# ABCA1 acts as a protective modulator in amyotrophic lateral sclerosis

## TL;DR

This study identifies a protective role for ABCA1 in amyotrophic lateral sclerosis and develops a nine-gene diagnostic signature for the disease.

## Contribution

ABCA1 is shown to have a protective causal relationship with reduced ALS risk through Mendelian randomization and experimental validation.

## Key findings

- A nine-gene diagnostic signature for ALS achieved an AUC of 0.75 in external validation.
- Serum ABCA1 levels are significantly elevated in ALS patients and correlate with BMI and LDL.
- ABCA1 expression is upregulated in ALS patient blood, spinal cords, and model mice.

## Abstract

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 (ABCA1) as a central feature. MR analyses supported a protective causal relationship between increased ABCA1 expression and reduced ALS risk (OR = 0.93, p = 0.02). We validated this at the protein level, finding serum ABCA1 significantly elevated in an in-house ALS cohort (p = 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.

•A nine-gene diagnostic signature is developed and validated for ALS diagnosis•Mendelian randomization supports a causal protective role for ABCA1 in ALS•Serum ABCA1 is elevated in ALS and correlates with BMI and LDL levels•ABCA1 exhibits spatial and temporal heterogeneity of expression in ALS

A nine-gene diagnostic signature is developed and validated for ALS diagnosis

Mendelian randomization supports a causal protective role for ABCA1 in ALS

Serum ABCA1 is elevated in ALS and correlates with BMI and LDL levels

ABCA1 exhibits spatial and temporal heterogeneity of expression in ALS

Health sciences