No level of alcohol is safe for the brain and even light drinking is linked to an increased risk for dementia, results of a large observational study suggested.

The research combined observational analyses, which showed a U-shaped relationship between alcohol consumption and dementia, with genetic analyses that pointed to a causal role for alcohol in dementia risk.

“Our study provides further evidence that moderate drinking isn’t protective, despite what many patients believe,” lead author Anya Topiwala, MD, PhD, senior clinical researcher at the Nuffield Department of Population Health, University of Oxford, Oxford, England, told Medscape Medical News.

“Even quite small amounts of alcohol can potentially harm the brain and increase the risk of dementia,” she added.

The findings were published online on September 23 in BMJ Evidence Based Medicine.

Contradictory Research

Previous research on the impact of alcohol use on dementia risk, has been “quite contradictory,” Topiwala noted.

Some studies have linked heavy drinking to a higher risk for dementia, while others suggest that moderate alcohol consumption might be protective. However, recent neuroimaging data has shown a harmful association between alcohol use and brain health even at low levels.

Most of these studies were observational and focused on older adults, often failing to distinguish between former drinkers and lifelong nondrinkers — factors that complicate efforts to establish causality.

“We wanted to provide some better insights, particularly using genetic analyses, which we think is the best approach in the absence of a randomized controlled trial,” said Topiwala. She added that such a trial would be impossible due to practical and ethical issues.

The study included data from participants in two large biobanks — the Million Veteran Program (MVP), which has enrolled US veterans of European, African, and Latin American ancestry since 2011, and the UK Biobank (UKB), which recruited volunteers, mostly of European ancestry, between 2006 and 2010.

For the observational analyses, researchers assessed alcohol intake using self-reported drinks per week (DPW), with one standard drink defined as roughly 14 g of ethanol. They also used the Alcohol Use Disorders Identification Test-Consumption, a clinical screening tool with scores ranging from zero to 12.

The study’s primary outcome was all-cause dementia. Rather than focusing solely on Alzheimer’s disease, the study examined a broad range of dementia phenotypes.

To reduce the risk for reverse causation, participants who had already been diagnosed with dementia at the time of enrollment were excluded from the analyses.

Investigators adjusted for age, sex, income, education, smoking, and BMI. For the MVP cohort, they also accounted for head injury, posttraumatic stress disorder, and substance use.

The observational analysis included 559,559 participants aged 56-72 years from the two cohorts. Among them, 14,540 in the US group and 12 in the UK group developed dementia over an average follow-up of 4 years. A total of 48,034 participants died during the study period. More than 90% of participants in both cohorts reported drinking alcohol.

A U-shaped Relationship

The observational analyses revealed a U-shaped relationship between self-reported alcohol intake and incident dementia among MVP and UKB participants of European ancestry, with the lowest risk observed in low-to-moderate drinkers rather than in nondrinkers.

Compared with light drinkers (< 7 DPW), nondrinkers (never or former drinkers), heavy drinkers (> 40 DPW), and dependent drinkers all had elevated risks for dementia (hazard ratio [HR] for dependent drinkers, 1.51; 95% CI, 1.42-1.60).

In the UKB, but not MVP, moderate drinkers (7-14 DPW) had a significantly lower dementia incidence than light drinkers.

When alcohol was measured closer to a dementia diagnosis, the harmful risks of heavy drinking were reduced, and moderate drinking was associated with an apparent protective effect (HR, 0.87; 95% CI, 0.78-0.97). This may be because drinkers who went on to develop dementia had reduced their alcohol consumption in the years preceding their diagnosis, the investigators noted.

Researchers also conducted genetic analyses involving 2.4 million participants from 45 genome-wide association studies. They examined drinking behavior, including quantity-frequency traits, as well as problematic alcohol use and alcohol use disorder (AUD) or dependency.

Using Mendelian randomization (MR), which leverages genetic data to estimate causal effects, investigators compared participants’ genetic risk for dementia. They applied the inverse variance weighted (IVW) method to assess whether alcohol use traits influence dementia risk and used reverse MR to evaluate whether dementia affects alcohol consumption.

Unlike the observational analyses, the genetic analyses included both incident and prevalent cases.

These analyses showed that higher genetic risk for alcohol consumption — including problematic and dependent drinking — was associated with an increased risk for dementia among participants of European ancestry.

For example, an increase from one to three DPW — or from five to 16 DPW — was associated with a 15% higher risk for dementia (IVW odds ratio [OR], 1.15; 95% CI, 1.03-1.27).

In addition, a twofold increase in genetic risk for AUD was associated with a 16% higher risk for dementia (IVW OR, 1.16; 95% CI, 1.03-1.30).

Genetics Analyses

Topiwala noted she and her colleagues could not “properly” conduct genetic analyses in those not of European ancestry due to sample sizes.

Unlike the observational analyses, low levels of alcohol intake showed no protective effect. Instead, dementia risk steadily increased with higher genetically predicted alcohol consumption. For example, participants averaging 12 DPW had an increased risk for dementia (OR, 1.09; 95% CI, 1.04-1.15).

Further analysis showed that these results were not influenced by age or sex — factors unaffected by alcohol — suggesting the findings reflect causal effects rather than confounding. However, Topiwala noted that the US veteran sample was predominantly men.

The consistency of the results across multiple alcohol-related phenotypes further strengthens their robustness, the investigators noted.

The analyses also ruled out reverse causation, indicating that dementia does not drive increased alcohol consumption.

Results of the genetic analyses using MR “have made us much more convinced that there’s a causal effect” of alcohol use on dementia, commented Topiwala.

The results have important public health implications. Cutting the prevalence of AUD in half “may reduce dementia cases by up to 16%, highlighting alcohol reduction as a potential strategy in dementia prevention policies,” the authors wrote.

The lack of power to detect effects in non-European groups was a possible limitation of this study. Another was that dementia diagnoses were from electronic health records, which may be subject to ascertainment bias.

Asked to comment, Heather M. Snyder, PhD, senior vice president of medical and scientific relations, Alzheimer’s Association, agreed the findings challenge previous findings of a potential protective effect of light-to-moderate drinking.

She noted that the study population is very large, but the analysis isn’t without limitations, and the findings need replication.

“In clinical practice, a healthcare provider may advise patients on the overall impact of limited or moderate alcohol use, such as increased risk for female breast cancer and atrial fibrillation,” said Snyder.

“The complexity of any alcohol use on cognition can now be part of that discussion, but specific guidance based solely on this paper is limited,” she added.

Meanwhile, “positive, everyday actions can make a difference in brain health,” said Snyder, pointing to the Alzheimer’s Association’s 10 Healthy Habits for Your Brain.

The Million Veteran Program was supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program, and the VA Cooperative Studies Program. Topiwala reported being supported by the Wellcome Trust.

Topiwala reported no relevant financial conflicts of interest.