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Alcohol Consumption as a Risk Factor for Dementia and Cognitive Decline: Meta-Analysis of Prospective Studies
CRITICAL REVIEW ARTICLE
Alcohol Consumption as a Risk Factor for Dementia and Cognitive Decline: Meta-Analysis of Prospective Studies Kaarin J. Anstey, Ph.D., Holly A. Mack, Ph.D., Nicolas Cherbuin, Ph.D.
The relationships between alcohol consumption and dementia and cognitive decline were investigated in a systematic review including meta-analyses of 15 prospective studies. Follow-ups ranged from 2 to 8 years. Meta-analyses were conducted on samples including 14,646 participants evaluated for Alzheimer disease (AD), 10,225 participants evaluated for vascular dementia (VaD), and 11,875 followed for any type of dementia (Any dementia). The pooled relative risks (RRs) of AD, VaD, and Any dementia for light to moderate drinkers compared with nondrinkers were 0.72 (95% CI ⫽ 0.61– 0.86), 0.75 (95% CI ⫽ 0.57– 0.98), and 0.74 (95% CI ⫽ 0.61– 0.91), respectively. When the more generally classified “drinkers,” were compared with “nondrinkers,” they had a reduced risk of AD (RR ⫽ 0.66, 95% CI ⫽ 0.47– 0.94) and Any dementia (RR ⫽ 0.53, 95% CI ⫽ 0.53– 0.82) but not cognitive decline. There were not enough data to examine VaD risk among “drinkers.” Those classified as heavy drinkers did not have an increased risk of Any dementia compared with nondrinkers, but this may reflect sampling bias. Our results suggest that alcohol drinkers in late life have reduced risk of dementia. It is unclear whether this reflects selection effects in cohort studies commencing in late life, a protective effect of alcohol consumption throughout adulthood, or a specific benefit of alcohol in late life. (Am J Geriatr Psychiatry 2009; 17:542–555) Key Words: Alzheimer disease, vascular dementia, mild cognitive impairment, epidemiology, systematic review, alcohol drinking
A
s alcohol drinking is a modifiable behavior, there is a public health imperative to ensure that the best information is available concerning its safe use. This is often made difficult by conflicting or complex messages about the protec-
tive or adverse effects of alcohol. Unlike smoking, which has no beneficial effects on health, low to moderate alcohol consumption seems to be beneficial for some health outcomes, resulting in “J”shaped or inverse U-shaped associations between
Received September 2, 2008; revised January 7, 2009; accepted January 30, 2009. From the Centre for Mental Health Research, Australian National University, Canberra (KJA, NC); and Prince of Wales Medical Research Institute, University of New South Wales, Randwick, NSW (HAM), Australia. Send correspondence to Professor Kaarin J. Anstey, Ageing Research Unit, Centre for Mental Health Research, Australian National University, Canberra ACT 0200, Australia. © 2009 American Association for Geriatric Psychiatry
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Anstey et al. alcohol and mortality,1 cognitive function and heart disease.2,3 There is also evidence of cognitive benefits of alcohol consumption from animal studies. For example, in a study where rats were fed a diet containing no, moderate, or high doses of alcohol, the animals on the moderate dose performed better on a visual memory task than the two other groups and showed no sign of impaired hippocampal neurogenesis or neurotoxicity found in the high alcohol group.4 Other animal studies have also shown memory facilitation effects of alcohol consumption.5–7 In addition, Wang et al.8 demonstrated in a mice model that low wine consumption attenuated A neuropathology typically associated with Alzheimer disease (AD). On the other hand, excessive alcohol use has been associated with brain damage in animals and humans.9 There are now many studies published that report associations between alcohol consumption and dementia and cognitive decline, with findings mostly showing either that alcohol drinkers have reduced risk or no difference in risk of dementia compared with nondrinkers.10 –12 However, there is a need to synthesize the available information and consider study characteristics and publication bias to interpret the overall findings from available literature. The present study aimed to synthesize available highquality information from prospective cohort studies to evaluate whether light, moderate or hazardous levels of alcohol consumption may increase or reduce risk of AD, vascular dementia (VaD), Any dementia, or cognitive decline in late life. A systematic review methodology developed in previous reviews of risk factors for dementia and cognitive decline was used to obtain estimates of the effect of alcohol on risk of dementia and cognitive decline.13,14 Importantly, this review excluded studies that did not screen for dementia or cognitive impairment at baseline.
METHODS Literature Search A literature search was conducted using the relevant databases PubMed (1950 to June 2007), PsycINFO (1872 to June 2007), and the Cochrane Library
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(1800 to June 2007), with searches being limited to studies in English and focused on humans. The reference lists of the retrieved articles were also hand searched for other applicable publications. The following combination of selected alcohol and cognition terms were used for the search, where * indicates a word truncation and # means wild card. The alcohol terms included ethanol, alcohol, alcohol*, drink*, drunk, drunk* (drunkenness), blood alcohol concentration/content, blood alcohol level, substance use/misuse/abuse/addiction, substance dependence/dependent, substance user(s), substance disorder(s), substance-related disorder(s), substance usage, substance abuser(s), substance addict(s), intoxicated, intoxication, abstinence, abstinent, abstainer(s), sober, sobriety, liquor, spirits, beer, ale, wine, brandy, gin, rum, tequila, vodka, whiskey/whisky, and champagne. The dementia and cognition terms included cognit*, cognitive, cognition, intell*, IQ, memory, Mini-Mental State Examination, Mini Mental Status Examination, dement* (dementia(s), demented, nondemented), VaD, Alzheimer*, senil*, presenil*, presenil*, mild cognitive impairment, mild cognitive impairment (MCI), neurocognit*, neurocognition, neurocognitive, neuropsychological assessment(s)/test(s)/testing/evaluation(s)/ exam(s)/examination(s)/measure(s)/ measurement(s), general mental ability, attention, executive function*, executive process*, executive process, executive control, psychomotor, perceptual speed, perceptual motor, reaction time, processing speed, speed of processing, crystallized intelligence#, crystallized ability#, fluid intelligence, and fluid ability. Inclusion and Exclusion Criteria Studies were required to have a minimum follow-up period of 1 year, and outcome measures had to include either dementia or cognitive decline. Studies on dementia needed to have screened for dementia at baseline or adjusted for cognitive function in the analyses. Studies evaluating cognitive change were required to have measured cognition at both baseline and follow-up periods and either implemented a dementia assessment at baseline, which excluded those participants with cognitive impairment or dementia, or adjusted for incident dementia and/or baseline cognition performance in analyses. To be included, all studies were also required to
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Alcohol, Dementia, and Cognitive Decline measure exposure to alcohol at baseline or during a follow-up period that preceded the final follow-up examination.15 Experimental and clinical studies (alcoholics compared with controls) were excluded. The selection criteria guidelines were parallel with the Cochrane Collaboration recommended search strategy.16,17 Retrieved articles were examined by at least two of the authors and rated against the selection criteria. Multiple Publications From a Single Study There were 14 cohort studies meeting criteria for which multiple publications were identified. To select individual publications for inclusion, precedence was given to studies (e.g., Zutphen Elderly Study), where alcohol was an independent predictor18 and not adjusted for in the analyses.19,20 Studies with a longer follow-up such as the Personnes Agées Quid21,22 or the Kame Project22 were included over those with a shorter observation period.23–26 If the publications from the same study (e.g., Duke Established Populations for Epidemiologic Studies of the Elderly) did not differ on follow-up period, cohort size or measures, then the more recent article22,27 was chosen over the earlier article.26,28 For the Kungsholmen Project, the article with the more detailed categorical measure for alcohol29 was chosen over the same alcohol measure that was dichotomized into yes/no groupings for alcohol consumption.30 No relevant multiple publications from a single study were identified that examined different alcohol measures or outcomes for dementia or cognition, or analyzed these assessments in different forms (categorical versus continuous). There were 22 studies meeting inclusion criteria that did not provide unique data.19,20,23–26,28,30 – 44 Outcomes Outcomes from the studies reviewed included AD, VaD, Any dementia, cognitive performance, MCI, or cognitive impairment as described previously.14 Several studies reported results by dementia subtype in addition to a general dementia outcome. Nine studies reported effects of alcohol for Alzheimer-type dementia10,11,29,45–50 and five reported on incidence of VaD.10,11,46,47,49 Eighteen studies assessed cognitive performance change, cognitive decline, MCI, or cognitive impairment.15,18,22,28,43,50 – 62
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Data Extraction From each of the selected journal articles, the following information was initially collated: study design (sample source, number of participants, observation period), sample characteristics (percentage female, average age, years of education), measurement of alcohol (amount and type of alcohol consumed, history of past consumption, frequency of consumption), measurement of dementia or cognition, unadjusted and adjusted estimates of association (odds ratio [OR], hazard ratio [HR], relative risk [RR], beta, and p values) with 95% confidence intervals and covariates. Data extraction was double checked by a second reviewer who was blinded to the title, authors, publication date, and journal name of the article. Data Compilation for Analysis Authors were contacted via E-mail for missing information. The longest follow-up period was chosen if an article reported data on multiple observations. For all studies, the number of participants analyzed for the association between alcohol and outcome was used as the sample size for this review. Preference was given to results adjusted for the most covariates. Type of Comparisons Articles meeting inclusion criteria reported various alcohol consumption categories ranging from broad measures of never versus ever consuming alcohol to “yes” versus “no” for past and/or current alcohol consumption.45,49 Most articles compared nondrinkers with various groups currently consuming alcohol (very light, light, mild, moderate, normal limits, exceeds normal limits, heavy, and excessive drinkers) or zero drinks versus number of drinks per week or per day. Frequency of consumption was converted to drinks or units per week. The classifications of light and moderate consumption described by authors were used without alteration. When possible, studies with similar comparison drinking frequency categories (light and mild drinkers) were combined. If grams of ethanol per unit/drink were reported conversions were performed to verify the accuracy of combining comparison groups.
