ABCA1 acts as a protective modulator in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease lacking reliable biomarkers and effective therapeutic targets. We performed an integrative multiscale analysis combining global epidemiology, whole-blood transcriptomics, machine learning, and Mendelian randomization (MR). We developed a nine-gene diagnostic signature (AUC = 0.75 in external validation) and identified ATP-binding cassette transporter A1 (<i>ABCA1</i>) as a central feature. MR analyses supported a protective causal relationship between increased ABCA1 expression and reduced ALS risk (OR = 0.93, <i>p</i> = 0.02). We validated this at the protein level, finding serum ABCA1 significantly elevated in an in-house ALS cohort (<i>p</i> = 0.006) and correlated with metabolic parameters (BMI and LDL). Spatiotemporal profiling confirmed ABCA1 upregulation in ALS patient blood and spinal cords, and progressive upregulation in ALS model mice. Collectively, we validated a diagnostic signature and identified ABCA1 as a protective, compensatory biomarker in ALS, emphasizing the link between metabolic adaptation and neurodegeneration.