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Meta-Analysis
. 2024 Oct;271(10):6956-6969.
doi: 10.1007/s00415-024-12665-x. Epub 2024 Sep 4.

Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study

Christos V Chalitsios  1 , Harriet Ley  1 , Jiali Gao  1 , Martin R Turner  1 , Alexander G Thompson  2
Affiliations
Meta-Analysis

Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study

Christos V Chalitsios et al. J Neurol. 2024 Oct.

Abstract

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS.

Methods: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications.

Results: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362).

Conclusion: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.

Keywords: ALS; Amyotrophic lateral sclerosis; FTD; Frontotemporal dementia; Lipids.

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Conflict of interest statement

None.

Figures

Fig. 1
Fig. 1
Study overview
Fig. 2
Fig. 2
Meta-analysis of the reported HR across cohort studies in the literature for the association between lipids and apolipoproteins and the risk of ALS. The overall HR reflects the pooled HR for an increase of 1 mmol/L for lipids and 1 g/L for apolipoproteins
Fig. 3
Fig. 3
Univariate MR of the association of genetically predicted lipids and apolipoproteins levels with (A) ALS and (B) FTD. Forest plot of the association between a 1-SD change in the lipid and apolipoprotein levels with ALS and FTD risk. An effect size of > 1.00 suggests an increased risk of disease associated with lipid and apolipoprotein levels. The p value corresponding to the IVW method is an FDR-adjusted p value. LDL-c low-density lipoprotein cholesterol, HDL-c high-density lipoprotein cholesterol, OR odds ratio, SNP single-nucleotide polymorphisms, ApoB Apolipoprotein B, ApoA1 Apolipoprotein A1
Fig. 4
Fig. 4
Univariate MR of the association of genetically proxied lipid-lowering drug targets with (A) ALS and (B) FTD. Forest plot of the association between a 1-SD change in the LDL-c levels of four lipid-lowering drug targets with ALS and FTD risk. An effect size of < 1.00 suggests a decreased risk of disease associated with lipid-lowering drug treatment. The p value corresponding to the IVW method is an FDR-adjusted p value. LDL-c low-density lipoprotein cholesterol, OR odds ratio, HR hazard ratio, SNP single-nucleotide polymorphisms, HMGCR HMG-CoA reductase, NPC1L1 Niemann–Pick C1-like protein 1, PCSK9 proprotein convertase subtilisin/kexin type 9, APOB Apolipoprotein B-100
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