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Anstey et al. Meta-analysis was conducted where there was more than one study compatible in terms of alcohol and outcome measures with groups formed by type of comparison, and further divided by type of outcome. There were enough data to conduct comparisons of light to moderate drinkers compared with nondrinkers, and heavy drinkers compared with nondrinkers for AD, VaD, and Any dementia outcomes. Analyses were also performed for the broad comparison of drinkers versus nondrinkers for AD, Any dementia, and cognitive decline. There were no compatible data to allow meta-analyses of the outcomes of cognitive impairment or cognitive performance change.
FIGURE 1.
Flowchart Describing the Process of Study Selection
Statistical Analysis For the current analyses, studies reporting OR, RR, or HR for dichotomous outcomes were considered the same effect size measure under the assumption that dementia is a rare event after previous similar studies.63,64 Meta-analyses were performed in RevMan (version 4.2). The fixed effects model with the generic inverse variance data type selection (option for log scale of OR, HR, and RR) was used in the calculation of pooled estimates unless heterogeneity was determined by 2 tests with a p value ⬍0.10; then the random effects method was used with the generic inverse variance data type selection.65
RESULTS Of the 38,611 abstracts identified in the database search, data were available for 25 reports from prospective cohort studies. Of these 15 reports included data suitable for inclusion in meta-analyses.10,11,21,29,46 – 49,52,53,62,66 – 68 Figure 1 shows the stages in identifying studies for inclusion in our review. The characteristics of the 15 studies included in the meta-analyses are shown in Table 1. Of the 15 studies, 14 screened for dementia at baseline, and one included cognition in analyses.52 A further 10 studies met selection criteria, but their data were not compatible with other studies and so they could not be included in meta-analyses. For meta-analysis, a total of 14,646 participants were included in the six studies on alcohol consump-
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tion and AD. Length of follow-up ranged from 2 to 7 years. A total of 10,225 participants were included in the five studies on alcohol and VaD. Length of follow-up ranged from 2 to 7 years. A total of 11,875 participants were included in the five studies on alcohol consumption and Any dementia with followups ranging from 2 to 8 years. Light to Moderate Drinkers Versus Nondrinkers Of the 15 studies suitable for meta-analysis, eight studies reported data on light to moderate drinkers.
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EVA; Nantes, Western France
WHIMS, Postmenopausal women aged 50–79 years
MoVIES, Largely rural, blue-collar community in Southwestern PA
Kungsholmen Project, Stockholm, Sweden, Community-based cohort 75⫹ years old PAQUID; Southwestern departments of Gironde and Dordogne, France; community residents aged 65 or older (seven strata or parishes)
Dufouil et al.52 (N ⫽ 1,094)
Espeland et al.62 (N ⫽ 4,372)
Ganguli et al.53 (N ⫽ 1,098)
Huang et al.29 (N ⫽ 378)
Larrieu et al.21 (N ⫽ 2,865)
Chongqing city, China; elderly people in six communities 60⫹ years old
Deng et al. (N ⫽ 2,632)
10
Study Name and Source
Fixed: 8
Varied: 3.7 (2.2)
Varied: 7.3 (2.7), Range 1.7–11.8
Varied: 4.2 (1.2)
Varied: 4 (NA)
Fixed: 2
Observation Period, Years (SDa)
Wine consumption, grouped by nondrinkers, mild drinkers, moderate drinkers; 1 glass ⫽ 125 mL
No drinking; minimal drinking (once a month or less); moderate drinking (more than once a month, averaging between daily and weekly) Categories by ethanol units: nondrinker light to moderate drinker and excessive drinkerd
Nondrinker (⬍1 unit per week), light-to-moderate drinker (1–21 units per week for men, or 1–14 units per week for women), excessive drinker (⬎21 units per week for men, or 0.14 units per week for women) Daily alcohol consumption was categorized as never, ⬍2 drinks, 2–5 drinks, or 5⫹ drinks Alcohol intake over past 3 months; if no current intake, but consumed in past asked if stopped due to health reasons
Alcohol Measure(s)
Characteristics of Studies Included in the Meta-Analyses
Study (No. Subjects)
TABLE 1.
Incident dementia
Incident dementia or AD (N ⫽ 85)
Cognitive decline
Probable dementia; mild cognitive impairment; cognitive decline
Cognitive decline
Incident dementia: All (N ⫽ 121); AD (N ⫽ 84); VaD (N ⫽ 17); other (N ⫽ 20)
Outcome
DSM-III-R, MMSE, subpopulation were those subjects with baseline MMSE score ⱖ24 (N ⫽ 293) DSM-III-R, NINCDSADRDA, Hachinski score
DSM-III-R, CDR, CERAD, MMSE,c Composite Cognitive Scores
3MSE, neurocognitive assessment, neuropsychiatric examination
MMSEb
MMSE DSM-III-R
Outcome Measure(s)
(Continued)
Range 65 to 85⫹, ⬃58%,e at least primary school level, validated by a diploma versus no diploma
84.2(5.3); Range 75–90⫹; 21.9% ⱖ90⫹, 81.8%, ⬇6.7 (3.1); 57% ⱕ8 years
70.9 (3.8), 100%, ⬍high school ⫽ 6.44%; high school/GED ⫽ 20.91%; ⬎high school ⬍4 year college ⫽ 39.26%; ⬎4 yearr college ⫽ 33.39% 74.6 (5.34); Range 66.8– 97.1, 63.3%, 61.8% HS graduate or higher education
65 (2.95) Range 59–71, 58.9%, 10.74 (3.46)
67.42 (7.42), 56.38%, 11.38 (0.09)
Demographics: Age (M, SD), Female, Education in Years (M, SD)
Alcohol, Dementia, and Cognitive Decline
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CHS: 4 US communities (Forsyth County, NC, Sacramento County, CA, Washington County, MD and Allegheny County, PA); 65⫹ residents from selected from medicare eligibility ISHA and Ibadan, Nigeria; Crosscultural Study: Indianapolis community-dwelling African Americans and Yoruba people, Ibadan, Nigeria
Mukamal et al.46 (cases, N ⫽ 151; controls, N ⫽ 123)
Ogunniyi et al.66 (ISHA: cases N ⫽ 89; controls ⫽ 381) (Yoruba: case N ⫽ 62; control ⫽ 461)
WHICAP; community dwelling 65⫹
CSHA, Canada; 65⫹ community residents
Luchsinger et al.11 (N ⫽ 970)
Lindsay et al. (N ⫽ 3,985)
45
Study Name and Source
Continued
Study (No. Subjects)
TABLE 1.
2 and 5-year follow-up 2
Varied: median 6.0 for controls, median 6.1 for cases
Varied: 4 .1 (1.5), recruited between 1991 and 1996 and followed annually
Varied: 5 (NA)
Observation Period, Years (SDa)
Regular alcohol consumption ⫽ ⬎10 drinks per week
Alcohol type categorized by nondrinkers (0 servings reported), light drinkers (1 serving a month to 6 servings a week), moderate drinkers (1–3 servings a day), and heavy drinkers (⬎3 servings a day) 1 unit ⫽ 12 g ethanol Weekly number of drinks; categories: none, ⬍1, 1–6, 7–13, 14⫹
Regular consumption of beer, wine, and spirits was defined as at least once a week
Alcohol Measure(s)
Incident dementia
Incident dementia
Incident dementia (N ⫽ 260), AD (N ⫽ 199), DAS (N ⫽61)
Incident dementia (N ⫽ 194 AD cases)
Outcome
CSI’D, DSM-III-R, NINCDS-ADRDA
Screening: 3MSE, IQCODE, clinical diagnoses: DSM-IV, NINCDS-ADRDA, NINDS-AIREN, SCADDTC, neurologic Examination, MMSE
DSM-IV, CDR
3MS, NINCDS-ADRDA
Outcome Measure(s)
ISHA Cases: 82.9 (7.1); Controls: 78.3 (7.0); Yoruba Cases: 82.2 (10.0); Controls: 77.3 (7.5); ISHA Cases: 69.7%; Controls: 68.8%; Yoruba Cases: 83.9%; Controls: 66.8%; ISHA Cases: 8.7 (3.3); Controls: 9.4 (3.2); Yoruba Cases: 0.1 (0.8); Controls: 0.6 (1.7) (Continued)
Case: 77.8 (5.5); control: 77.5 (5.2); Total sample: 77.65 (5.35), 58.45%, 14.6 (4.6)
73.3 ⫾ 6.0; AD ⫽ 81.0; No A/D ⫽ 72.9, 55.11%; AD ⫽ 67.5%; No AD ⫽ 57.5%, 11.0 ⫾ 3.7; AD ⫽ 9.9; No AD ⫽ 11.1 75.3 ⫾ 5.8, 67%, 9.1 (4.6)
Demographics: Age (M, SD), Female, Education in Years (M, SD)
Anstey et al.
