APOE ε4 defines a systemic immune endophenotype independent of clinical trajectory in amyotrophic lateral sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is clinically heterogeneous, and genetic modifiers may drive molecular endophenotypes without obvious clinical stratification. The apolipoprotein E ε4 ( APOE ε4) allele is a major Alzheimer’s disease risk allele, but its biological impact in ALS remains unclear. Methods Using the Answer ALS cohort, longitudinal motor, cognitive, and neuropsychiatric measures were modelled using mixed-effects approaches. Patient induced pluripotent stem cell-derived motor neuron multiomics (chromatin accessibility, transcriptomics, and proteomics) were analysed using supervised machine learning. Plasma SomaScan profiling was used to derive an APOE ε4-associated protein signature and to test its stability across serial visits, biological pathway enrichment, and associations with clinical progression. Results APOE ε4 carriage was not associated with baseline severity or rate of functional decline and showed no consistent effects on cognitive or neuropsychiatric trajectories. Motor neuron multiomic profiles similarly demonstrated no reproducible APOE ε4 signal and did not reliably classify genotype. In contrast, plasma proteomics identified an APOE ε4 protein signature that classified ε4 status with high accuracy in ALS (AUC 0.98) and non-ALS motor neuron disease (AUC 0.86) and was enriched for immune and inflammatory biology. This systemic signature was highly stable across repeated sampling, indicating a persistent genotype-associated state. Within this plasma endophenotype, a small set of proteins tracked functional decline and a composite score stratified fast versus slow progression. Baseline composite scores were elevated in APOE ε4 carriers in both ALS and neurologically unimpaired controls, consistent with a stable systemic shift detectable beyond overt disease status. Conclusions APOE ε4 defines a persistent, immune-enriched systemic proteomic endophenotype in ALS that is not captured by clinical trajectories or motor neuron-only profiling yet relates to disease progression. Plasma-based, genotype-informed endophenotyping offers a translational pathway for biomarker stratification and therapeutic prioritisation in ALS and potentially other heterogeneous neurodegenerative disorders.