Critique 255:  Wine consumption and the risk of cognitive decline in the elderly – 29 June 2022

Lucerón-Lucas-Torres M, Cavero-Redondo I, Martínez-Vizcaíno V, Saz-Lara A, Pascual-Morena1 C, Álvarez-Bueno C.  Association Between Wine Consumption and Cognitive Decline in Older People: A Systematic Review and Meta-Analysis of Longitudinal Studies.  Frontiers in Nutrition 2022;9:863059

Authors’ Abstract

Background: Low-to-moderate alcohol consumption appears to have potential health benefits. Existing evidence concludes that wine may be associated with a lower incidence of certain diseases. This systematic review and meta-analysis aim to examine evidence on the association between wine consumption and cognitive decline and to analyze whether this association varies depending on the wine consumption level or is affected by individual and study characteristics, including mean age, percentage of women participants, and follow-up time.

Methods: In this systematic review and meta-analysis, we undertook a search in MEDLINE (via PubMed), Scopus, Cochrane, and Web of Science databases for longitudinal studies measuring the association between wine consumption and cognitive decline from their inception to May 2021. Effect sizes were calculated using the DerSimonian and Laird and Hartung-Knapp-Sidik-Jonkman methods.

Results: The search retrieved 6,055 articles, 16 of which were included in this systematic review. In total, 12 studies were included in the meta-analysis. The studies were published between 1997 and 2019. They were conducted in nine different countries. The sample size of the included studies ranged from 360 to 10,308 with a mean age of 70 years old. Using the DerSimoniand and Laird method, the pooled RR for the effect of wine consumption on cognitive decline was 0.72 (95% CI 0.63–0.80; I 2 = 82.4%; τ 2 : 0.0154). Using the Hartung-Knapp-Sidik-Jonkman method, the RR was 0.65 (95% CI 0.52–0.79; I 2 = 94,531%; τ 2 : 0.057).

Conclusions: This study may show a protective effect of wine consumption against cognitive decline. However, it would be important for future research to differentiate the types of wine within consumption.

Forum Critique

While the results of epidemiologic studies have usually shown that the moderate consumption of all alcoholic beverages tends to be associated with a number of healthy outcomes, especially cardiovascular disease, the association is generally much stronger for the intake of wine than for other types of beverage.  Further, in prospective cohort studies, moderate wine consumption has usually been seen to be associated with protection against cognitive decline and dementia. 

In the present paper, the authors have carried out a systematic review of the literature between 1997 and 2019 and found 16 publications relating levels of wine consumption to changes in cognitive level over time in follow-up studies.  The number of subjects in the studies included in their meta-analysis ranged between 360 and 10,308, with a total number of subjects of 46,472 subjects.  The mean age of subjects was 70 years, and the follow-up period of subjects in the included studies ranged from 2 to 43 years.  A large battery of tests was used at baseline and at follow-up to judge changes in cognitive level.  

Forum member Skovenborg noted: “I am missing some important caveats from this study. Information about modifying factors such as the Mediterranean diet (wine drinkers may be prone to eat a more healthy diet and drink their wine with meals); confounding factors (wine drinkers may generally have a healthier lifestyle and better socioeconomic status); and reverse causation (studies show that dementia is a long process with a period of up to 9 years of slow cognitive decline before diagnosis.  During that period of slow loss of cognition you might change your normal drinking habits and drinking pattern).” 

Reviewer McEvoy wrote: “I agree with the problems noted in this critique by other Forum members.  However I do not agree with the conclusion that this study supports a protective role of wine on cognitive function because of the lack of consideration of any potential confounders of the associations, and the lack of differentiation of the non-drinking group. The latter is likely to include former drinkers in most of the studies reviewed.  Thus this study lacks sufficient rigor for drawing any conclusions on the association of wine intake with cognitive decline.”

Reviewer Parente stated: “Although the results of the meta-analysis are encouraging regarding protective effects on cognition with low-moderate alcohol consumption, I agree with others re the lack of stratification for drinking pattern and other potential factors such as healthier lifestyle habits and circumstances of wine drinkers.  The study heterogeneity (I-squared) was moderately high in the within- and above-WHO guidelines groups and very high for the unclassified group.  Despite the length of some studies, only one of the within/above WHO guidelines studies assessed alcohol intake more than once. 

Forum members also noted the recent publication of another study based on MRI of the brain that reported a decrease in volume of a number of brain areas among drinkers (Topiwala et al, 2022)  Reviewer Parente commented: “As far as the Topiwala et al MRI studies, I cannot interpret those findings in parallel with significance for cognitive function. (Some of it reminds me of the hype surrounding fMRI’s ability to disentangle psychiatric disorders; some of it reminds me of tarot cards.)  The authors of the Topiwala et al paper found that while MRI measures were associated with cognitive test performance, the only direct associations between alcohol and cognition were observed among those with lower educational level, which might call into question the validity of some results.”