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Dubbo Study, NSW Australia; 60⫹ community dwelling MRC-CFAS; populationbased Rural2 and urban3 sites in UK
Simons et al.67 (N ⫽ 2,805) Varied: 16 years, followed every 2 years 2 and 6-year follow-up, Using 6 year follow-up data only from wave 3 Fixed: 7
Varied: 2.4 (0.3)
Varied: 6 (NA)
Observation Period, Years (SDa)
Alcohol consumption (yes/no)
Alcohol intake: ever, never, unknown
Alcohol intake grouped by # drinks/week: None, ⬍1 drink/week, 1 drink/ week—1 drink/day, 1–4 drinks/day, 4⫹ drinks/ day. Also characterized by type of alcohol: beer, wine, liquor, or fortified wine Average weekly intake, estimate lifetime alcohol consumption measured in drinks. Also type of drinker: nondrinker, past heavy drinker, problem drinker Standard drinks per week: any vs. nil
Alcohol Measure(s)
Incident dementia (N ⫽ 103), VaD: N ⫽ 50; AD: N ⫽ 42; Mixed: N ⫽ 2; Other: N⫽9
Incident MCI and dementia (N ⫽ 285) Incident dementia: wave 2: N ⫽ 133; wave 3: N ⫽ 142
Incidence dementia (All N ⫽ 44; AD N ⫽ 33)
Incident dementia (N ⫽ 197) AD: 146/197; VaD: 29/ 197; other dementia: 22/197
Outcome
MMSE, HDS, HDS-R, DSM-III-R, NINCDSADRDA, NINDSAIREN
Geriatric Mental State (AGECAT), MMSE
SPMSQ, ICD-9-CM, ICD10-AM
MMSE, Korean Dementia Rating Scale, DSM-IV
MMSE, DSM-III-R, NINCDS-ADRDA, NINDS-AIREN, GMS organic level, CAMDEX
Outcome Measure(s)
73.6 (5.9); Men Range 65– 92; Women Range 65–98, 60%, 25.95% low educational level (completion of only 6 years of elementary school)
Range 65–90⫹, 63.12%, 8.58% ⬍9 years
69.2 (7.0), 56.04%, 10.1 (1.8)
71.7 (4.9), 56.1%, Median interquartile range 3 years (0–6)
67.38 (7.48), 59%, 35% (N ⫽ 1854) primary education only; dichotomised into primary education or less, and more than primary education.
Demographics: Age (M, SD), Female, Education in Years (M, SD)
b
SD ⫽ Standard deviation. MMSE used as an outcome measure for analysis but was part of a larger neuropsychological assessment. c Composite Cognitive Scores created from: Trailmaking Tests A and B, Word List Learning and Delayed Recall, Story Immediate Retell and Delayed Recall, Initial Letter and Category Fluency, 15-item Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) version of the Boston Naming Test, CERAD Constructional Praxis, Clock Drawing. d Categories by ethanol units: nondrinker (⬍1 unit per week); light to moderate drinker (1–21 units per week for men, or 1–14 units per week for women); excessive drinker (⬎21 units per week for men, or ⬎14 units per week for women). In the present study, 18 occasional drinkers (⬍1 unit per week) were included in the nondrinker category. e Values are for the cohort analyzed in a separate PAQUID study article by Helmer.24 f Reported N analyzed for Wave 3 data collection.
a
Yoshitaker et al.49 (N ⫽ 826)
Hisayama Study, Japan; Hisayama residents 65⫹ in 1985
10/66 Dementia in developing Countries Research Program, Republic of Korea; community residents
Shin et al.48 (N ⫽ 510)
Yip et al.68 (N ⫽ 1,489f)
Rotterdam Study, Netherlands; Population cohort based
Ruitenberg et al.47 (N⫽ 5,395)
Study Name and Source
Continued
Study (No. Subjects)
TABLE 1.
Alcohol, Dementia, and Cognitive Decline
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Anstey et al. Four of these had different criteria to classify men and women10,29,48,68 and four studies used the same criteria to classify men and women.11,21,46,47 Combining men and women, three studies defined light to moderate drinking as 1–21 units of alcohol per week,10,29,68 1–27 drinks per week,11 2–28 drinks per week,21 and 1–14 drinks per week.48 Two studies did not specify a range for light to moderate, and reported results for different drinking frequencies. In both instances, results from three categories were combined to create a pooled estimate of light to moderate drinking46,47 that was comparable with the other studies. In one case, this included those reporting 1–13 drinks per week46 and in the other case this yielded a group reporting 1–21 drinks per week.47 All studies adjusted for age and sex in their analyses. The pooled RR of AD, VaD, and Any Dementia, for light to moderate drinkers compared with nondrinkers are shown in Table 2. Light to moderate
TABLE 2.
drinkers had significantly reduced risks of AD (RR ⫽ 0.72, z ⫽ 3.69, p ⫽ 0.0002), VaD (RR ⫽ 0.75, z ⫽ 2.13, p ⫽ 0.03), and Any Dementia (RR ⫽ 0.74, z ⫽ 2.89, p ⫽ 0.004). The test for heterogeneity was significant for AD (2[5] ⫽ 11.43, p ⫽ 0.04). To evaluate sex differences, results from the three studies reporting results separately for men and women were pooled.10,46,47 Compared with male nondrinkers, male light to moderate drinkers had reduced risks of AD (RR ⫽ 0.58, CI ⫽ 0.45– 0.75, z ⫽ 4.25, p ⬍0.001), VaD (RR ⫽ 0.49, CI ⫽ 0.31– 0.79, z ⫽ 2.98, p ⫽ 0.003), and Any dementia (RR ⫽ 0.55, CI ⫽ 0.42– 0.74, z ⫽ 3.99, p ⬍0.001). Compared with female nondrinkers, female light to moderate drinkers had reduced risks of AD (RR ⫽ 0.83, CI ⫽ 0.81– 0.85, z ⫽ 15.30, p ⬍0.001), VaD (RR ⫽ 0.57, CI ⫽ 0.34 – 0.95, z ⫽ 2.16, p ⫽ 0.030), and Any dementia (RR ⫽ 0.73, CI ⫽ 0.61– 0.88, z ⫽ 3.30, p ⬍0.001).
Relative Risks of Dementia for Light to Moderate Drinkers Versus Nondrinkers
Outcome Alzheimer disease
Vascular dementia
Any dementia
Study 29a
Huang et al. Luchsinger et al.11b Mukamal et al.46c Ruitenberg et al.47d Larrieu et al.21e Deng et al.10f Pooled Luchsinger et al.11b Ruitenberg et al.47g Deng et al.10f Mukamal et al.46c Pooled Yip et al.68h Espeland et al.62i Huang et al.29a Deng et al.10f Mukamal et al.46j Ruitenberg et al.47d Larrieu et al.21e Pooled
Weight (%)
Relative Risk
95% Confidence Interval
6.68 14.40 15.81 17.78 18.39 26.94 100 18.62 18.97 29.15 33.26 100 6.91 9.05 10.51 11.00 18.09 21.72 22.72 100
0.70 0.97 0.54 0.85 0.79 0.63 0.72 0.93 0.46 0.84 0.79 0.75 1.60 1.14 0.60 0.52 0.59 0.72 0.80 0.74
0.39, 1.26 0.69, 1.36 0.40, 0.73 0.65, 1.12 0.61, 1.03 0.55, 0.72 0.61, 0.86 0.50, 1.72 0.25, 0.85 0.51, 1.38 0.50, 1.25 0.57, 0.98 0.81, 3.15 0.65, 2.00 0.36, 1.00 0.32, 0.85 0.44, 0.80 0.57, 0.91 0.65, 0.99 0.61, 0.91
a
Estimates were adjusted for age, sex, education, smoking status, institutionalization, and baseline MMSE score. Estimates were adjusted for age, sex, education, and apolipoprotein E (APOE) E4 allele presence. c Estimates were adjusted for age, sex, race, diabetes, APOE E4 allele, and history of stroke. d Estimates were adjusted for age, sex, education, body mass index (BMI), systolic blood pressure, diabetes, and smoking. e Estimates were adjusted for age, sex, and education. f Estimates were adjusted for age, sex, education, blood pressure, current smoking status, history of stroke and MMSE score. g Estimates were adjusted for age and sex. h Estimates were adjusted for age, sex, social class, and education. i Estimates were adjusted for age, number of years since menopause, education, ethnicity, family income, smoking status, BMI, hypertension status, prior CVD, diabetes, statin use, aspirin use, prior hormone therapy, and baseline 3MSE score. j Estimates were adjusted for age, sex, race, APOE E4 allele, educational attainment, income level, marital status, estrogen replacement therapy, current smoking, former smoking, diabetes, BMI, total cholesterol level, atrial fibrillation, history of congestive heart failure, history of stroke, history of transient ischemic attack, and Kcal expended in daily activities. b
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Alcohol, Dementia, and Cognitive Decline
TABLE 3.
