Artikel i BMJ Evidence-Based-Medicine

https://ebm.bmj.com/content/early/2025/09/16/bmjebm-2025-113913
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Original research

Alcohol use and risk of dementia in diverse populations: evidence from cohort, case–control and Mendelian randomisation approaches

 

 

Abstract

Objectives
To investigate the relationship between alcohol consumption and dementia.

 

Design
Prospective cohort and case–control analyses combined with linear and non-linear Mendelian randomisation.

 

Setting
Two large-scale population-based cohorts: the US Million Veteran Programme and the UK Biobank. Genetic analyses used summary statistics from genome-wide association studies (GWAS).

 

Participants
559 559 adults aged 56–72 years at baseline were included in observational analyses (mean follow-up: 4 years in the US cohort; 12 years in the UK cohort). Genetic analyses used summary data from multiple large GWAS consortia (2.4 million participants).

 

Main outcome measures
Incident all-cause dementia, determined through health record linkage, and genetic proxies.

 

Results
During follow-up, 14 540 participants developed dementia and 48 034 died. Observational phenotype-only analyses revealed U-shaped associations between alcohol and dementia risk: higher risk was observed among non-drinkers, heavy drinkers (>40 drinks per week; HR 1.41, 95% CI 1.15 to 1.74), and those with alcohol use disorder (AUD) (HR 1.51, 95% CI 1.42 to 1.60) compared with light drinkers.

 

In contrast, Mendelian randomisation genetic analysis identified a monotonic increase in dementia risk with greater alcohol consumption. A 1 SD increase in log-transformed drinks per week was associated with a 15% dementia increase (inverse-variance weighted (IVW) OR 1.15, 95% CI 1.03 to 1.27). A twofold increase in AUD prevalence was associated with a 16% increase in dementia risk (IVW OR 1.16, 95% CI 1.03 to 1.30). Alcohol intake increased dementia, but individuals who developed dementia also experienced a decline in alcohol intake over time, suggesting reverse causation—where early cognitive decline leads to reduced alcohol consumption—underlies the supposed protective alcohol effects in observational studies.

 

Conclusions
These findings provide evidence for a relationship between all types of alcohol use and increased dementia risk.

 

While correlational observational data suggested a protective effect of light drinking, this could be in part attributable to reduced drinking seen in early dementia; genetic analyses did not support any protective effect, suggesting that any level of alcohol consumption may contribute to dementia risk. Public health strategies that reduce the prevalence of alcohol use disorder could potentially lower the incidence of dementia by up to 16%.

 

 

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Previous observational studies have reported a J-shaped association between alcohol consumption and dementia, suggesting that light-to-moderate drinking may be protective.
• However, these findings may reflect ascertainment of state rather than trait alcohol use phenotypes, residual confounding or reverse causation, rather than a causal effect.

 

 

WHAT THIS STUDY ADDS

• In the largest combined observational and genetic study to date, light alcohol consumption was associated with the lowest dementia risk observationally, but genetic analyses showed a monotonic increasing dementia risk with increased alcohol intake.
• Mendelian randomisation suggests a causal role of alcohol consumption in increasing dementia risk, with no evidence supporting a protective effect at any consumption level.

 

 

HOW MIGHT THIS STUDY AFFECT RESEARCH, PRACTICE OR POLICY

• These findings challenge the notion that low levels of alcohol are neuroprotective and suggest that public health efforts to reduce alcohol use disorder could significantly lower dementia incidence.
• Halving the population prevalence of alcohol use disorder may reduce dementia cases by up to 16%, highlighting alcohol reduction as a potential strategy in dementia prevention policies.

 

 

From the Discussion

 

Discussion

Conventional observational analyses showed a U-shaped association between alcohol consumption and dementia (as has been seen in previous studies), seeming to support the proposal that low or moderate alcohol use is associated with lower dementia risk than no alcohol at all.

 

However, less-confounded genetic analyses provided evidence that alcohol consumption in general, as well as problematic drinking, increases dementia risk. A monotonically increasing risk of alcohol consumption on all-cause dementia was observed, contradicting the interpretation that one can drink alcohol to decrease dementia risk. Furthermore, drinkers who went on to develop dementia typically reduced their alcohol consumption in the years preceding diagnosis, suggesting that the apparent protective effects of moderate drinking may be a consequence of reverse causation.

 

The observational analysis was also susceptible to being influenced by the current, as opposed to lifetime, nature of the trait as ascertained. The genetics analyses, in contrast, considered lifetime genetically predicted risk, a prediction that is quite stable especially in large samples such as those we studied.

 

The reduction in alcohol use before dementia onset aligns with findings from studies of other putative dementia risk factors, including body mass index.28 This has important general implications for study design and for the interpretation of prior studies. Reverse causation is further supported by our finding of a higher incidence of dementia among non-drinkers, in line with previous studies.5 These groups may include ‘sick quitters’—individuals with prior heavy use13 —often with earlier deaths, which may explain their higher dementia risk.

