Critique 223: A new major review of the relation of alcohol consumption to the risk of dementia. 17 January 2019

Rehm J, Hasan OSM, Black SE, Shield KD, Schwarzinger M.  Alcohol use and dementia: a systematic scoping review.  Alzheimer’s Research & Therapy 2019; 11: pre-publication.  https://doi.org/10.1186/s13195-018-0453-0

Authors’ Abstract

Background: Alcohol use has been identified as a risk factor for dementia and cognitive decline. However, some patterns of drinking have been associated with beneficial effects.

Methods and Results: To clarify the relationship between alcohol use and dementia, we conducted a scoping review based on a systematic search of systematic reviews published from January 2000 to October 2017 by using Medline, Embase, and PsycINFO.

Overall, 28 systematic reviews were identified: 20 on the associations between the level of alcohol use and the incidence of cognitive impairment/dementia, six on the associations between dimensions of alcohol use and specific brain functions, and two on induced dementias. Although causality could not be established, light to moderate alcohol use in middle to late adulthood was associated with a decreased risk of cognitive impairment and dementia. Heavy alcohol use was associated with changes in brain structures, cognitive impairments, and an increased risk of all types of dementia. 

Conclusion: Reducing heavy alcohol use may be an effective dementia prevention strategy.

Forum Comments

Background:  While many studies have shown that excessive alcohol intake is associated with cognitive impairment, with among the most serious being conditions such as Korsakoff psychosis (which may occur among alcoholics), many cohort studies have shown that the risk of cognitive impairment and dementia are lower for light-to-moderate consumers of alcohol than among abstainers.  More recent studies have shown that this relation is seen even when the comparison group is made up of lifetime abstainers, and does not include “sick quitters.”  Some, but not all such studies, show an increased risk of cognitive impairment with heavier drinking.

In an overview of the topic, Forum member Stockley wrote: “There have been many evidence-based research studies on alcohol and cognition undertaken over the last 10 years, and there are multiple international reviews of these studies. Although there is variation in methodology between studies assessing aspects of cognitive function and alcohol consumption, both current and over a lifetime, the reviews consistently suggest that, on balance, there is a J- or U-shaped relationship between alcohol consumption and the risk of cognitive impairment or dysfunction and the development of dementias such as Alzheimer’s disease.  For example, this relationship has been often observed even when taking into account beverage type, drinking patterns and follow-up periods, as well as demographics, genetics, and lifestyle factors such as smoking.

“An excellent paper by Neafsey & Collins in 2011 (previously critiqued by our Forum) included 143 papers published between 1997 and 2011 in a meta-analysis. The meta-analysis showed a 23% reduction in risk of cognitive impairment and dementia for light to moderate consumers compared to non-drinkers, irrespective of whether former drinkers were included with lifetime abstainers (sick quitter hypothesis).  Furthermore, in studies that did not separate lifetime abstainers from former drinkers, the finding that alcohol consumption has neuroprotective effects becomes stronger, since former drinkers, especially if many were heavy drinkers, would be expected to be at an increased risk at baseline otherwise.  While it is difficult to determine an ‘optimal’ amount because the designs/methods among the studies differ, there are no data suggesting that lifetime or long-term light-to-moderate alcohol consumption exacerbates age-related cognitive impairment/dysfunction.”

Emphasis on heavy drinking in this paper.  In the present analyses, the authors report that for subjects identified as “light or moderate drinkers,” the results almost always showed a reduced risk of cognitive decline or dementia, but they do not discuss this finding very much in their Discussion.  It appears to Forum reviewers that the main purpose of this paper was to demonstrate adverse effects on the brain of heavier drinking.  The Discussion of the paper focuses only on the authors’ inability from their data to show that any alcohol intake is bad for the brain.  All of their suggestions for future research are for potential studies to show that alcohol-use disorders or other indices of heavy drinking lead to more dementia.  This seems misdirected, as it is clear that heavy alcohol is not good for you (or for society) in many ways, which questions the need for further research on this topic.  Instead, Forum members agree that we should diligently seek more effective ways for preventing such alcohol consumption in the first place, not just adding another adverse effect of heavy drinking.

Stated Reviewer Finkel: “I found very interesting the implied mindset of the authors; they seem to me to expend a lot of space to ensure no one takes this as simply another meta-analysis.  The emphasis suggests bias: an example is their concluding sentence in the abstract, referring only to the (inconclusive) evidence from their review of the increased dementia with alcohol consumption.”

Reviewer Skovenborg also commented: “In the present paper the authors found that the majority of the systematic reviews indicated that there was a statistically significant association between light to moderate alcohol use and a lower risk of (i) being diagnosed with cognitive impairment and different types of dementia and (ii) dying from dementia; however, two systematic reviews found inconsistent results.  Further, they do not mention that three of the systematic reviews did not find an association between heavy alcohol use and cognitive impairment or dementia.”

