Critique 053: An extensive review of the effects of alcohol consumption on the risk of cognitive impairment and dementia – 25 August 2011

Neafsey EJ, Collins MA.  Moderate alcohol consumption and cognitive risk.  Neuropsychiatric Disease and Treatment 2011:7:465–484.

Authors’ Abstract

We reviewed 143 papers that described the relationship between moderate drinking of alcohol and some aspect of cognition.  Two types of papers were found: (1) those that provided ratios of risk between drinkers and nondrinkers (74 papers in total) and (2) those that, although they did not provide such ratios, allowed cognition in drinkers to be rated as “better,” “no different,” or “worse” than cognition in nondrinkers (69 papers in total).

The history of research on moderate drinking and cognition can be divided into two eras: 1977–1997 and 1998–present.  Phase I (1977–1997) was the era of neuropsychological evaluation involving mostly young to middle-aged (18–50 years old) subjects.  Although initial studies indicated moderate drinking impaired cognition, many later studies failed to confirm this, instead finding no difference in cognition between drinkers and nondrinkers.

Phase II (1998–present) was and is the era of mental status exam evaluation involving mostly older (≥55 years old) subjects.  These studies overwhelmingly found that moderate drinking either reduced or had no effect on the risk of dementia or cognitive impairment.  When all the ratios of risk from all the studies in phase II providing such ratios are entered into a comprehensive meta-analysis, the average ratio of risk for cognitive risk (dementia or cognitive impairment/decline) associated with moderate “social” (not alcoholic) drinking of alcohol is 0.77, with nondrinkers as the reference group.  The benefit of moderate drinking applied to all forms of dementia (dementia unspecified, Alzheimer’s disease, and vascular dementia) and to cognitive impairment (low test scores), but no significant benefit against cognitive decline (rate of decline in test scores) was found.  Both light and moderate drinking provided a similar benefit, but heavy drinking was associated with nonsignificantly higher cognitive risk for dementia and cognitive impairment.

Although the meta-analysis also indicated that wine was better than beer or spirits, this was based on a relatively small number of studies because most studies did not distinguish among these different types of alcohol.  Furthermore, a number of the studies that did make the distinction reported no difference among the effects of these different types of alcohol.  Therefore, at present this question remains unanswered.  Analysis also showed that the presence of the apolipoprotein E epsilon 4 allele eliminated the benefit of moderate drinking.  However, this was based on a relatively small number of studies and several other studies have found a beneficial effect of the epsilon e4 allele.  Further studies are necessary to settle this question.  The benefit of moderate alcohol for cognition was seen in both men and women, although the amount and pattern of drinking is very different between the two sexes.  Lastly, the finding of unaffected or significantly reduced cognitive risk in light to moderate drinkers was seen in 14/19 countries for which country-specific ratio data were available, with three of the five remaining countries showing nonsignificant reductions as well.

Overall, light to moderate drinking does not appear to impair cognition in younger subjects and actually seems to reduce the risk of dementia and cognitive decline in older subjects.

Forum Comments

Background:  Many studies in the past decade have shown that light-to-moderate consumers of alcohol tend to be at lower risk of dementia.  Two meta-analyses published recently that were restricted to “higher quality” studies found significantly lower risk (about 25% lower) for moderate drinkers than for nondrinkers.  Using a different approach, the present study by Neafsey and Collins included all studies providing adequate data to obtain what they considered to be “the big picture” and to complement the recent more restrictive or selective analyses.

Comments on the study:  Overall, Forum reviewers thought that this was a very well-done and presented paper.  As one reviewer commented, “Several likable features of this study included its inspiration from a rat brain experiment, an innovative grouping of studies, plausible results, and an interesting comparison of the effect of moderate alcohol consumption with other dementia risk-reducing activities.”

The analysis is divided into two phases, with the first consisting of studies in which risk ratios for dementia according to alcohol consumption were not provided, but “drinkers” were compared with “non-drinkers” in terms of whether their risk of dementia was “better,” “worse,” or not different.  Most of these studies were prior to 1998 and generally in younger people, and provide limited information on the association of alcohol intake of varying amounts and cognitive function in the elderly.

There were 74 “Phase II” studies, with a total of more than 250,000 subjects; they were reported mainly after 1998, were predominantly among older subjects (92% were ≥ 55 years of age and 70% ≥ 65 years of age), and almost all employed mental status examinations to diagnose cognitive impairment.  For the meta-analysis of Phase II studies, the overall weighted mean value from a random-effects model indicated a 23% reduction in risk of dementia, cognitive impairment, or cognitive decline in drinkers when compared with non-drinkers.  The RR of 0.77 in this study is similar to the RR of 0.73 reported by Peters et al¹ and the RR of 0.74 reported byAnstey et al² from their meta-analyses based on more restricted groups of studies. 

Another Forum reviewer also liked the paper:  “I agree, the paper is sound and well done. And it is important because it covers a field which is not yet very familiar to physicians and the general public alike.”  Overall, the reviewers agreed that this very large meta-analysis supports previous papers, including recent meta-analyses, showing that there is “substantial evidence that light to moderate drinking, particularly of wine, reduces the risk of dementia and cognitive impairment.”