Relative Risks of Dementia for Heavy/Excessive Drinkers Versus Nondrinkers
Outcome
Study
Alzheimer disease
Vascular dementia
Any dementia
10a
Deng et al. Ruitenberg et al.47b Shin et al.48c Mukamal et al.46d Pooled Ruitenberg et al.47e Mukamal et al.46d Deng et al.10a Pooled Deng et al.10a Ruitenberg et al.47b Mukamal et al.46f Shin et al.48c Pooled
Weight (%)
Relative Risk
95% Confidence Interval
11.11 15.10 35.23 38.56 100 18.63 34.32 47.05 100 11.05 18.22 32.27 38.46 100
1.35 1.17 0.71 0.95 0.92 1.53 0.93 1.72 1.36 1.45 1.00 1.22 0.84 1.04
0.35–5.21 0.37–3.73 0.33–1.53 0.46–1.96 0.59–1.45 0.31–7.56 0.29–3.02 0.63–4.70 0.68–2.71 0.43–4.89 0.39–2.58 0.60–2.49 0.44–1.61 0.69–1.56
a
Estimates were adjusted for age, sex, education, blood pressure, current smoking status, history of stroke and MMSE score. Estimates were adjusted for age, sex, body mass index (BMI), systolic blood pressure, diabetes, smoking, and education. c Estimates were adjusted for age, gender, education, and lifetime alcohol consumption. d Estimates were adjusted for age, sex, race, diabetes, APOE E4 allele, and history of stroke. e Estimates were adjusted for age and sex. f Estimates were adjusted for age, sex, race, APOE E4 allele, educational attainment, income level, marital status, estrogen replacement therapy, current smoking, former smoking, diabetes, BMI, total cholesterol level, atrial fibrillation, history of congestive heart failure, history of stroke, history of transient ischemic attack, and Kcal expended in daily activities. b
Heavy/Excessive Drinkers Versus Nondrinkers
Drinkers Versus Nondrinkers
The pooled RRs of AD, VaD, and Any dementia for heavy/excessive drinkers versus nondrinkers are shown in Table 3. No significant effects were found, and no test of heterogeneity was significant.
The pooled RRs of AD, Any Dementia, and cognitive decline for drinkers compared with nondrinkers are shown in Table 4. Drinkers had reduced risk of AD and Any dementia (RR ⫽ 0.66), but there was no
TABLE 4.
Relative Risks of Dementia and Cognitive Decline for Drinkers Versus Nondrinkers
Outcome Alzheimer disease
Any dementia
Cognitive decline
Study 49a
Yoshitake et al. Lindsay et al.45b Pooled Ogunniyi et al.66c,d Yip et al.68e Ogunniyi et al.66f,d Simons et al.67g Pooled Ganguli et al.53h Dufouil et al.52i Pooled
Weight (%)
Relative Risk
95% Confidence Interval
13.99 86.01 100 7.31 10.07 11.79 70.84 100 46.04 53.96 100
0.56 0.68 0.66 0.82 0.80 0.49 0.66 0.66 0.08 0.84 0.28
0.22–1.43 0.47–0.99 0.47–0.94 0.36–1.85 0.40–1.60 0.26–0.93 0.51–0.83 0.53–0.82 0.02–0.30 0.66–1.07 0.03–2.83
a
Estimates were adjusted for age. Estimates were adjusted for age, sex, and education. c Ogunniyi et al. (2006) Yoruba sample. d Unadjusted estimates. e Estimates were adjusted for age, sex, social class, and education. f Ogunniyi et al. (2006) Indianapolis Study of Health and Aging (ISHA) sample. g Estimates were adjusted for age, sex, marital status, education, prior history of stroke, and activities of daily living. h Estimates were adjusted for age, sex, educational level, smoking status, depressive symptoms, recruitment status, baseline cognitive scores, and incident dementia. i Estimates were adjusted for age, gender, education level, cognitive functions, hypertension, and depressive symptoms at study entry. b
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Anstey et al. significant result for cognitive decline. The test for heterogeneity was significant for cognitive decline (2[1] ⫽ 11.80, p ⫽ 0.00006) suggesting that the pooled results for only two studies may not be reliable. Results of Studies Meeting Criteria but Not Compatible for Meta-Analyses Of the 10 studies providing data that met search criteria, but were not compatible for meta-analysis, no effect of alcohol on cognitive outcomes was found in four studies.18,51,58,60 A protective effect of alcohol use on 1 of 10 cognitive measures was found in one study.50 In another study, drinkers showed less decline on one of three cognitive measures although this disappeared when ounces of alcohol were considered.54 One study found that male problem drinkers had an increased risk of memory problems over a 6-year follow-up period.56 A protective effect of light to moderate alcohol consumption against cognitive decline was reported in three studies.22,57,61 Adjustment for Covariates We also recorded whether adjustment for covariates increased or decrease the effect sizes reported. Unadjusted and adjusted results were available for eight studies.10,11,29,46,47,49,62,67 Of these, the effect sizes increased in the adjusted analyses in five studies10,11,46,49,62 and were unchanged in the remaining three studies. Comparison of Former Drinkers and Lifetime Abstainers Five articles recorded information on former drinkers compared with lifetime abstainers.46 – 48,53,62 Three studies found no differences between former drinkers and abstainers on either baseline cognitive scores,62 or overall results4748 involving cognitive outcomes. One study53 found that when former drinkers were excluded from the nondrinker group, the effect sizes of the study reduced. These authors concluded that much of the difference between nondrinkers and drinkers is explained by the group of former drinkers, many who may have stopped drinking due to health problems. Another study found that former drinkers had 20%– 60% higher odds of incident dementia than abstainers.46
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DISCUSSION The results from this meta-analysis indicated that light to moderate alcohol intake was associated with a 25%–28% reduction in risk of AD, VaD, and Any dementia compared with alcohol abstinence in older adults. Heavy drinking was not associated with increased risk of dementia in the present study. This may have been due to sampling effects such that very heavy drinkers may be less likely to participate in cohort studies, or to achieve follow-up. It may also reflect survival effects. Alcohol dependence is associated with higher rates of cancer, liver disease, neurological damage, and mental disorders9 all of which increase mortality risk. As the samples included in the study were relatively old, there may have been a low probability of individuals with alcohol dependence being selected into these samples. Heavy drinkers may have already developed cognitive impairment or dementia and hence been screened out of the analyses reported. Although the analyses comparing drinkers with nondrinkers were based on very broad categories, it showed again that alcohol consumption was associated with reduced risk of dementia. The strengths of this study are the strict selection criteria such as the exclusion of studies that did not screen for dementia at baseline, the inclusion of both dementia and cognitive decline as outcome variables, and the reduction of publication bias by including studies from article reference lists, as well as those studies that included alcohol as a covariate, not just the main predictor. The results were consistent across comparisons of light to moderate drinkers and the broad range analysis of alcohol consumption versus no alcohol consumption. The study of alcohol drinking as a risk factor for health outcomes is complicated by issues such as beverage type, standard measurements of quantity, and other individual characteristics or behaviors that may interact with alcohol consumption to affect cognitive performance.69 With the exception of one study, all publications included in this review adjusted for multiple confounders. Nearly all studies adjusted for smoking status, which has been shown to increase the risk of dementia14 and in people with alcohol use disorders to compound the effects of chronic alcohol consumption.70,71 Where studies re-
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Alcohol, Dementia, and Cognitive Decline ported results for adjusted and unadjusted analyses, the ORs increased after adjustment in most studies. Definitions of mild to moderate drinking varied across studies in terms of number of units or drinks, and the definition of a unit or drink. This reflects the problem of comparing alcohol consumption data generally. However, all studies excluded very heavy drinkers from these categories. The different criteria for moderate drinking means that there is a lack of specificity of the results in relation to the upper end of the moderate drinking category. If some studies did include harmful drinkers and heavy drinking is a risk factor for dementia, then this would weaken the observed effect. This would occur particularly with women, because the level of harmful alcohol consumption for women is lower than for men. A limitation of the review was the pooling of men and women in most analyses, which was required because most studies did not report results separately for men and women. However, all studies adjusted for gender and separate results for men and women were pooled from three studies. The fact that reduced risk of all dementia outcomes were found for both men and women light to moderate drinkers shows that the overall effects observed in analyses including both genders were not specific to men or women. It is notable that the reduced risks of dementia associated with light to moderate drinking in men were larger than those observed in women. This may have been due to the same number of drinks being used to classify men and women in two of the studies46,47 that were included in the subanalyses of men and women. A limitation of the review was that there were too few studies within consistent outcome criteria to enable analysis according to beverage type. Furthermore, there is a lack of published data on how ethnicity interacts with alcohol to effect brain development and dementia. Overall, our findings suggest that among older adults participating in cohort studies, light to moderate alcohol consumption is associated with reduced risk of dementia in older adults over 2– 8 years of follow-up. As no studies included follow-up of individuals from early or mid-adulthood, it is unknown how selection effects may have biased the results. For example, very heavy drinkers may have already had cognitive impairment or dementia and hence been screened out of these studies or analyses.