Potential mechanisms for an association between alcohol and dementia:  Reviewer Skovenborg also stated: “Considering the important Bradford Hill criteria of plausibility, the present authors do not quote the very interesting observation of beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake, on glymphatic function (as described by Lundgaard et al).  The glymphatic function is a brain-wide metabolite clearance system connected to the peripheral lymphatic system.  In research by those investigators, the glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure, while chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers.”

Forum member Keil noted: “Dementia is a syndrome, not a disease entity, and if you look at age-specific figures of dementia over time, this syndrome appears to be decreasing over time.  One explanation for this decrease is better risk factor prevention, resulting in quite dramatic declines in the risk of stroke and coronary heart disease.  This adds support to the premise that ‘What is good for the heart is good for the brain.’  Furthermore, I do not agree with the statement of the authors, ‘Given the lack of high-quality research on alcohol, AD, and cognitive functioning/impairment, future randomized prevention and secondary prevention trials with alcohol interventions are needed.’  To the contrary I think there is a lot of high quality research on alcohol use and cognitive functioning; it is surprising to me that the very important paper by Hoffman et al in Rotterdam has not been cited.  Clearly I will also support clinical trials as long as we are able to really carry them out.”  (Other Forum members considered that a clinical trial with dementia as an outcome would not be feasible.)

Reviewer Keil continued: “Why is it so difficult for the authors to make a clear statement on light to moderate alcohol intake and dementia in the conclusions of both the abstract and the paper, although they make this statement within the text?  I am afraid that their statements may confuse the public by not clearly demonstrating differences between moderate and heavy consumption.  We have known for decades (actually for millennia, as in Homer’s Odyssey) that heavy alcohol use is not good for your health or well being, but we are sincerely interested in the benefits (or harms) of light to moderate alcohol intake on cognitive functioning and many other conditions.”

Key outcomes in studying alcohol and dementia:  The authors state in their methods that they included reviews of the association between alcohol use and brain structure; for their main analyses, it appears that the reviews included only those that were those focusing on indices of cognitive function/dementia.  Forum member Ellison considers that the most important outcomes for evaluation are increased independence and a better level of functioning in old age, and survival; these may provide more relevant data than just changes seen on X-rays or scans.

On the other hand, reviewer McEvoy comments: “One note on the imaging findings (which I do think are worth considering when evaluating potential effects of alcohol on cognitive health).  The authors of this review briefly note that Verbaten’s review of MRI studies found that low to moderate alcohol use was related to grade of white matter integrity and in a curvilinear manner only in adults over age 65.  In our own studies, we reported that with sensitive measures of white matter microstructure, protective associations between moderate drinking and white matter microstructure were also apparent in men from the Vietnam Era Twin Study of Aging who were between 56-66 years old (McEvoy et al).  The authors did not note this corroborating evidence for protective associations in those younger than 65.”

Differences according to type of beverage and pattern of drinking:  Most previous, well-done cohort studies and experimental studies have shown that alcohol (regardless of the specific beverage) plays an important role in preventing cardiovascular disease.  However, for cognitive impairment and dementia, in a number of studies where beverage–specific data are available, there are often large differences noted between wine drinkers and spirits drinkers.  For example, Mehlig et al, in a cohort of Swedish women with repeated assessments of alcohol intake over more than 30 years, found that the risk of dementia was lower among wine drinkers but higher for consumers of spirits, even when adjustments were made for other lifestyle and SES-related factors.  Specifically, they report: “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).”

Sabia et al (2018), in their recent study that involved repeated assessments of intake over 23 years, similarly found “a reduced risk of dementia for moderate wine consumption and a linear increased risk of dementia in those consuming spirits.”  Forum reviewers emphasize that future studies should focus not only on total alcohol consumed and the pattern of dinking, but on the type of beverage usually being consumed.   Further, results from studies that do not adjust for concomitant smoking and other lifestyle factors, as well as socioeconomic confounders, have limited implications for setting policy.

Mendelian randomization?  The authors state that there is a real need for Mendelian randomization studies to prove that any alcohol is bad for the brain, but they had to admit that the three such studies that have been done and they reference do not support their premise.  Reviewer Ellison states that he does not believe that we have adequate instrumental variables (that reflect not only genetic factors but the ability to adjust for level of alcohol intake, pattern of drinking, and other lifestyle behaviors or SES that modify the effects of alcohol) to put much importance yet on Mendelian randomization studies.  

Considering reverse causation in epidemiologic studies:  Forum member Skovenborg commented: “Reverse causation is one of the problems with establishing a causal relationship for any lifestyle factor.  For example, in the Whitehall II cohort study of physical activity (Sabia et al, 2017), cognitive decline, and risk of dementia with 28 year follow-up, and exposures including time spent in mild, moderate to vigorous, and total physical activity assessed seven times during the study period, physical activity in people with dementia began to decline up to nine years before diagnosis.  That study found no evidence of a neuroprotective effect of physical activity and suggested that previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation — that is, due to a decline in physical activity levels in the preclinical phase of dementia.

“In contrast, in a separate analysis, the association of alcohol consumption and risk of dementia in the Whitehall II cohort study with 23 year follow-up and three assessments of alcohol consumption in midlife (Sabia et al, 2018) found abstinence in midlife was associated with a higher risk of dementia (hazard ratio 1.47, 95% confidence interval 1.15 to 1.89) compared with consumption of 1-14 units/week, with no indication of reverse causation.”  Added Ellison: “Such findings also emphasize the importance of having repeated assessments of exposure data (such as alcohol consumption) when seeking to judge causality for any exposure related to the development of dementia; unfortunately, many of our studies do not have such information.”

References from Forum Critique

Hoffman LA, Sklar AL, Nixon SJ. The effects of acute alcohol on psychomotor, set-shifting, and working memory performance in older men and women. Alcohol 2015;49:185-191. doi: 10.1016/j.alcohol.2015.02.001.

Lundgaard I, Wang W, Eberhardt A, Vinitsky HS, Reeves BC, Peng S, Lou N, Hussain R, Nedergaard M.  Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function. Sci Rep 2018;8:2246.

McEvoy LK, Fennema-Notestine C, Elman JA, Eyler LT, Franz CE, Hagler DJ, Jr., et al. Alcohol intake and brain white matter in middle aged men: Microscopic and macroscopic differences. Neuroimage Clin 2018;18:390-398.

Mehlig K1, Skoog I, Guo X, Schütze M, Gustafson D, Waern M, Ostling S, Björkelund C, Lissner L.  Alcoholic beverages and incidence of dementia: 34-year follow-up of the prospective population study of women in Goteborg.  Am J Epidemiol 2008;167:684-691. doi: 10.1093/aje/kwm366.

Neafsey EJ, Collins MA.   Moderate alcohol consumption and cognitive risk.  Neuropsychiatr Dis Treat 2011;7:465–484.  doi: 10.2147/NDT.S23159

Sabia S, Dugravot A, Dartigues J-F, Abell J, Elbaz A, Kivimäki M, Singh-Manoux A.  Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study.  BMJ 2017;357:j2709.

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.

Verbaten MN.  Chronic effects of low to moderate alcohol consumption on structural and functional properties of the brain: beneficial or not?  Hum Psychopharmacol 2009;24:199-205. doi: 10.1002/hup.1022.

Forum Summary

While many studies have shown that excessive alcohol intake is associated with cognitive impairment and increased risk of dementia, most cohort studies have shown that the risks of these outcomes are lower among light-to-moderate drinkers than among abstainers.  The authors of this paper conducted a scoping review on this topic, based on a systematic search of systematic reviews published from January 2000 to October 2017.  A total of 28 systematic reviews were identified relating alcohol intake at various time periods to incidence of cognitive impairment/dementia, specific brain functions, or induced dementias.  The authors report that light to moderate alcohol use in middle to late adulthood was associated with a decreased risk of cognitive impairment and dementia, but heavy alcohol use was associated with changes in brain structures, cognitive impairments, and an increased risk of all types of dementia.

Forum members considered this to be a well-done analysis, but were concerned that the focus was only on the potentially adverse effects of heavy drinking, with little regard or discussion of the findings of protection against such cognitive outcomes among light or moderate drinkers.  Forum members point out that there are very many adverse health effects, both for the drinker and for society, resulting from heavy drinking.  To them, the most interesting and provocative aspect of this paper was the conclusion of a protective effect against cognitive decline and dementia associated with light-to-moderate alcohol consumption.

Scientific data, including the results of the present systematic analysis, are very consistent in showing that cognitive decline, associated impairments in the functions of daily living, incident dementia, and survival are all associated favorably with light-to-moderate consumption of alcohol in middle age.  The reasons and mechanisms that lead to these associations deserve further evaluation.  With the increasing ageing of populations throughout the world, cognitive decline and dementia are expected to increase and create serious challenges for health care providers.  Insight into ways of preventing or delaying the onset of such cognitive decline (in addition to decreasing the prevalence of heavy alcohol intake, the focus of this paper) could be extremely important in planning for the future.

Reference: Rehm J, Hasan OSM, Black SE, Shield KD, Schwarzinger M.  Alcohol use and dementia: a systematic scoping review.  Alzheimer’s Research & Therapy 2019; 11: pre-publication.  https://doi.org/10.1186/s13195-018-0453-0

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

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

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

Susan J. van Rensburg, PhD, Department of Pathology, Stellenbosch University, Tygerberg, South Africa

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

Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Adjunct Senior Lecturer at the University of Adelaide, Australia

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

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

Ulrich Keil, MD, PhD, Professor Emeritus, Institute of Epidemiology & Social Medicine, University of Muenster, Germany

Lynn Gretkowski, MD, Obstetrics/Gynecology, Mountainview, CA, Stanford University, Stanford, CA, USA

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

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

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