 

Additionally, non-drinkers tended to have lower socioeconomic status and education levels, both of which are associated with poorer pre-morbid cognitive function and increased vulnerability to dementia. Imperfect control means that even though these factors were accounted for statistically, measurement errors mean residual confounding could still underlie apparent observational associations with dementia. In line with many,1 4 but not all,5 prior studies, heavy alcohol use was associated with an increased dementia risk.

 

Variability in alcohol phenotypes, timing of alcohol self-report (especially between mid-life and late-life),5 and differing methods for adjusting for confounding factors are likely to contribute to these discrepancies. Ethnic diversity in alcohol use and dementia risk has been understudied, but our analyses across European, African and Latin American ancestry populations observed similar risks associated with alcohol use disorder.5

Importantly, MR, which has a lower risk of both residual confounding and reverse causation, supported a potential causal role of alcohol use, including DWP, and problematic and dependent use, in increasing dementia risk. We suggest two explanations for discrepancies between our MR results and previous null result studies.14

 

Earlier studies considered a narrow range of alcohol phenotypes and focused on late-onset Alzheimer’s disease, with one exception,29 whereas we included a broader range of alcohol and neurodegenerative pathologies. Second, our study had greater statistical power. Furthermore, our non-linear analyses did not support the previously hypothesised protective effects of low alcohol consumption on dementia and instead showed a monotonically increasing risk with alcohol dose. These results are consistent with a lower powered one-sample MR study in current drinkers of white British ancestry,12 as well as neuroimaging findings.3 30 31

 

This finding has key public health implications, as it challenges the longstanding notion that moderate alcohol intake might have a protective effect on the brain.

 

Several important sensitivity analyses strengthened our findings, including use of age and sex as negative controls to rule out potential biases. Additionally, the consistency of these findings across multiple alcohol phenotypes enhances the robustness of our conclusions.

 

Despite the strengths of our study—a large sample size, cross-ancestry analyses and triangulation of observational and genetically informed approaches using both quantity-frequency and use disorder alcohol phenotypes—there are limitations. Most notably, analyses had the greatest power to detect effects in EUR groups, and dementia diagnoses from EHR may be subject to ascertainment bias, though this would likely bias associations toward the null. MR methods rely on unverifiable assumptions, and the estimates we derived reflect the accumulated effect of alcohol over a lifetime and do not necessarily translate into potential consequences resulting from an adult life intervention. Heterogeneity in estimates between genetic variants may plausibly be due to alcohol acting via different pathways and organs to damage the brain, or failure of the homogeneity or linearity assumptions.32 The latter were tested and held. Non-linear MR estimates at the lower alcohol doses have less precision than those at higher doses, with potential implications for detecting J-shaped relationships; however, negative controls for age and sex did not indicate bias across strata.27

 

In summary, our study findings support a detrimental effect of all types of alcohol consumption on dementia risk, with no evidence supporting the previously suggested protective effect of moderate drinking. The pattern of reduced alcohol use before dementia diagnosis observed in our study underscores the complexity of inferring causality from observational data, especially in ageing populations. Our findings highlight the importance of considering reverse causation and residual confounding in studies of alcohol and dementia, and they suggest that reducing alcohol consumption may be an important strategy for dementia prevention.

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Design
Prospective cohort and case–control analyses combined with linear and non-linear Mendelian randomisation.

Setting
Two large-scale population-based cohorts: the US Million Veteran Programme and the UK Biobank. Genetic analyses used summary statistics from genome-wide association studies (GWAS).

 

 

”I ett försök att ta reda på mer har nu forskare vid bland annat University of Oxford i Storbritannien utfört två sorters undersökningar. Dels en konventionell observationsstudie där studiedeltagarna själva fick uppge hur mycket de dricker, dels en studie där man utgått från genetiska markörer hos studiedeltagarna, som man vet påverkar alkoholkonsumtionen.”

”– Det är en oerhört imponerande studie. Genom att man utgår från genetiska markörer kommer man runt de problem som finns med observationsstudier, eftersom det är väldigt svårt att kontrollera för olika sorters bakgrundsfaktorer i sådana studier, säger Sven Andréasson, prof emeritus om alkohol och alkoholskador.

”Men all forskning som visar att lite alkohol kan ha en skyddande effekt?

– Det är observationsstudier som har de här metodologiska bristerna, eftersom du inte kan lotta personer till att antingen dricka alkohol eller vara nykter i tio år. Genom att titta på genetiska markörer i stället får man en mer rättvisande bild, säger Sven Andréasson.”

”Forskningen alltså visar att riskökningen egentligen börjar redan vid första glaset.

– Så är det och inte bara för demens. För fallolyckor, till exempel, är det väldigt tydligt.”

 

 

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