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AlzRisk Risk Factor Discussion
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Risk Factor:
  (Ethanol, Drinking, Alcohol consumption, Alcohol intake, Alcoholic beverage)
Risk Factor Type: Behavior, Nutrition and supplements
Current Understanding:
The tables below present a modest number of reports whose results, taken collectively, suggest an association between moderate alcohol consumption and reduced risk of both clinical Alzheimer disease (AD) and total dementia. Overall, these data suggest that moderate alcohol consumption is a modifiable protective factor, while heavy alcohol consumption may promote dementia. Results from other lines of research corroborate the value of moderate alcohol consumption in relation to cognitive decline in older adults, as well as better cardiovascular health. This research also documents the neurotoxic effect and other negative health consequences of heavy use, particularly among older individuals. Thus, starting or increasing alcohol consumption in late life for prevention of Alzheimer’s disease is not recommended. Specific aspects of the relationship between alcohol and cognitive outcomes still remain unclear, including the optimal quantity, timing, and type of alcohol consumption to reduce the risk of AD and cognitive decline; whether the observed protective effect is directly causal or mediated through the effect on cardiovascular health; and the active biological agents and mechanism of action. For a review of the putative mechanisms by which alcohol consumption may influence AD risk and a more detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Literature Extraction: Search strategy  * New *
Last Search Completed: 28 April 2013 - Last content update released on 11 Nov 2013.

Risk Factor Overview

James BD, Weuve J, Jackson JW, Blacker D. "Alcohol Intake." The AlzRisk Database. Alzheimer Research Forum. Available at: http://www.alzrisk.org. Accessed [date of access]*.

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Introduction

The tables on the Risk Factor Overview present a modest number of reports whose results, taken collectively, suggest that light to moderate alcohol intake (defined variously, but approximately 1-6 drinks per week) compared with abstaining, is associated with a reduced risk of both dementia overall and a clinical diagnosis of Alzheimer disease (AD). For heavy alcohol intake (defined variously), on the other hand, there was a suggestion of an increased risk of AD (with limited power to detect an effect given the relatively small number of exposed individuals). The lack of agreed-upon categories of alcohol intake and its relevant dimensions makes it difficult to meta-analyze the data in the tables without making several untenable assumptions.

Potential Mechanism of Action

Two putative mechanisms are widely discussed to explain the reduced rate of AD dementia among moderate drinkers. The first is that moderate alcohol consumption may protect against cardiovascular disease (Collins, et al., 2009, Di Castelnuovo, et al., 2009), particularly cerebrovascular disease, which has been shown to contribute to clinical dementia and AD(Luchsinger, et al., 2004, Newman, et al., 2005, Schneider, et al., 2004). Ethanol appears to inhibit platelet aggregation (Fenn, Littleton, 1982), to improve serum lipid profile (Miller, et al., 1988), and to have anti-inflammatory properties (Sierksma, et al., 2002), all of which are thought to underlie protection against atherosclerosis and thrombosis systemically and in the central nervous system.

The second proposed mechanism is that many alcoholic drinks contain antioxidants, which may compensate for oxidative stress in the aging brain (Larrieu, et al., 2004). Red wine is particularly rich in the polyphenolic antioxidant resveratrol, so many studies of alcohol consumption and AD have focused on wine consumption. However, it should be pointed out that the amount of resveratrol in red wine is such that very heavy drinking would be required to achieve meaningful blood levels.

In contrast to these potential benefits of moderate alcohol consumption, there is a good deal of evidence that the high concentrations of alcohol characteristic of heavy use can have neurotoxic effects and even lead to loss of brain cells (Crews, et al., 2004, U.S. Department of Health and Human Services, 2000). An intriguing hypothesis has emerged recently that this effect may even underlie the benefits of moderate consumption in that low levels of exposure to alcohol stress brain cells enough to increase their “fitness” rather than causing the damage associated with greater exposure (Collins, Neafsey, Mukamal, Gray, Parks, Das, Korthuis, 2009).

