Critique 081: Alcohol intake in the elderly affects risk of cognitive decline and dementia — 22 May 2012

Kim JW, Lee DY, Lee BC, Jung MH, Kim H, Choi YS, Choi I-G.  Alcohol and Cognition in the Elderly: A Review.  Psychiatry Investig 2012;9:8-16;  On-line:

Authors’ Abstract

Consumption of large amounts of alcohol is known to have negative effects, but consumption in smaller amounts may be protective.  The effect of alcohol may be greater in the elderly than in younger adults, particularly with regard to cognition.  However, the drinking pattern that will provide optimal protection against dementia and cognitive decline in the elderly has not been systematically investigated.  The present paper is a critical review of research on the effect of alcohol on cognitive function and dementia in the elderly.  

Studies published from 1971 to 2011 related to alcohol and cognition in the elderly were reviewed using a PubMed search.  Alcohol may have both a neurotoxic and neuroprotective effect.  Longitudinal and brain imaging studies in the elderly show that excessive alcohol consumption may increase the risk of cognitive dysfunction and dementia, but low to moderate alcohol intake may protect against cognitive decline and dementia and provide cardiovascular benefits.  Evidence suggesting that low to moderate alcohol consumption in the elderly protects against cognitive decline and dementia exists; however, because of varying methodology and a lack of standardized definitions, these findings should be interpreted with caution.  It is important to conduct more, well-designed studies to identify the alcohol drinking pattern that will optimally protect the elderly against cognitive decline and dementia.

Forum Comments

Alzheimer’s disease (AD) and other types of dementia are most common in the very elderly, and are associated with huge health costs.  With a rapidly ageing population throughout the world, factors that affect the risk of cognitive decline and dementia are of great importance.  At present, there are no proven agents to prevent cognitive decline or dementia, although a number of prospective epidemiologic studies have shown a lower risk of such conditions among light to moderate drinkers in comparison with non-drinkers.1-4  (Other studies have found that beneficial effects are seen only among certain sub-groups of subjects.5-6)  A recent meta-analysis by Peters et al7 of subjects over the age of 65 in longitudinal studies concluded that light-to-moderate alcohol consumption, in comparison with abstinence, was associated with approximately 35-45% lower risk of cognitive decline or dementia.7

This paper provides a summary of what is known about the mechanisms by which alcohol consumption, especially heavy drinking, can be neurotoxic,  and how light-to-moderate drinking may help protect against cognitive decline and dementia.  The authors state that their intent is to determine if there is an “optimal pattern of drinking” that may protect the elderly against such conditions.

Comments on the present paper:  While much of the present publication deals with neurotoxic effects of heavy drinking, a key feature of the paper relates to potential mechanisms by which light-to-moderate drinking may be neuroprotective.  The authors tabulate potential protective mechanisms; they then conclude that such mechanisms could explain a neuroprotective effect of moderate wine and alcohol intake.  In an excellent previous review paper, Collins et al8 suggested that many of the protective mechanisms of wine and alcohol against cardiovascular disease may well be protective against neurological disease as well.8 

Potential mechanisms of neuroprotection from light-to-moderate drinking:  Forum member Creina Stockley summarizes the potential mechanisms of neuroprotection: “The beneficial effects of alcohol on the risk of cardiovascular and cerebrovascular diseases have been partly attributed to changes in lipid and hemostatic or blood flow factors, possibly through reduction in cerebral atherosclerosis.  Wright et al,9 however, showed that the appearance of plaque in the carotid artery, which carries blood to the brain, was not associated with alcohol consumption or with alcohol-associated improvements in cognitive function.  This suggests that alcohol may impact cognition through a separate vascular or degenerative pathway than through cerebral atherosclerosis.  Among older persons without cerebrovascular disease, those who consume alcohol moderately have been shown to have fewer white-matter abnormalities and infarcts on magnetic resonance imaging than abstainers or heavy drinkers,10 and pronounced reductions in the risk of both vascular dementia and Alzheimer’s disease have been shown among persons consuming light-to-moderate amounts of alcohol.11

Dr. Stockley continues: “There is also evidence which suggests that a light to moderate amount of alcohol may stimulate the release of acetylcholine in the hippocampus leading to improved cognitive function.  Small amounts of alcohol have been shown to improve memory for events experienced before consumption, while the impairment of memory performance by chronic and heavy alcohol consumption parallels the reduction of acetylcholine neurotransmission.12  In addition, specific to memory, it has been shown that small amounts of alcohol increased the expression of the NR1 receptor on the surface of neurons in the hippocampus region of the brain that plays a role in memory; increasing the number of NR1 receptors improved memory in rats similar to the improvement seen with moderate alcohol consumption.” 