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Alternatively, participants with neurological conditions or dementia may have ceased drinking as a consequence of their disease. The low prevalence of heavy drinkers in population-based studies of older adults may have reduced the likelihood of this review identifying significant associations between harmful alcohol use and dementia or cognitive decline. Hence, the null result reported here must be taken as a preliminary finding, with further analyses on larger samples of hazardous drinkers required to fully assess this potential association. Research has shown that even young adult alcohol abstainers have lower cognitive test scores,72 so it is possible that the findings in late life reflect individual differences associated with drinking patterns across the entire lifespan. It is also possible that other health conditions, life style behaviors, and medications may explain the associations found between alcohol consumption and dementia and cognition because the studies reviewed did not adjust for the same covariates. Our results are for the most part consistent with another systematic review of the association between alcohol consumption and dementia.73 That review also found a protective effect of alcohol consumption for AD and dementia, but unlike our study, did not find a protective effect for VaD. The present review pooled data on the basis of level of alcohol consumption and conducted analyses separately for AD, VaD, Any dementia, and cognitive decline. The previous review pooled results on the basis of outcome but not the level of alcohol consumption. If the direction of effects of alcohol on dementia risk vary according to the level of consumption, then pooling across different levels of consumption may obfuscate findings. Compared with the previous review, our review included a wider list of search terms, and did not have a minimum date for inclusion of articles. Our review also excluded articles, where the sample had not been screened for dementia at baseline. This is particularly important because incipient dementia may affect alcohol drinking patterns and cognitive performance and is likely to be prevalent samples of older adults. The mechanisms underlying a putative protective effect of alcohol on cognition remain unclear. It is widely accepted that moderate alcohol consumption increases high-density cholesterol, which helps lower risk for cardiovascular events.74 –76 Alcohol in moderation also increases cerebral blood flow,77 de-
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Anstey et al. creases blood coagulation, increases antithrombotic activity (especially red wine), increases endothelial relaxation, and increases insulin sensitivity.75,78 Such effects are protective against atheroma, vascular occlusion, and cerebral hypoperfusion. The Northern Manhattan Study’s evaluation of inflammatory markers and Mini-Mental State Examination scores suggested that light to moderate alcohol consumption may modify inflammation as participants with a history of moderate alcohol consumption had lower IL-6 levels than abstainers nondrinkers or those who drank intermediate and heavy amounts.79 An antiinflammatory effect maybe one reason for the apparent protective effects moderate alcohol consumption has on cardiovascular disease, which may in turn reduce the risk of dementia.80,81 We conclude that light to moderate alcohol consumption in older adults is associated with reduced risk of dementia. Further research is required to clarify the mechanisms underlying the observed association between alcohol and brain function, to determine how this may be affected by cardiovascular disease. Importantly, further research is required to determine whether the results reported here will remain over longer follow-up intervals and how alcohol consumption (including binge drinking) in early
and midlife affects later dementia risk. Finally, the extent to which alcohol consumption interacts with other risk factors such as apolipoprotein E to moderate dementia risk needs to be evaluated before making recommendations on alcohol consumption to protect against dementia in the population. The clinical implications of this review are that low levels of alcohol may be beneficial for cognitive function in late life. However, these findings do not address broader potential adverse drinking outcomes associated with other clinical conditions or medication use. Hence, the overall safety of alcohol use in later life needs to be evaluated in relation to all of the available evidence regarding its associations with health and disease outcomes.
The authors thank Richard Burns, Haley Caldwell, and Jennifer Young. They also thank the authors who kindly provided data for the meta-analyses. This work was supported by Dementia Collaborative Research Centres, an Australian Government Initiative (to HAM), NHMRC Research Fellowship No. 366756 (to KJA), Alzheimer’s Australia Research and the Centre for Mental Health Research at the Australian National University (to NC).
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Alcohol Consumption as a Risk Factor for Dementia and Cognitive Decline: Meta-Analysis of Prospective Studies Kaarin J. Anstey, Ph.D., Holly A. Mack, Ph.D., Nicolas Cherbuin, Ph.D.
The relationships between alcohol consumption and dementia and cognitive decline were investigated in a systematic review including meta-analyses of 15 prospective studies. Follow-ups ranged from 2 to 8 years. Meta-analyses were conducted on samples including 14,646 participants evaluated for Alzheimer disease (AD), 10,225 participants evaluated for vascular dementia (VaD), and 11,875 followed for any type of dementia (Any dementia). The pooled relative risks (RRs) of AD, VaD, and Any dementia for light to moderate drinkers compared with nondrinkers were 0.72 (95% CI ⫽ 0.61– 0.86), 0.75 (95% CI ⫽ 0.57– 0.98), and 0.74 (95% CI ⫽ 0.61– 0.91), respectively. When the more generally classified “drinkers,” were compared with “nondrinkers,” they had a reduced risk of AD (RR ⫽ 0.66, 95% CI ⫽ 0.47– 0.94) and Any dementia (RR ⫽ 0.53, 95% CI ⫽ 0.53– 0.82) but not cognitive decline. There were not enough data to examine VaD risk among “drinkers.” Those classified as heavy drinkers did not have an increased risk of Any dementia compared with nondrinkers, but this may reflect sampling bias. Our results suggest that alcohol drinkers in late life have reduced risk of dementia. It is unclear whether this reflects selection effects in cohort studies commencing in late life, a protective effect of alcohol consumption throughout adulthood, or a specific benefit of alcohol in late life. (Am J Geriatr Psychiatry 2009; 17:542–555) Key Words: Alzheimer disease, vascular dementia, mild cognitive impairment, epidemiology, systematic review, alcohol drinking
A
s alcohol drinking is a modifiable behavior, there is a public health imperative to ensure that the best information is available concerning its safe use. This is often made difficult by conflicting or complex messages about the protec-
tive or adverse effects of alcohol. Unlike smoking, which has no beneficial effects on health, low to moderate alcohol consumption seems to be beneficial for some health outcomes, resulting in “J”shaped or inverse U-shaped associations between
Received September 2, 2008; revised January 7, 2009; accepted January 30, 2009. From the Centre for Mental Health Research, Australian National University, Canberra (KJA, NC); and Prince of Wales Medical Research Institute, University of New South Wales, Randwick, NSW (HAM), Australia. Send correspondence to Professor Kaarin J. Anstey, Ageing Research Unit, Centre for Mental Health Research, Australian National University, Canberra ACT 0200, Australia. © 2009 American Association for Geriatric Psychiatry
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Anstey et al. alcohol and mortality,1 cognitive function and heart disease.2,3 There is also evidence of cognitive benefits of alcohol consumption from animal studies. For example, in a study where rats were fed a diet containing no, moderate, or high doses of alcohol, the animals on the moderate dose performed better on a visual memory task than the two other groups and showed no sign of impaired hippocampal neurogenesis or neurotoxicity found in the high alcohol group.4 Other animal studies have also shown memory facilitation effects of alcohol consumption.5–7 In addition, Wang et al.8 demonstrated in a mice model that low wine consumption attenuated A neuropathology typically associated with Alzheimer disease (AD). On the other hand, excessive alcohol use has been associated with brain damage in animals and humans.9 There are now many studies published that report associations between alcohol consumption and dementia and cognitive decline, with findings mostly showing either that alcohol drinkers have reduced risk or no difference in risk of dementia compared with nondrinkers.10 –12 However, there is a need to synthesize the available information and consider study characteristics and publication bias to interpret the overall findings from available literature. The present study aimed to synthesize available highquality information from prospective cohort studies to evaluate whether light, moderate or hazardous levels of alcohol consumption may increase or reduce risk of AD, vascular dementia (VaD), Any dementia, or cognitive decline in late life. A systematic review methodology developed in previous reviews of risk factors for dementia and cognitive decline was used to obtain estimates of the effect of alcohol on risk of dementia and cognitive decline.13,14 Importantly, this review excluded studies that did not screen for dementia or cognitive impairment at baseline.
