Influence of LDL-C, Apolipoprotein B on ALS and FTD Risk and Benefits of APOB Inhibition

The following is a summary of “Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study,” published in the September 2024 issue of Neurology by Chalitsios et al.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping clinical, pathological, and genetic features, and lipid pathways have been implicated in ALS.

Researchers conducted a retrospective study examining the impact of blood lipid levels on the risk and survival of ALS and FTD.

They analyzed high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), total cholesterol, triglycerides, and apolipoproteins B and A1 levels about ALS. A 2-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationships between exposures and ALS, FTD, and survival in ALS. Effects of lipid-lowering drugs using genetic proxies for the targets were also examined.

The results showed 3 cohort studies and meta-analysis indicated an association between elevated LDL-c (HR_{per mmol/L} = 1.07, 95% CI: 1.02–1.12; I² = 18%) and reduced HDL-c (HR_{per mmol/L} = 0.83, 95% CI: 0.74–0.94; I²= 0%) with a heightened risk of ALS, MR analysis suggested relationships between higher LDL-c (OR_IVW = 1.085, 95% CI: 1.008–1.168, p_FDR = 0.0406), total cholesterol (OR_IVW = 1.081, 95% CI: 1.013–1.154, p_FDR = 0.0458), and apolipoprotein B (OR_IVW = 1.104, 95% CI: 1.041–1.171, p_FDR = 0.0061) with an increased risk of ALS. Higher apolipoprotein B levels were also linked to an increased risk of FTD (OR_IVW = 1.424, 95% CI: 1.072–1.829, p_FDR = 0.0382). Lowering LDL-c through apolipoprotein B (ApoB) inhibition was associated with a reduced risk of both ALS (OR_IVW = 0.84, 95% CI: 0.759–0.929, p_FDR = 0.00275) and FTD (OR_IVW = 0.581, 95% CI: 0.387–0.874, p_FDR = 0.0362).

They concluded that LDL-c, total cholesterol, and apolipoprotein B were associated with the risk of ALS and FTD, suggesting potential benefits of APOB inhibition.

Source: link.springer.com/article/10.1007/s00415-024-12665-x

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