# Testosterone Supplementation: A Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis

## TL;DR

This study suggests that low levels of bioavailable testosterone may increase the risk of ALS, indicating testosterone supplementation could be a potential treatment.

## Contribution

The study identifies bioavailable testosterone as a novel risk factor for ALS using proteomics and Mendelian randomization.

## Key findings

- High levels of SHBG are a risk factor for ALS.
- Low levels of bioavailable testosterone are associated with increased ALS risk.
- Testosterone supplementation may offer a promising therapeutic direction for ALS.

## Abstract

Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. Methods: We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. Results: A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. Conclusions: A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.