METHODS Literature Search A literature search was conducted using the relevant databases PubMed (1950 to June 2007), PsycINFO (1872 to June 2007), and the Cochrane Library
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(1800 to June 2007), with searches being limited to studies in English and focused on humans. The reference lists of the retrieved articles were also hand searched for other applicable publications. The following combination of selected alcohol and cognition terms were used for the search, where * indicates a word truncation and # means wild card. The alcohol terms included ethanol, alcohol, alcohol*, drink*, drunk, drunk* (drunkenness), blood alcohol concentration/content, blood alcohol level, substance use/misuse/abuse/addiction, substance dependence/dependent, substance user(s), substance disorder(s), substance-related disorder(s), substance usage, substance abuser(s), substance addict(s), intoxicated, intoxication, abstinence, abstinent, abstainer(s), sober, sobriety, liquor, spirits, beer, ale, wine, brandy, gin, rum, tequila, vodka, whiskey/whisky, and champagne. The dementia and cognition terms included cognit*, cognitive, cognition, intell*, IQ, memory, Mini-Mental State Examination, Mini Mental Status Examination, dement* (dementia(s), demented, nondemented), VaD, Alzheimer*, senil*, presenil*, presenil*, mild cognitive impairment, mild cognitive impairment (MCI), neurocognit*, neurocognition, neurocognitive, neuropsychological assessment(s)/test(s)/testing/evaluation(s)/ exam(s)/examination(s)/measure(s)/ measurement(s), general mental ability, attention, executive function*, executive process*, executive process, executive control, psychomotor, perceptual speed, perceptual motor, reaction time, processing speed, speed of processing, crystallized intelligence#, crystallized ability#, fluid intelligence, and fluid ability. Inclusion and Exclusion Criteria Studies were required to have a minimum follow-up period of 1 year, and outcome measures had to include either dementia or cognitive decline. Studies on dementia needed to have screened for dementia at baseline or adjusted for cognitive function in the analyses. Studies evaluating cognitive change were required to have measured cognition at both baseline and follow-up periods and either implemented a dementia assessment at baseline, which excluded those participants with cognitive impairment or dementia, or adjusted for incident dementia and/or baseline cognition performance in analyses. To be included, all studies were also required to
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Alcohol, Dementia, and Cognitive Decline measure exposure to alcohol at baseline or during a follow-up period that preceded the final follow-up examination.15 Experimental and clinical studies (alcoholics compared with controls) were excluded. The selection criteria guidelines were parallel with the Cochrane Collaboration recommended search strategy.16,17 Retrieved articles were examined by at least two of the authors and rated against the selection criteria. Multiple Publications From a Single Study There were 14 cohort studies meeting criteria for which multiple publications were identified. To select individual publications for inclusion, precedence was given to studies (e.g., Zutphen Elderly Study), where alcohol was an independent predictor18 and not adjusted for in the analyses.19,20 Studies with a longer follow-up such as the Personnes Agées Quid21,22 or the Kame Project22 were included over those with a shorter observation period.23–26 If the publications from the same study (e.g., Duke Established Populations for Epidemiologic Studies of the Elderly) did not differ on follow-up period, cohort size or measures, then the more recent article22,27 was chosen over the earlier article.26,28 For the Kungsholmen Project, the article with the more detailed categorical measure for alcohol29 was chosen over the same alcohol measure that was dichotomized into yes/no groupings for alcohol consumption.30 No relevant multiple publications from a single study were identified that examined different alcohol measures or outcomes for dementia or cognition, or analyzed these assessments in different forms (categorical versus continuous). There were 22 studies meeting inclusion criteria that did not provide unique data.19,20,23–26,28,30 – 44 Outcomes Outcomes from the studies reviewed included AD, VaD, Any dementia, cognitive performance, MCI, or cognitive impairment as described previously.14 Several studies reported results by dementia subtype in addition to a general dementia outcome. Nine studies reported effects of alcohol for Alzheimer-type dementia10,11,29,45–50 and five reported on incidence of VaD.10,11,46,47,49 Eighteen studies assessed cognitive performance change, cognitive decline, MCI, or cognitive impairment.15,18,22,28,43,50 – 62
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Data Extraction From each of the selected journal articles, the following information was initially collated: study design (sample source, number of participants, observation period), sample characteristics (percentage female, average age, years of education), measurement of alcohol (amount and type of alcohol consumed, history of past consumption, frequency of consumption), measurement of dementia or cognition, unadjusted and adjusted estimates of association (odds ratio [OR], hazard ratio [HR], relative risk [RR], beta, and p values) with 95% confidence intervals and covariates. Data extraction was double checked by a second reviewer who was blinded to the title, authors, publication date, and journal name of the article. Data Compilation for Analysis Authors were contacted via E-mail for missing information. The longest follow-up period was chosen if an article reported data on multiple observations. For all studies, the number of participants analyzed for the association between alcohol and outcome was used as the sample size for this review. Preference was given to results adjusted for the most covariates. Type of Comparisons Articles meeting inclusion criteria reported various alcohol consumption categories ranging from broad measures of never versus ever consuming alcohol to “yes” versus “no” for past and/or current alcohol consumption.45,49 Most articles compared nondrinkers with various groups currently consuming alcohol (very light, light, mild, moderate, normal limits, exceeds normal limits, heavy, and excessive drinkers) or zero drinks versus number of drinks per week or per day. Frequency of consumption was converted to drinks or units per week. The classifications of light and moderate consumption described by authors were used without alteration. When possible, studies with similar comparison drinking frequency categories (light and mild drinkers) were combined. If grams of ethanol per unit/drink were reported conversions were performed to verify the accuracy of combining comparison groups.
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Anstey et al. Meta-analysis was conducted where there was more than one study compatible in terms of alcohol and outcome measures with groups formed by type of comparison, and further divided by type of outcome. There were enough data to conduct comparisons of light to moderate drinkers compared with nondrinkers, and heavy drinkers compared with nondrinkers for AD, VaD, and Any dementia outcomes. Analyses were also performed for the broad comparison of drinkers versus nondrinkers for AD, Any dementia, and cognitive decline. There were no compatible data to allow meta-analyses of the outcomes of cognitive impairment or cognitive performance change.
FIGURE 1.
Flowchart Describing the Process of Study Selection
Statistical Analysis For the current analyses, studies reporting OR, RR, or HR for dichotomous outcomes were considered the same effect size measure under the assumption that dementia is a rare event after previous similar studies.63,64 Meta-analyses were performed in RevMan (version 4.2). The fixed effects model with the generic inverse variance data type selection (option for log scale of OR, HR, and RR) was used in the calculation of pooled estimates unless heterogeneity was determined by 2 tests with a p value ⬍0.10; then the random effects method was used with the generic inverse variance data type selection.65
RESULTS Of the 38,611 abstracts identified in the database search, data were available for 25 reports from prospective cohort studies. Of these 15 reports included data suitable for inclusion in meta-analyses.10,11,21,29,46 – 49,52,53,62,66 – 68 Figure 1 shows the stages in identifying studies for inclusion in our review. The characteristics of the 15 studies included in the meta-analyses are shown in Table 1. Of the 15 studies, 14 screened for dementia at baseline, and one included cognition in analyses.52 A further 10 studies met selection criteria, but their data were not compatible with other studies and so they could not be included in meta-analyses. For meta-analysis, a total of 14,646 participants were included in the six studies on alcohol consump-
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tion and AD. Length of follow-up ranged from 2 to 7 years. A total of 10,225 participants were included in the five studies on alcohol and VaD. Length of follow-up ranged from 2 to 7 years. A total of 11,875 participants were included in the five studies on alcohol consumption and Any dementia with followups ranging from 2 to 8 years. Light to Moderate Drinkers Versus Nondrinkers Of the 15 studies suitable for meta-analysis, eight studies reported data on light to moderate drinkers.
545
546
EVA; Nantes, Western France
WHIMS, Postmenopausal women aged 50–79 years
MoVIES, Largely rural, blue-collar community in Southwestern PA
Kungsholmen Project, Stockholm, Sweden, Community-based cohort 75⫹ years old PAQUID; Southwestern departments of Gironde and Dordogne, France; community residents aged 65 or older (seven strata or parishes)
Dufouil et al.52 (N ⫽ 1,094)
Espeland et al.62 (N ⫽ 4,372)
Ganguli et al.53 (N ⫽ 1,098)
Huang et al.29 (N ⫽ 378)
Larrieu et al.21 (N ⫽ 2,865)
Chongqing city, China; elderly people in six communities 60⫹ years old
Deng et al. (N ⫽ 2,632)
10
Study Name and Source
Fixed: 8
Varied: 3.7 (2.2)
Varied: 7.3 (2.7), Range 1.7–11.8
Varied: 4.2 (1.2)
Varied: 4 (NA)
Fixed: 2
Observation Period, Years (SDa)
Wine consumption, grouped by nondrinkers, mild drinkers, moderate drinkers; 1 glass ⫽ 125 mL
No drinking; minimal drinking (once a month or less); moderate drinking (more than once a month, averaging between daily and weekly) Categories by ethanol units: nondrinker light to moderate drinker and excessive drinkerd
Nondrinker (⬍1 unit per week), light-to-moderate drinker (1–21 units per week for men, or 1–14 units per week for women), excessive drinker (⬎21 units per week for men, or 0.14 units per week for women) Daily alcohol consumption was categorized as never, ⬍2 drinks, 2–5 drinks, or 5⫹ drinks Alcohol intake over past 3 months; if no current intake, but consumed in past asked if stopped due to health reasons
Alcohol Measure(s)
Characteristics of Studies Included in the Meta-Analyses
Study (No. Subjects)
TABLE 1.
Incident dementia
Incident dementia or AD (N ⫽ 85)
Cognitive decline
Probable dementia; mild cognitive impairment; cognitive decline
Cognitive decline
Incident dementia: All (N ⫽ 121); AD (N ⫽ 84); VaD (N ⫽ 17); other (N ⫽ 20)
Outcome
DSM-III-R, MMSE, subpopulation were those subjects with baseline MMSE score ⱖ24 (N ⫽ 293) DSM-III-R, NINCDSADRDA, Hachinski score
DSM-III-R, CDR, CERAD, MMSE,c Composite Cognitive Scores
3MSE, neurocognitive assessment, neuropsychiatric examination
MMSEb
MMSE DSM-III-R
Outcome Measure(s)
(Continued)
Range 65 to 85⫹, ⬃58%,e at least primary school level, validated by a diploma versus no diploma
84.2(5.3); Range 75–90⫹; 21.9% ⱖ90⫹, 81.8%, ⬇6.7 (3.1); 57% ⱕ8 years
70.9 (3.8), 100%, ⬍high school ⫽ 6.44%; high school/GED ⫽ 20.91%; ⬎high school ⬍4 year college ⫽ 39.26%; ⬎4 yearr college ⫽ 33.39% 74.6 (5.34); Range 66.8– 97.1, 63.3%, 61.8% HS graduate or higher education
65 (2.95) Range 59–71, 58.9%, 10.74 (3.46)
67.42 (7.42), 56.38%, 11.38 (0.09)
Demographics: Age (M, SD), Female, Education in Years (M, SD)
Alcohol, Dementia, and Cognitive Decline
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CHS: 4 US communities (Forsyth County, NC, Sacramento County, CA, Washington County, MD and Allegheny County, PA); 65⫹ residents from selected from medicare eligibility ISHA and Ibadan, Nigeria; Crosscultural Study: Indianapolis community-dwelling African Americans and Yoruba people, Ibadan, Nigeria
Mukamal et al.46 (cases, N ⫽ 151; controls, N ⫽ 123)
Ogunniyi et al.66 (ISHA: cases N ⫽ 89; controls ⫽ 381) (Yoruba: case N ⫽ 62; control ⫽ 461)
WHICAP; community dwelling 65⫹
CSHA, Canada; 65⫹ community residents
Luchsinger et al.11 (N ⫽ 970)
Lindsay et al. (N ⫽ 3,985)
45
Study Name and Source
Continued
Study (No. Subjects)
TABLE 1.