One question on the meta-analysis raised by a reviewer was whether the various risk ratios (ORs, RRs and HRs) are truly equivalent and may be pooled and plotted together. The odds ratio is a reasonable approximation of the relative risk when the outcome is relatively rare (e.g., when less than 1% of people exposed to an agent develop disease).  Using the odds ratio as an approximation of the relative risk produces progressively larger errors as the outcome rate rises above 1%.^3,4

Another reviewer was “surprised that the link between ApoE4 polymorphism and early dementia with alcohol consumption has not been demonstrated more clearly.  Research linked to genetic risk factors for dementia needs to be stimulated to identify whether alcohol could be a trigger for low-penetrance genes, as surely people with certain genetic abnormalities may not respond positively to alcohol consumption.”

Specific questions on the topic addressed by this paper:  Forum reviewers were particularly glad to see an attempt by the authors to answer specific questions that have been raised from previous analyses.  These include the following:

(1)  Does the presence of “sick quitters” in the non-drinking reference group affect the outcomes.  Here, their analyses indicate that the answer in no.

(2)  Does statistical adjustment for age, education, sex and smoking change the effect of alcohol on cognitive risk?  Again, their analyses indicate that the answer is no.

(3)  Does the type of instrument used for assessing dementia (using MMSE or not using the MMSE) affect the results.  The investigators found no difference according to the instrument(s) used to define dementia.

(4)  Are there differences in alcohol effects for different types of dementia?  There were no significant differences found between alcohol’s effects on overall dementia, Alzheimer’s dementia, or vascular dementia.

(5)  Are there differences in effects of moderate drinking on cognitive impairment and cognitive decline?  Unlike measures of cognitive impairment, the risk for cognitive decline was not significantly reduced by moderate alcohol intake; however, the latter analysis was based only on a small number of studies.

(6)  Are there differences between the effects of light, moderate, and heavy drinking on cognitive risk?  Both light and moderate drinking were associated with reduced risk, while heavy drinking was associated with increased cognitive risk. 

(7)  Are there differences between the consumption of beer, wine, and spirits?  Wine provided a significant reduction in cognitive risk while beer and spirits did not.  However, the authors state that this conclusion must be qualified by a relatively small number of studies providing beverage-specific results and a number of other studies reporting only that there were “no significant differences by type of beverage.” 

(8)  Does the presence of the ApoE ε4 allele modify results?  Data are conflicting on this.

(9)  Does the sex of the drinker alter the effect?  For moderate drinkers, in comparison with non-drinkers, the investigators found very similar effects on the risk of cognitive impairment for males (RR=0.74) and females (RR=0-.69). 

(10)  Does the effect of alcohol on cognition vary with country?  In general, no.  For some studies from countries where initial analyses did not show a significantly lower risk for drinkers, exclusion of heavy drinkers or those with ApoE ε4 alleles resulted in the typical finding of lower risk for drinkers. 

References from Forum review:

1.  Peters R, Peters J, Warner J, et al.  Alcohol, dementia and cognitive decline in the elderly: a systematic review.  Age Ageing 2008;37:505–512.

2.  Anstey KJ, Mack HA, Cherbuin N.  Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies.  Am J Geriatr Psychiatry 2009;17:542–555.

3.  Bigby M.  Odds ratios and relative risks.  Arch Dermatol 2000;136:770-771.

4.  Altman DG, Bland JM.  Interaction revisited: the difference between two estimates.  BMJ 2003;326:219.

Forum Summary

The authors of this paper have carried out an excellent review of the relation of alcohol consumption to the risk of cognitive impairment and dementia.  They reviewed a total of 143 previous publications on the topic. There were 74 studies, based on a total of more than 250,000 subjects, that provided risk estimates for varying levels of alcohol consumption which allowed the investigators to include them in a comprehensive meta-analysis.  These papers were published mainly after 1998, were predominantly among older subjects (92% were ≥ 55 years of age and 70% ≥ 65 years of age), and almost all employed mental status examinations to define cognitive impairment/dementia.  

As stated by the authors, “These studies overwhelmingly found that moderate drinking either reduced or had no effect on the risk of dementia or cognitive impairment.”  Overall, in the new meta-analysis based on these studies, the average ratio of risk for cognitive risk associated with moderate drinking of alcohol was 0.77, with nondrinkers as the reference group.  This estimate is close to the estimates of reduction in the risk of cognitive dysfunction (RR of 0.73 and 0.74) seen in other recent selective meta-analyses.  The present study found that both light and moderate drinking provided a similar benefit, but heavy drinking was associated with non-significantly higher cognitive risk for dementia and cognitive impairment.

Forum reviewers of this paper were particularly pleased that the authors attempted to answer a number of specific questions on this topic that have been raised from previous research.  Their results included finding no appreciable differences whether or not “sick quitters” were included in the reference group, little effect from adjustments for other lifestyle factors, and no significant differences between alcohol’s effects on dementia, Alzheimer’s dementia, or vascular dementia (but, based on a small number of studies, no significant reduction in risk of cognitive decline over time).  The investigators concluded that there were no differences between results in men and women.  Their analyses also led to the conclusion that wine is associated with more beneficial effects on cognition than beer or spirits, but the authors caution that these results are based on a limited number of reports, and that many studies show no significant differences according to type of beverage.

Forum reviewers agreed with the conclusions of the authors that “Overall, light to moderate drinking does not appear to impair cognition in younger subjects and actually seems to reduce the risk of dementia and cognitive decline in older subjects.”

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Contributions to this critique were provided by the following members of the International Scientific Forum on Alcohol Research:

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine,  University of Münster, Münster, Germany

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona. Italy

Creina Stockley, clinical pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

Pierre-Louis Teissedre, PhD, Faculty of Oenology – ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia