Assessing the repurposing potential of disease-modifying antirheumatic drug targets to reduce Alzheimer's disease risk: a Mendelian randomization study

TL;DR

This study explores whether drug targets used for rheumatoid arthritis could also be used to treat Alzheimer's disease, finding that only one target, FCGR3B, may increase Alzheimer's risk.

Contribution

The first Mendelian randomization and colocalization study on DMARD targets and Alzheimer's disease risk using cis-pQTLs as instruments.

Findings

Higher levels of FCGR3B are associated with increased Alzheimer's disease risk (OR: 1.10; 95% CI [1.02, 1.19]).

Most other DMARD targets showed little evidence of affecting Alzheimer's disease risk.

Colocalization analysis found no strong evidence of shared genetic signals between DMARD targets and Alzheimer's disease.

Abstract

Systemic inflammation plays a key role in the development and progression of Alzheimer's disease (AD). However, the repurposing potential of select anti-inflammatory drug targets for AD treatment remains unclear.

Two-sample Mendelian randomization (MR) and colocalization analyses were conducted to estimate the effects of select disease-modifying antirheumatic (DMARD) targets on AD risk. We investigated 9 DMARD targets, using blood protein quantitative trait loci (pQTLs) from the UK Biobank Pharma Proteomics Project (n = 54,219). Outcome associations were extracted from the International Genomics of Alzheimer's Project (ncases = 21,982, ncontrols = 41,944).

Our MR estimates suggest that higher levels of FCGR3B, an etanercept target, increased the risk of AD (OR: 1.10; 95% CI [1.02, 1.19]; p = 0.01). We found little evidence that the remaining DMARD targets affected AD risk. Colocalization analysis provided little evidence that target pQTLs, including FCGR3B, colocalized with AD.

Our findings suggest a causal effect of FCGR3B on AD risk, but not for the remainder of the analyzed DMARD targets. Further research is recommended to elucidate the causal role of FCGR3B in AD and build upon the current literature on viable AD therapeutic targets.

•This is the first MR and colocalization study on select DMARD targets and AD risk, using cis-pQTLs as instruments.•MR suggests that higher plasma FCGR3B levels increase the risk of AD.•There was little evidence of an effect for the remaining targets.•This suggests that the majority of these targets in plasma are unlikely to be effective candidates for reducing AD risk.

This is the first MR and colocalization study on select DMARD targets and AD risk, using cis-pQTLs as instruments.

MR suggests that higher plasma FCGR3B levels increase the risk of AD.

There was little evidence of an effect for the remaining targets.

This suggests that the majority of these targets in plasma are unlikely to be effective candidates for reducing AD risk.

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