Methodological Issues

Exposure

Assessment of alcohol consumption is complicated because there is extensive variation in the frequency and amount of consumption, as well as in the concentration or ethanol and other potentially active compounds in different alcoholic beverages. There are also substantial differences in the patterns of consumption over the short term (e.g., binge vs. regular drinking) and over the lifespan. The tables report on categories of self-reported alcohol consumption, sometimes by type of alcohol, with varying definitions of nondrinkers. Each assessment approach has inherent advantages and disadvantages in terms of the relevance of the exposure they capture in relation to AD risk.

Dose and timing. The studies reported in the tables focused on either frequency of consumption, amount consumed, or both. Even within these metrics, studies drew different divisions between levels. Some studies attempted to divide participants into “drinkers” and “non-drinkers,” but differed how they categorized people who drank infrequently and in small quantities. Moreover, few studies collected detailed data on participants’ long-term drinking histories in order to further classify non-drinking participants as never drinkers or former drinkers, a distinction that could be important for understanding the source of apparent risk among non-drinkers (discussed below). Studies that assessed a range of consumption varied in the thresholds they set for moderate and heavy drinking.

Type. The type of alcohol consumed (i.e., wine, beer, liquor) also varies. While studies typically accounted for the large differences in ethanol concentration across the major categories of alcoholic beverage, smaller differences within categories were not accounted for, and, particularly for liquor, such differences are not trivial. In addition, other ingredients such as the anti-oxidant resveratrol also vary within and across these types. Only some studies accounted for type of alcoholic beverage at all, and even these studies did not account for what may be critical ingredients present in some and not other beverages within the broad categories. Furthermore, it is common for individuals to regularly consume more than one type of alcohol, and no study examined a specific type while controlling for consumption of other types. Overall, the support for differences across the type of alcoholic beverage consumed is very limited. In the specific case of alcohol's impact on cardiovascular disease risk, one interpretation is that whatever constitutes the “beverage of moderation” within a given culture is most strongly linked to lower risk (Rimm, Stampfer, 2002).

Self-report. By necessity, the studies assessed alcohol consumption by self-report. There are few, if any, biomarkers that could act as indicators of regular alcohol consumption. Estimates of ethanol intake computed from self-reported drinking are subject to substantial measurement error, which could, in general, attenuate estimates of association with AD dementia. In particular, errors in reported intake could depend on true intake: given the social stigma of heavy alcohol use, underreporting is thought to be greater when consumption is higher; to the extent the moderate drinker category includes underreporting heavy drinkers whose risk is actually increased, this could bias findings toward no association. More unique to studies of AD, recall of intake could be especially problematic if persons in the beginning stages of cognitive impairment are more likely to misrepresent alcohol consumption, which could bias findings in either direction.

Design and Analysis

Confounding. Although most studies adjusted for standard confounders such as age, sex, race, and education, unmeasured or residual confounding is still likely, especially by socioeconomic status (SES), health status, or related health behaviors such as smoking, which have been reported to be associated with both alcohol consumption and risk for AD. Appropriate adjustment for confounders can be challenging, because alcohol consumption overall is associated with health risk behaviors such as smoking, but moderate alcohol consumption is more prevalent at higher SES, and is also linked to certain health-promoting behaviors such as social activity and healthy diet. Furthermore, most of the studies reported here controlled for potential cardiovascular risk factors including BMI, hypertension, cholesterol, and diabetes. However, these may not be confounders but may rather fall along the causal pathway between alcohol consumption and clinical diagnosis of AD, and thus adjusting for them may represent overadjustment.

Definition of the reference category. A potential source of bias for observational studies of alcohol consumption is the use of non-drinkers as the reference category. At least minimal alcohol use is common in many populations, so non-drinkers --particularly when defined stringently-- may represent a fairly selective group who differ from persons who drink alcohol on a number of characteristics that may be related to AD risk such as religious background (which may be associated with relevant genetic or cultural differences), smoking, dietary practices and personality type, and many of these are typically not accounted for in analytic models. Perhaps more concerning, if non-drinkers are defined based on consumption at study baseline rather than longstanding patterns, the category may include several groups of former drinkers with elevated risk of dementia: those who have stopped because of concerns about their memory, those who have stopped drinking due to poor health such as cardiovascular disease (i.e. “sick quitters”), and those who have stopped because of prior heavy use. Therefore, the observed association between moderate alcohol and lowered risk for dementia may be due to an elevated risk of dementia in non-drinkers, the reference category, rather than a decreased risk for moderate drinkers. However, a recent review showed that studies that excluded former drinkers from the reference group still found the same protective association (Neafsey, Collins, 2011).

Selection bias due to survival differences. Another source of bias is the elimination of heavy drinkers with a potentially elevated risk of AD dementia before the beginning of studies due to selective nonparticipation or selective mortality (Klatsky, et al., 1992). However, this seems unlikely to explain the J-shaped association of AD dementia risk with level of drinking. Another concern is selective mortality of drinkers over the course of follow-up before they have the chance to develop AD or another form of dementia.

Results from Other Lines of Research

Cohort studies examining total dementia (and ineligible for inclusion here because they did not include AD as a specific outcome) have also reported an association between moderate alcohol consumption and a reduced risk of overall dementia (Anttila, et al., 2004, Simons, et al., 2006) and a reduced risk for MCI as well (Anttila, Helkala, Viitanen, Kareholt, Fratiglioni, Winblad, Soininen, Tuomilehto, Nissinen, Kivipelto, 2004, DeCarli, et al., 2001), though findings have been mixed (Espeland, et al., 2005, Yip, et al., 2006). One study reported that moderate drinkers had lower rate of progression from MCI to dementia (Solfrizzi, et al., 2007).

Similarly, cohort studies of longitudinal change in cognition have reported that moderate alcohol consumption is related to less cognitive decline (Arntzen, et al., 2010, Espeland, Gu, Masaki, Langer, Coker, Stefanick, Ockene, Rapp, 2005, Galanis, et al., 2000, Ganguli, et al., 2005, Gross, et al., 2011, Stampfer, et al., 2005), though some have reported mixed results (Broe, et al., 1998, Stott, et al., 2008), or a null association (Lobo, et al., 2010). At least one study found an increase in cognitive decline associated with wine-drinking (Leibovici, et al., 1999).

From studies of clinical populations of alcohol-dependent individuals, heavy alcohol consumption is known to cause memory loss and impair cognition, even in alcoholics who currently abstain (Eckardt, Martin, 1986, Munro, et al., 2000). Alcohol also clearly causes impaired neuropsychological performance(Rourke, Grant, 2009), and presents additional risk in older individuals, who have slower metabolism and lower tolerance, and are more likely to take other medications that may interact with alcohol. A particular concern is the risk of falls from alcohol alone or in combination with other central nervous system depressants, and the potentially greater consequences of falls in this age group. In addition, alcohol carries a risk for abuse and dependence, and heavy use carries risk of multiple poor health outcomes including liver disease, osteopenia, and neuropathy (U.S. Department of Agriculture and U.S. Department of Health and Human Services, 2010, U.S. Department of Health and Human Services, 2000)

Discussion and Recommendations

Overall, the body of evidence suggests a protective role for moderate alcohol consumption in the development of dementia and cognitive impairment, but it is unclear whether such consumption is directly related to AD, to cerebrovascular disease, or to some other factor such as better health and health-related behaviors. On the other hand, heavy use appears to increase risk of dementia. In any case, heavy alcohol consumption and alcoholism have known neurotoxic effects that can be extremely detrimental to the aging brain and multiple other adverse health consequences. Given the lack of knowledge about the boundaries between beneficial and harmful alcohol consumption, it is not recommended that older adults increase their alcohol intake for the purpose of decreasing their AD risk. In fact, clinicians generally recommend that moderate drinkers scale back in late life due to slower metabolism and increased susceptibility to the sedative effects of alcohol (particularly in the setting of other central nervous system depressants). Overall, further research is needed into the relationship between moderate alcohol consumption and cognitive outcomes, including the optimal quantity, timing, and type of alcohol consumption to reduce the risk of AD dementia and cognitive decline; whether the observed protective effect is directly causal or mediated through the effect on cardiovascular health; and the active biological agents and mechanism of action.


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