Association between alcohol consumption and incidence of dementia in current drinkers: linear and non-linear mendelian randomization analysis
Research article
Summary
Background
Previous conventional epidemiological studies found a J-shape relationship between alcohol consumption and dementia, but this result was subject to confounding biases and reverse causation. Therefore, the researchers aimed to investigate the potential linear or non-linear causal link between alcohol consumption and the incident risk of dementia in current alcohol users.
Methods
This study used data from the UK Biobank to investigate the relationship between alcohol consumption and dementia risk.
313,958 White British current alcohol users, who were free of dementia during 2006–2010, were followed up until 2021. Alcohol consumption was self-reported and calculated according to the National Health Service guideline.
The primary outcome was all-cause dementia identified through hospital and mortality records.
The researchers used multivariable Cox models with restricted cubic splines for conventional analysis and both non-linear and linear Mendelian Randomization (MR) analyses to assess causal relationships, employing a genetic score based on 95 SNPs identified from a meta-genome-wide association study of 941,280 people from Europe.
Findings
313,958 current alcohol users consumed an average of 13.6 units/week alcohol (men averaged 20.2 units/week and women 9.5 units/week).
During a mean follow-up of 13.2 years, 5394 (1.7%) developed dementia.
Multivariable Cox model with restricted cubic spline functions identified a J-shaped relationship between alcohol consumption and dementia risk, with the lowest risk at 12.2 units/week. The non-linear MR failed to identify a significant non-linear causal relationship (p = 0.45).
Both individual-level (HR: 2.22) and summary-level (1.89) linear MR analyses indicated that higher genetically predicted alcohol consumption increased dementia risk.
Interpretation
This study identified a positive linear causal relationship between alcohol consumption and dementia among current alcohol users. The J-shaped association found in conventional epidemiological analysis was not supported by non-linear MR analyses.
The study findings suggested that there was no safe level of alcohol consumption for dementia.
Research in context
Evidence before this study
Previous conventional epidemiological studies found a J-shape relationship between alcohol consumption and dementia, but this result was subject to several biases. Mendelian randomization (MR) analysis in genetic epidemiology studies, is similar to a “genetic randomized control trial” due to the random allocation of genotypes from parents to offspring, and thus, not affected by reverse causation and is independent of confounding factors that may influence disease outcomes.
Therefore, the researchers searched PubMed, Web of Science, and the Cochrane Library databases for studies published in English from database inception to December 30, 2023, that investigated the causal relationship between alcohol consumption and dementia risk, using the terms: (“alcohol consumption”, “alcohol use”, or “drinking”) and (“dementia”, or “Alzheimer”) and “mendelian randomization”.
Two previous two-sample MR studies showed that genetically predicted alcohol consumption was not associated with dementia. However, both analyses were based on summary-level data and traditional linear MR, the heterogeneity of different data source may diminish statistical efficacy and linear MR may yield negative results if the J-shape relationship between alcohol consumption and dementia really exists.
Added value of this study
This study employed both linear and non-linear Mendelian randomization analyses on a large sample from the UK Biobank, specifically focusing on current drinkers of White British descent.
The study findings contradicted the widely reported J-shaped relationship by demonstrating a positive linear association between alcohol consumption and the incidence of dementia among current alcohol consumers.
This study highlighted that no level of alcohol consumption is safe in terms of dementia risk.
Implications of all the available evidence
MR studies clarify the causal relevance of alcohol intake with diseases by accounting for confounding biases and reversal causation in conventional epidemiological studies. The linear and non-linear MR provides evidence on linear causal harmful effects of alcohol use on dementia.
This finding improves the understanding of the adverse effects of alcohol use on dementia among current alcohol users.