients; however, factors contributing to this heterogeneity remain unclear. Apolipoprotein E ( APOE ) ε4 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 – largely restricted to motor regions – and type 2 – characterized by widespread cortical involvement. APOE genotypes and rare variants in known ALS-associated genes were determined by exome sequencing. Amyloid-β and tau pathologies were assessed neuropathologically using established staging systems. Structural equation modeling (SEM) was applied to disentangle direct and indirect relationships among APOE ε4, temporal clinical parameters, Alzheimer’s disease-related pathologies, and ALS TDP-43 subtype. Furthermore, we also performed an unbiased evaluation using random forest model. APOE ε4 carriers showed a significantly higher proportion of type 2 pathology than non-carriers. Bayesian SEM demonstrated that APOE ε4 was directly associated with the type 2, widespread TDP-43 subtype, independent of amyloid-β and tau pathology, while also reproducing the canonical cascade linking APOE ε4 to amyloid-β and tau. Rare variants in ALS-associated genes showed no clear effect on TDP-43 subtype. These findings indicate that APOE ε4 modifies the anatomical distribution of TDP-43 pathology in sporadic ALS through mechanisms independent of classical Alzheimer’s disease pathology. Incorporation of APOE genotype into ALS stratification may be informative for biologically grounded subtype-specific therapeutic approaches.

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