Reviewer Ellison wrote: “Unfortunately, we cannot directly compare these two studies, as the primary result of decreases in cognitive functioning over time was not evaluated in the paper on MRI measurements.  I also have some other questions about the Topiwala et al paper: Who made up the cohort? The study was based on subjects in the UK, where I thought that beer consumption was the usual, but the paper reports that the vast majority (76.9%) are listed as being solely wine drinkers!  In the supplemental data, the authors report there were 5,080 subjects who solely drank wine; 1,193 who solely drank beer; and only 329 who solely drank spirits.  Further, the median alcohol intake was 13.5 units (102 grams of alcohol) weekly, a much higher value than is usually seen in population-based surveys.  Among the more than 25,000 subjects, there were only 691 never-drinkers, 617 former drinkers, and 24,069 current drinkers; certainly, too few non-drinkers to use as a comparison group.  Also, the authors write that among those stating they were ‘drinkers’ there were 3,760 who then reported that their usual weekly intake was 0; instead of adding these to the light drinkers, they excluded them from the analyses.  Given that the paper was focused primarily on anatomical measurements from the brain scans, there is little to compare with the present paper by Torres et al.”

Ellison added: “Differences between the consumption of wine and spirits were noted in a very long follow-up analysis by Mehlig et al, where the authors state: ‘During 34 years of follow up, wine was protective for dementia (hazard ratio (HR) = 0.6, 95% confidence interval (CI): 0.4, 0.8) in the updated model, and the association was strongest among women who consumed wine only (HR = 0.3, 95% CI: 0.1, 0.8).  In contrast, consumption of spirits at baseline was associated with slightly increased risk of dementia (HR = 1.5, 95% CI: 1.0, 2.2), when compared with non-drinkers.’  We realize that people do not normally drink ‘alcohol,’ it is always in the form of beer, wine, or spirits.  Analyses of ‘alcohol effect’ on health should report results separately for each beverage as their effects may vary.”

“In another paper, Streppel et al reported that ‘Long-term light alcohol intake, that is < or =20 g per day, compared with no alcohol, was strongly and inversely associated with cerebrovascular (HR 0.43, 95% CI 0.26 to 0.70), total cardiovascular (HR 0.70, 95% CI 0.55 to 0.89) and all-cause mortality (HR 0.75, 95% CI 0.63 to 0.91).  Independent of total alcohol intake, long-term wine consumption of, on average, less than half a glass per day was strongly and inversely associated with coronary heart disease (HR 0.61, 95% CI 0.41 to 0.89), total cardiovascular (HR 0.68, 95% CI 0.53 to 0.86) and all-cause mortality (HR 0.73, 95% CI 0.62 to 0.87). These results could not be explained by differences in socioeconomic status. Life expectancy was about 5 years longer in men who consumed wine compared with those who did not use alcoholic beverages.’  Thus, as stated, it is important not to group all alcohol-containing beverages together as the exposure, which may be especially true when relating their intake to the risk of cognitive decline or dementia.”

Forum member Skovenborg provided additional comments, and summarized previous research on wine, alcohol, and cognition: “The association of alcohol intake and cognition health has been studied for many years – I have at present 175 different studies on this topic on file from 1977 to 2022. However, Topiwala et al do not include a single reference to that relevant study category.  They state: ‘There are a few substantiated claims that red wine has beneficial effects’, and list a clinical study of the effect on oxidative stress by daily intake of 300 ml red and white wine for 15 days (Pignatelli et al). Later on, the famous mortality study by Grønbæk is mentioned together with a study of young adults on psychological functioning and social status as confounding factors (Mortensen et al).

“A longitudinal study of the association between wine consumption and cognitive decline would have been more relevant and there are plenty of those studies. The Whitehall II cohort study with a 23 year follow-up may be the best study of alcohol consumption and dementia because the long follow-up period eliminates the risk of reverse causation bias (Sabia et al).  Topiwala published a MRI examination study of the Whitehall II cohort in 2017 and cannot claim innocence by ignorance of the paper by Sabia et al.

“What are plausible biological mechanisms? At the end of the day we should ask for a plausible biological mechanism for the association of reduced grey matter volumes with drinking as little as 56-112 g alcohol weekly. On one hand a small glass of wine with your meal (8 g alcohol/day) will shrink your brain according to Topiwala et al.  On the other hand, consumption of wine within WHO recommendations (30 g/day for men; 20 g/day for women) is associated with a protection against cognition decline according to Torres et al.  Obviously, we look forward to further studies that focus on changes in cognition associated with all alcoholic-beverages.” 

