Deciphering the causal relationship between blood metabolites and Alzheimer’s Disease: a Mendelian Randomization study

Abstract

There are currently no disease modifying treatments for Alzheimers Disease (AD). Epidemiological studies have highlighted blood metabolites as potential biomarkers, but possible confounding and reverse causation prevent causal conclusions. Here, we investigated whether nineteen metabolites previously associated with midlife cognitive function, are on the causal pathway to AD. Summary statistics from the largest Genome-Wide Association Studies (GWAS) for AD and for metabolites were used to perform bi-directional univariable Mendelian Randomisation (MR). Bayesian model averaging MR (MR-BMA) was additionally performed to address high correlation between metabolites and to identify metabolite combinations which may be on the AD causal pathway. Univariable MR indicated three Extra-Large High-Density Lipoproteins (XL.HDL) to be on the causal pathway to AD: Free Cholesterol (XL.HDL.FC: OR=0.86, 95% CI=0.78-0.94), Total Lipids (XL.HDL.L: OR=0.88, 95% CI=0.80-0.97), and Phospholipids (XL.HDL.PL: OR=0.87, 95% CI=0.81-0.97); significant at an adjusted threshold of p<0.009. MR-BMA corroborated XL.HDL.FC to be amongst the top three causal metabolites, additionally to Total Cholesterol in XL.HDL (XL.HDL.C) and Glycoprotein Acetyls (GP) (posterior probabilities=0.112, 0.113, 0.287 respectively). Both XL.HDL.C and GP also demonstrated suggestive evidence of univariable causal associations (XL.HDL.C:OR=0.88, 95% CI=0.79-0.99; GP:OR=1.2, 95% CI=1.05-1.38); significant at the 5% level. This study offers insight into the causal relationship between metabolites previously demonstrating association with mid-life cognition, and AD. It highlights GP in addition to several XL.HDLs as causal candidates which warrant further investigation. As the pathological changes underpinning AD are thought to develop decades prior to symptom onset, progressing these findings could hold special value in informing future risk reduction strategies.

Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease

“…As with our previous study (20), XL.HDL.FC demonstrated a protective causal effect on AD. This aligns with wider literature which consistently regards HDLs as health promoting, while LDLs and IDLs are their risk-increasing counterparts (50–52).…”

“…Three additional HDL sub-fractions, as well as one marker of inflammation – glycoprotein acetyls – demonstrated evidence of causal association with AD in our previous study (20). These were not estimated here due to their lack of polygenic association with AD.…”

“…These were not estimated here due to their lack of polygenic association with AD. This highlights the importance of adopting an expanded repertoire of screening methods for identifying causal candidates, with previous selection based on phenotypic associations with midlife cognition (20), while selection here concentrated on genetic overlap with AD-specific diagnosis.…”

“…In a previous study, we utilised MR to investigate causal relationships between nineteen candidate metabolites and AD. A protective effect of extra-large high-density lipoproteins (XL.HDLs), and a risk increasing effect of glycoprotein acetyls (GP) was found (20). Whilst offering preliminary insight, candidate metabolites were restricted to those previously associated with midlife cognition (21), rather than AD specifically, neglecting other causal candidates which may be of relevance.…”

“…In a previous study, we utilised MR to investigate causal relationships between nineteen candidate metabolites and AD. A protective effect of extra-large high-density lipoproteins (XL.HDLs), and a risk increasing effect of glycoprotein acetyls (GP) was found (20).…”