Amyotrophic lateral sclerosis and neurodegenerative diseases: A Mendelian randomization study

Abstract

In this study, we used the Mendelian randomization (MR) method to systematically examine whether there is a bidirectional causal relationship between amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). We analyzed data from 6,44,924 participants using MR to evaluate causality. We employed inverse variance weighted and MR-Egger regression tests for MR analysis. Additionally, we performed sensitivity analyses using the MR-Egger test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. The inverse variance weighted analysis found no evidence of a risk effect between ALS and the neurodegenerative diseases AD, PD, FTD, MSA, and DLB. However, the MR-Egger analysis showed that both AD (odds ratio: 1.079, 95% confidence interval: 1.017-1.145, P = .029) and PD (odds ratio: 1.210, 95% confidence interval: 1.046-1.401, P = .020) have a risk effect on ALS, indicating that AD and PD increase the risk of ALS. Our MR analysis suggests that AD and PD may have a potential causal relationship with ALS. Conversely, ALS does not appear to have a causal relationship with the other neurodegenerative diseases examined (FTD, MSA, DLB).

Keywords: Alzheimer’s disease; Mendelian randomization study; Parkinson’s disease; amyotrophic lateral sclerosis; dementia with Lewy bodies; frontotemporal dementia; multiple system atrophy.

Figure 1.

Flow chart of the research process. AD = Alzheimer’s disease, ALS = amyotrophic lateral sclerosis, DLB = dementia with Lewy bodies, FTD = frontotemporal dementia, MR = Mendelian randomization, MR-PRESSO = Mendelian Randomization Pleiotropy RESidual Sum and Outlier, MSA = multiple system atrophy, PD = Parkinson’s disease, SNPs = single nucleotide polymorphisms.

Figure 2.

Causal effects of neurodegenerative diseases on ALS (IVW). AD = Alzheimer’s disease, ALS = amyotrophic lateral sclerosis, DLB = dementia with Lewy bodies, FTD = frontotemporal dementia, IVW = inverse variance weighted, LCI = lower confidence interval, MSA = multiple system atrophy, NSNP = number of single nucleotide polymorphisms, OR = odds ratio, PD = Parkinson’s disease, UCI = upper confidence interval.