References from Forum critique

Grønbæk M, Deis A, Sørensen TI, Becker U, Schnohr P, Jensen G.  Mortality associated with moderate intakes of wine, beer, or spirits.  BMJ 1995;310:1165-1169.

Mehlig K, Skkoog I, Guo M, Schütze M, Gusfafson D, Waern M, Ostling S, Bjorkelund C,  Lissner L.  Alcoholic beverages and incidence of dementia: 34-year follow-up of the prospective population study of women in Goteborg.  A J Epidemiol 2008;167:684-691.  doi: 10.1093/aje/kwm366. 

Mortensen EL, Jensen HH, Sanders SA, Reinisch JM.  Better psychological functioning and higher social status may largely explain the apparent health benefits of wine: a study of wine and beer drinking in young Danish adults.  Arch Intern Med 2001;161:1844-1848.

Pignatelli P, Ghiselli A, Buchetti B, Carnevale R, Natella F, Germanò G, Fimognari F, Di Santo S, L Lenti, Violi F.  Polyphenols synergistically inhibit oxidative stress in subjects given red and white wine.  Atherosclerosis 2006;188:77-83.

Sabia S, Fayosse A, Dumurgier J, Dugravot A, Akbaraly T, Britton A, Kivimäki M, Singh-Manoux A.  Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study.  BMJ 2018;362:k2927.

Streppel MT, Oaké MC, Boshuizen HC, Kok FJ , Kromhout D.  Long-Term Wine Consumption is Independent of Moderate Alcohol Intake Related to Cardiovascular Mortality and Life Expectancy: The Zutphen Study. Circulation 2007;115:57-57; Age Ageing 2008;37:505-512  doi: 10.1093/ageing/afn095.

Topiwala, A., Allan, C.L., Valkanova, V., Zsoldos, E., Filippini, N., Sexton, C., Mahmood, A., Fooks, P., Singh-Manoux, A., Mackay, C.E., Kivimäki, M., Ebmeier, K.P.  Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. Br Med J 2017;357:j2353.

Topiwala A, Ebmeier KP, Maullin-Sapey T, Nichols TE.  Alcohol consumption and MRI markers of brain structure and function: Cohort study of 25,378 UK Biobank participants. Neurological Clinical 2022;35.103066.  Doi .org/10.1015/j.nicl.eoee.103066.

Forum Summary

The results of this systematic review and meta-analysis of longitudinal studies showed that, in almost every study, both wine consumption within the usual guidelines (no more than 2 drinks/day for men or 1 drink/day for women), as well as consumption in excess of these limits, were similarly associated with a lower risk of cognitive decline.  For studies providing data on the amount of alcohol consumed, the risk of cognitive decline was reduced by 41% for both wine consumers drinking within the recommended guidelines as well as those reporting wine consumption in excess of the guidelines, when compared with abstainers.  In studies where the amount of wine consumption was not reported, the estimate was an 18% reduction in the risk of cognitive decline for wine consumers versus abstainers. 

Forum member note that many potential confounders of the relation of alcoholic beverage consumption and cognition may modify the effects of alcohol on cognition, and were not evaluated very well in this study. Especially important may be the pattern of drinking (regularly or irregularly, with or without food, with associated binge drinking, etc),  Forum members agreed that the calculations of the authors support a protective effect of wine consumption against cognitive decline, but their conclusions may be limited because of residual confounding by the pattern of drinking and other key factors not included in their analyses.    

Forum members also noted another recent paper relating brain MRI markers to alcohol intake.  However, changes in cognitive function were not assessed in the latter paper, and a direct comparison between the two papers cannot be done.  However, we conclude that there remain questions regarding the effects of wine and other beverages containing alcohol on cognition.  Other studies have shown divergent effects on the risk of dementia associated with wine consumption and the intake of spirits, so there may indeed be different effects on cognition with wine intake, the factor studied in the present paper.  And, when compared with non-drinking or drinking of other beverages, extensive research supports health and mortality advantages when wine is consumed moderately, and especially with meals. 

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Comments on this paper have been provided by the following members of the International Scientific Forum on Alcohol Research:

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

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

Ramon Estruch, MD, PhD, Hospital Clinic, IDIBAPS, Associate Professor of Medicine, University of Barcelona, Spain

Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)

Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA

Dominique Lanzmann-Petithory, MD, PhD, Nutrition Geriatrics, Hôpital Emile Roux, APHP Paris, Limeil-Brévannes, France

Linda McEvoy, PhD, Department of Radiology, University of California at San Diego (UCSD), La Jolla, CA, USA

Matilda Parente, MD, consultant in molecular pathology/genetics and emerging technologies, San Diego, CA, USA

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical

Alcohol Board, Aarhus, Denmark

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

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, USA