2 and 5-year follow-up 2
Varied: median 6.0 for controls, median 6.1 for cases
Varied: 4 .1 (1.5), recruited between 1991 and 1996 and followed annually
Varied: 5 (NA)
Observation Period, Years (SDa)
Regular alcohol consumption ⫽ ⬎10 drinks per week
Alcohol type categorized by nondrinkers (0 servings reported), light drinkers (1 serving a month to 6 servings a week), moderate drinkers (1–3 servings a day), and heavy drinkers (⬎3 servings a day) 1 unit ⫽ 12 g ethanol Weekly number of drinks; categories: none, ⬍1, 1–6, 7–13, 14⫹
Regular consumption of beer, wine, and spirits was defined as at least once a week
Alcohol Measure(s)
Incident dementia
Incident dementia
Incident dementia (N ⫽ 260), AD (N ⫽ 199), DAS (N ⫽61)
Incident dementia (N ⫽ 194 AD cases)
Outcome
CSI’D, DSM-III-R, NINCDS-ADRDA
Screening: 3MSE, IQCODE, clinical diagnoses: DSM-IV, NINCDS-ADRDA, NINDS-AIREN, SCADDTC, neurologic Examination, MMSE
DSM-IV, CDR
3MS, NINCDS-ADRDA
Outcome Measure(s)
ISHA Cases: 82.9 (7.1); Controls: 78.3 (7.0); Yoruba Cases: 82.2 (10.0); Controls: 77.3 (7.5); ISHA Cases: 69.7%; Controls: 68.8%; Yoruba Cases: 83.9%; Controls: 66.8%; ISHA Cases: 8.7 (3.3); Controls: 9.4 (3.2); Yoruba Cases: 0.1 (0.8); Controls: 0.6 (1.7) (Continued)
Case: 77.8 (5.5); control: 77.5 (5.2); Total sample: 77.65 (5.35), 58.45%, 14.6 (4.6)
73.3 ⫾ 6.0; AD ⫽ 81.0; No A/D ⫽ 72.9, 55.11%; AD ⫽ 67.5%; No AD ⫽ 57.5%, 11.0 ⫾ 3.7; AD ⫽ 9.9; No AD ⫽ 11.1 75.3 ⫾ 5.8, 67%, 9.1 (4.6)
Demographics: Age (M, SD), Female, Education in Years (M, SD)
Anstey et al.
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548
Dubbo Study, NSW Australia; 60⫹ community dwelling MRC-CFAS; populationbased Rural2 and urban3 sites in UK
Simons et al.67 (N ⫽ 2,805) Varied: 16 years, followed every 2 years 2 and 6-year follow-up, Using 6 year follow-up data only from wave 3 Fixed: 7
Varied: 2.4 (0.3)
Varied: 6 (NA)
Observation Period, Years (SDa)
Alcohol consumption (yes/no)
Alcohol intake: ever, never, unknown
Alcohol intake grouped by # drinks/week: None, ⬍1 drink/week, 1 drink/ week—1 drink/day, 1–4 drinks/day, 4⫹ drinks/ day. Also characterized by type of alcohol: beer, wine, liquor, or fortified wine Average weekly intake, estimate lifetime alcohol consumption measured in drinks. Also type of drinker: nondrinker, past heavy drinker, problem drinker Standard drinks per week: any vs. nil
Alcohol Measure(s)
Incident dementia (N ⫽ 103), VaD: N ⫽ 50; AD: N ⫽ 42; Mixed: N ⫽ 2; Other: N⫽9
Incident MCI and dementia (N ⫽ 285) Incident dementia: wave 2: N ⫽ 133; wave 3: N ⫽ 142
Incidence dementia (All N ⫽ 44; AD N ⫽ 33)
Incident dementia (N ⫽ 197) AD: 146/197; VaD: 29/ 197; other dementia: 22/197
Outcome
MMSE, HDS, HDS-R, DSM-III-R, NINCDSADRDA, NINDSAIREN
Geriatric Mental State (AGECAT), MMSE
SPMSQ, ICD-9-CM, ICD10-AM
MMSE, Korean Dementia Rating Scale, DSM-IV
MMSE, DSM-III-R, NINCDS-ADRDA, NINDS-AIREN, GMS organic level, CAMDEX
Outcome Measure(s)
73.6 (5.9); Men Range 65– 92; Women Range 65–98, 60%, 25.95% low educational level (completion of only 6 years of elementary school)
Range 65–90⫹, 63.12%, 8.58% ⬍9 years
69.2 (7.0), 56.04%, 10.1 (1.8)
71.7 (4.9), 56.1%, Median interquartile range 3 years (0–6)
67.38 (7.48), 59%, 35% (N ⫽ 1854) primary education only; dichotomised into primary education or less, and more than primary education.
Demographics: Age (M, SD), Female, Education in Years (M, SD)
b
SD ⫽ Standard deviation. MMSE used as an outcome measure for analysis but was part of a larger neuropsychological assessment. c Composite Cognitive Scores created from: Trailmaking Tests A and B, Word List Learning and Delayed Recall, Story Immediate Retell and Delayed Recall, Initial Letter and Category Fluency, 15-item Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) version of the Boston Naming Test, CERAD Constructional Praxis, Clock Drawing. d Categories by ethanol units: nondrinker (⬍1 unit per week); light to moderate drinker (1–21 units per week for men, or 1–14 units per week for women); excessive drinker (⬎21 units per week for men, or ⬎14 units per week for women). In the present study, 18 occasional drinkers (⬍1 unit per week) were included in the nondrinker category. e Values are for the cohort analyzed in a separate PAQUID study article by Helmer.24 f Reported N analyzed for Wave 3 data collection.
a
Yoshitaker et al.49 (N ⫽ 826)
Hisayama Study, Japan; Hisayama residents 65⫹ in 1985
10/66 Dementia in developing Countries Research Program, Republic of Korea; community residents
Shin et al.48 (N ⫽ 510)
Yip et al.68 (N ⫽ 1,489f)
Rotterdam Study, Netherlands; Population cohort based
Ruitenberg et al.47 (N⫽ 5,395)
Study Name and Source
Continued
Study (No. Subjects)
TABLE 1.
Alcohol, Dementia, and Cognitive Decline
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Anstey et al. Four of these had different criteria to classify men and women10,29,48,68 and four studies used the same criteria to classify men and women.11,21,46,47 Combining men and women, three studies defined light to moderate drinking as 1–21 units of alcohol per week,10,29,68 1–27 drinks per week,11 2–28 drinks per week,21 and 1–14 drinks per week.48 Two studies did not specify a range for light to moderate, and reported results for different drinking frequencies. In both instances, results from three categories were combined to create a pooled estimate of light to moderate drinking46,47 that was comparable with the other studies. In one case, this included those reporting 1–13 drinks per week46 and in the other case this yielded a group reporting 1–21 drinks per week.47 All studies adjusted for age and sex in their analyses. The pooled RR of AD, VaD, and Any Dementia, for light to moderate drinkers compared with nondrinkers are shown in Table 2. Light to moderate
TABLE 2.
drinkers had significantly reduced risks of AD (RR ⫽ 0.72, z ⫽ 3.69, p ⫽ 0.0002), VaD (RR ⫽ 0.75, z ⫽ 2.13, p ⫽ 0.03), and Any Dementia (RR ⫽ 0.74, z ⫽ 2.89, p ⫽ 0.004). The test for heterogeneity was significant for AD (2[5] ⫽ 11.43, p ⫽ 0.04). To evaluate sex differences, results from the three studies reporting results separately for men and women were pooled.10,46,47 Compared with male nondrinkers, male light to moderate drinkers had reduced risks of AD (RR ⫽ 0.58, CI ⫽ 0.45– 0.75, z ⫽ 4.25, p ⬍0.001), VaD (RR ⫽ 0.49, CI ⫽ 0.31– 0.79, z ⫽ 2.98, p ⫽ 0.003), and Any dementia (RR ⫽ 0.55, CI ⫽ 0.42– 0.74, z ⫽ 3.99, p ⬍0.001). Compared with female nondrinkers, female light to moderate drinkers had reduced risks of AD (RR ⫽ 0.83, CI ⫽ 0.81– 0.85, z ⫽ 15.30, p ⬍0.001), VaD (RR ⫽ 0.57, CI ⫽ 0.34 – 0.95, z ⫽ 2.16, p ⫽ 0.030), and Any dementia (RR ⫽ 0.73, CI ⫽ 0.61– 0.88, z ⫽ 3.30, p ⬍0.001).