Forum reviewer Harvey Finkel points out other experimental data, in mice. that support a reduction in carotid atherosclerosis from moderate alcohol administration, but only if the animals were given alcohol on a regular basis.  The experiment demonstrated that daily moderate alcohol administration, the human equivalent of about 2 typical drinks per day, led to greatly reduced narrowing of the arteries.  On the other hand, binge drinking (the same total weekly amount of alcohol given on only two days each week) led to a marked increase in carotid atherosclerosis.13

Importance of Apolipoprotein E in the risk of Alzheimer’s Disease (AD):  One of the few genetic factors found to help predict the development of AD is Apolipoprotein E (ApoE).  Forum member David Vauzour provides the following summary of the association of ApoE with AD.  “As highlighted by the authors in this review, the apolipoprotein epsilon genotype (ApoE4), represents the only firmly established common genetic risk factor for dementia.  ApoE4 carriers are at 3-16 fold increased risk of AD with a 10-year earlier age of onset.  Furthermore, the ‘importance’ of ApoE4 as an AD risk factor is highlighted by the fact that more than 60% of AD patients are carriers of this allele, while it is present only in approximately 25% of the general Caucasian population.  

“The mechanisms by which ApoE genotype impacts on AD pathophysiology is not fully understood, but its relatively moderate effect on the plasma lipid profile is unlikely to be the sole explanation for the genotype-mediated increase in disease risk.  Recently, the immuno-modulatory and inflammation-modulatory properties of the apoE protein have been recognised and shown to be altered in an isoform dependent manner.”  Such findings may help to explain the significantly increased AD risk in ApoE4 carriers and may suggest potential interactions by which wine and other alcoholic beverages may affect risk.  Vauzour continues: “Although it has been reported that flavonoids are able to delay the initiation of and/or slow the progression of AD-like pathology, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation) or to disrupt amyloid β aggregation and to affect the amyloid precursor protein processing, this seems particularly true in ApoE4 non carriers.”  Specific interactions between alcohol and the ApoE-dementia association remain unclear. 

Other potential mechanisms of neuroprotection:  Forum reviewer Andrew Waterhouse is yet to be convinced that the key mechanisms are known.  “I would agree there is good data on mechanisms for prevention of ischemic stroke and related cardiovascular issues, but the other neurological diseases, i.e., cognitive decline, dementia, etc., do not have much solid mechanistic explanations behind them.  The epidemiology may be strong, but this paper does not describe all the potentially relevant mechanisms.  Antioxidants in wine might deserve a closer look for their potential role.”  Forum member Erik Skovenborg agrees and believes that the evidence favors the consumption of wine over other beverages: “In the field of cognition and dementia the protective effects of wine consumption, versus consumption of other beverages, has been more pronounced than for cardio-vascular disease and diabetes.  The reason might be the anti-inflammatory effects of red wine polyphenols.”

Combining data from epidemiology and basic science:  Forum member Fulvio Ursini provides an overview of how varying types of research must be combined to reach scientific “truth.”  He states: “This nice review paper elegantly brings to the focus the dual nature of medical research: epidemiology searching for associations aimed to become causality and biomedical research.  Getting a consensus is an incredibly hard task, crucial to drive the right conclusions and appropriate nutritional guidelines.  Epidemiology requires a statistical validation that is by far easier when relationships follow a linear regression.  This is why the J-shaped association we generally find with alcohol may lead to disappointment for some — unfortunately this is life.

“Basic science, by necessity, describes different mechanism for the biological effect of a given compound.  Some effects are referred to as ‘positive’ for health, some ‘negative’ – although these concepts descend from an epistemological analysis.  In basic science, the expected relationship between negative (or positive) effect and dose cannot be linear, descending for the sum of several independent dose-effect relationships.  All available information must be epistemologically processed and the evidence cannot be straight forward.  Nevertheless it is correct that the available biomedical evidence strongly supports the concept that moderate intake of ethanol is not simply less dangerous for cognitive function, but is positively protective instead.  This is the same conclusion reached by epidemiologic studies.”

References from Forum review:

1.  Ganguli M, Vander Bilt J, Saxton JA, Shen C, Dodge HH. Alcohol con­sumption and cognitive function in late life: a longitudinal community study. Neurology 2005;65:1210-1217.

2.  Stampfer MJ, Kang JH, Chen J, Cherry R, Grodstein F. Effects of mod­erate alcohol consumption on cognitive function in women. N Engl J Med 2005;352:245-253.

3.  Lang I, Wallace RB, Huppert FA, Melzer D. Moderate alcohol con­sumption in older adults is associated with better cognition and well-being than abstinence. Age Ageing 2007;36:256-261.

4.  Ngandu T, Helkala EL, Soininen H, Winblad B, Tuomilehto J, Nissin­en A, et al. Alcohol drinking and cognitive functions: findings from the Cardiovascular Risk Factors Aging and Dementia (CAIDE) Study. Dement Geriatr Cogn Disord 2007;23:140-149.

5.  Launer LJ, Feskens EJ, Kalmijn S, Kromhout D. Smoking, drinking, and thinking. The Zutphen Elderly Study. Am J Epidemiol 1996;143:219-227.

6.  McGuire LC, Ajani UA, Ford ES. Cognitive functioning in late life: the impact of moderate alcohol consumption. Ann Epidemiol 2007;17:93-99.

7.  Peters R, Peters J, Warner J, Beckett N, Bulpitt C. Alcohol, dementia and cognitive decline in the elderly: a systematic review. Age Ageing 2008;37:505-512.

8.  Collins MA, Neafsey EJ, Mukamal KJ, et al.  Alcohol in moderation, cardioprotection, and neuroprotection: Epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 2009;33:206–219.

9.  Wright CB, Elkind MS, Luo X, Paik MC, Sacco RL.  Reported alcohol consumption and cognitive decline: the Northern Manhattan Study.  Neuroepidemiology 2006;27:201-207.

10.  Mukamal KJ, Longstreth WT Jr, Mittleman MA, Crum RM, Siscovick DS.  Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults.  The Cardiovascular Health Study.  Stroke 2001;32:1939-1945. 

11.  Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WT Jr, Mittleman MA, Siscovick DS. Prospective study of alcohol consumption and risk of dementia in older adults. JAMA 2003;289:1405-1413.

12.  Fadda F, Rossetti ZL.  Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Prog Neurobiol 1998;56:385-431.

13.  Liu W, Redmond EM, Morrow D, Cullen J.  Differential effects of daily-moderate versus weekend-binge alcohol consumption on atherosclerotic plaque development in mice.  Atherosclerosis 2011;219:448-454.

Forum Summary

A well-done review paper on the association between alcohol consumption and cognition in the elderly provides an excellent summary of potential mechanisms by which alcohol may affect cognitive function and the risk of dementia, both adversely and favorably.  Current scientific data indicate that heavy drinking is associated with an increased risk of neurological disease and dysfunction, while regular light-to-moderate alcohol intake seems to be associated with a reduced risk of such dysfunction, including a lower risk of developing Alzheimer’s disease.

At present, the mechanisms by which the moderate intake of wine and other alcoholic beverages reduces the risk of cardiovascular diseases are much better defined than they are for cognition.  Forum members agree with the authors that further research is needed to evaluate a potential role that wine and other alcoholic beverages may play in reducing the risk of dementia.  Forum members also agree that, at present, the specific mechanisms of such putative protection are not well defined, and it would be premature to recommend light-to-moderate drinking for reducing the risk of dementia.  On the other hand, current epidemiologic and biomedical data suggest that most elderly subjects who are responsible and moderate drinkers would not benefit from being advised to stop their alcohol consumption. 

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Comments on the present paper were provided by the following members of the International Scientific Forum on Alcohol Research:

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

Creina Stockley, MSc, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA

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

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

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

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

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

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