Relative Risks of Dementia for Light to Moderate Drinkers Versus Nondrinkers
Outcome Alzheimer disease
Vascular dementia
Any dementia
Study 29a
Huang et al. Luchsinger et al.11b Mukamal et al.46c Ruitenberg et al.47d Larrieu et al.21e Deng et al.10f Pooled Luchsinger et al.11b Ruitenberg et al.47g Deng et al.10f Mukamal et al.46c Pooled Yip et al.68h Espeland et al.62i Huang et al.29a Deng et al.10f Mukamal et al.46j Ruitenberg et al.47d Larrieu et al.21e Pooled
Weight (%)
Relative Risk
95% Confidence Interval
6.68 14.40 15.81 17.78 18.39 26.94 100 18.62 18.97 29.15 33.26 100 6.91 9.05 10.51 11.00 18.09 21.72 22.72 100
0.70 0.97 0.54 0.85 0.79 0.63 0.72 0.93 0.46 0.84 0.79 0.75 1.60 1.14 0.60 0.52 0.59 0.72 0.80 0.74
0.39, 1.26 0.69, 1.36 0.40, 0.73 0.65, 1.12 0.61, 1.03 0.55, 0.72 0.61, 0.86 0.50, 1.72 0.25, 0.85 0.51, 1.38 0.50, 1.25 0.57, 0.98 0.81, 3.15 0.65, 2.00 0.36, 1.00 0.32, 0.85 0.44, 0.80 0.57, 0.91 0.65, 0.99 0.61, 0.91
a
Estimates were adjusted for age, sex, education, smoking status, institutionalization, and baseline MMSE score. Estimates were adjusted for age, sex, education, and apolipoprotein E (APOE) E4 allele presence. c Estimates were adjusted for age, sex, race, diabetes, APOE E4 allele, and history of stroke. d Estimates were adjusted for age, sex, education, body mass index (BMI), systolic blood pressure, diabetes, and smoking. e Estimates were adjusted for age, sex, and education. f Estimates were adjusted for age, sex, education, blood pressure, current smoking status, history of stroke and MMSE score. g Estimates were adjusted for age and sex. h Estimates were adjusted for age, sex, social class, and education. i Estimates were adjusted for age, number of years since menopause, education, ethnicity, family income, smoking status, BMI, hypertension status, prior CVD, diabetes, statin use, aspirin use, prior hormone therapy, and baseline 3MSE score. j Estimates were adjusted for age, sex, race, APOE E4 allele, educational attainment, income level, marital status, estrogen replacement therapy, current smoking, former smoking, diabetes, BMI, total cholesterol level, atrial fibrillation, history of congestive heart failure, history of stroke, history of transient ischemic attack, and Kcal expended in daily activities. b
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Alcohol, Dementia, and Cognitive Decline
TABLE 3.
Relative Risks of Dementia for Heavy/Excessive Drinkers Versus Nondrinkers
Outcome
Study
Alzheimer disease
Vascular dementia
Any dementia
10a
Deng et al. Ruitenberg et al.47b Shin et al.48c Mukamal et al.46d Pooled Ruitenberg et al.47e Mukamal et al.46d Deng et al.10a Pooled Deng et al.10a Ruitenberg et al.47b Mukamal et al.46f Shin et al.48c Pooled
Weight (%)
Relative Risk
95% Confidence Interval
11.11 15.10 35.23 38.56 100 18.63 34.32 47.05 100 11.05 18.22 32.27 38.46 100
1.35 1.17 0.71 0.95 0.92 1.53 0.93 1.72 1.36 1.45 1.00 1.22 0.84 1.04
0.35–5.21 0.37–3.73 0.33–1.53 0.46–1.96 0.59–1.45 0.31–7.56 0.29–3.02 0.63–4.70 0.68–2.71 0.43–4.89 0.39–2.58 0.60–2.49 0.44–1.61 0.69–1.56
a
Estimates were adjusted for age, sex, education, blood pressure, current smoking status, history of stroke and MMSE score. Estimates were adjusted for age, sex, body mass index (BMI), systolic blood pressure, diabetes, smoking, and education. c Estimates were adjusted for age, gender, education, and lifetime alcohol consumption. d Estimates were adjusted for age, sex, race, diabetes, APOE E4 allele, and history of stroke. e Estimates were adjusted for age and sex. f Estimates were adjusted for age, sex, race, APOE E4 allele, educational attainment, income level, marital status, estrogen replacement therapy, current smoking, former smoking, diabetes, BMI, total cholesterol level, atrial fibrillation, history of congestive heart failure, history of stroke, history of transient ischemic attack, and Kcal expended in daily activities. b
Heavy/Excessive Drinkers Versus Nondrinkers
Drinkers Versus Nondrinkers
The pooled RRs of AD, VaD, and Any dementia for heavy/excessive drinkers versus nondrinkers are shown in Table 3. No significant effects were found, and no test of heterogeneity was significant.
The pooled RRs of AD, Any Dementia, and cognitive decline for drinkers compared with nondrinkers are shown in Table 4. Drinkers had reduced risk of AD and Any dementia (RR ⫽ 0.66), but there was no
TABLE 4.
Relative Risks of Dementia and Cognitive Decline for Drinkers Versus Nondrinkers
Outcome Alzheimer disease
Any dementia
Cognitive decline
Study 49a
Yoshitake et al. Lindsay et al.45b Pooled Ogunniyi et al.66c,d Yip et al.68e Ogunniyi et al.66f,d Simons et al.67g Pooled Ganguli et al.53h Dufouil et al.52i Pooled
Weight (%)
Relative Risk
95% Confidence Interval
13.99 86.01 100 7.31 10.07 11.79 70.84 100 46.04 53.96 100
0.56 0.68 0.66 0.82 0.80 0.49 0.66 0.66 0.08 0.84 0.28
0.22–1.43 0.47–0.99 0.47–0.94 0.36–1.85 0.40–1.60 0.26–0.93 0.51–0.83 0.53–0.82 0.02–0.30 0.66–1.07 0.03–2.83
a
Estimates were adjusted for age. Estimates were adjusted for age, sex, and education. c Ogunniyi et al. (2006) Yoruba sample. d Unadjusted estimates. e Estimates were adjusted for age, sex, social class, and education. f Ogunniyi et al. (2006) Indianapolis Study of Health and Aging (ISHA) sample. g Estimates were adjusted for age, sex, marital status, education, prior history of stroke, and activities of daily living. h Estimates were adjusted for age, sex, educational level, smoking status, depressive symptoms, recruitment status, baseline cognitive scores, and incident dementia. i Estimates were adjusted for age, gender, education level, cognitive functions, hypertension, and depressive symptoms at study entry. b
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Anstey et al. significant result for cognitive decline. The test for heterogeneity was significant for cognitive decline (2[1] ⫽ 11.80, p ⫽ 0.00006) suggesting that the pooled results for only two studies may not be reliable. Results of Studies Meeting Criteria but Not Compatible for Meta-Analyses Of the 10 studies providing data that met search criteria, but were not compatible for meta-analysis, no effect of alcohol on cognitive outcomes was found in four studies.18,51,58,60 A protective effect of alcohol use on 1 of 10 cognitive measures was found in one study.50 In another study, drinkers showed less decline on one of three cognitive measures although this disappeared when ounces of alcohol were considered.54 One study found that male problem drinkers had an increased risk of memory problems over a 6-year follow-up period.56 A protective effect of light to moderate alcohol consumption against cognitive decline was reported in three studies.22,57,61 Adjustment for Covariates We also recorded whether adjustment for covariates increased or decrease the effect sizes reported. Unadjusted and adjusted results were available for eight studies.10,11,29,46,47,49,62,67 Of these, the effect sizes increased in the adjusted analyses in five studies10,11,46,49,62 and were unchanged in the remaining three studies. Comparison of Former Drinkers and Lifetime Abstainers Five articles recorded information on former drinkers compared with lifetime abstainers.46 – 48,53,62 Three studies found no differences between former drinkers and abstainers on either baseline cognitive scores,62 or overall results4748 involving cognitive outcomes. One study53 found that when former drinkers were excluded from the nondrinker group, the effect sizes of the study reduced. These authors concluded that much of the difference between nondrinkers and drinkers is explained by the group of former drinkers, many who may have stopped drinking due to health problems. Another study found that former drinkers had 20%– 60% higher odds of incident dementia than abstainers.46
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DISCUSSION The results from this meta-analysis indicated that light to moderate alcohol intake was associated with a 25%–28% reduction in risk of AD, VaD, and Any dementia compared with alcohol abstinence in older adults. Heavy drinking was not associated with increased risk of dementia in the present study. This may have been due to sampling effects such that very heavy drinkers may be less likely to participate in cohort studies, or to achieve follow-up. It may also reflect survival effects. Alcohol dependence is associated with higher rates of cancer, liver disease, neurological damage, and mental disorders9 all of which increase mortality risk. As the samples included in the study were relatively old, there may have been a low probability of individuals with alcohol dependence being selected into these samples. Heavy drinkers may have already developed cognitive impairment or dementia and hence been screened out of the analyses reported. Although the analyses comparing drinkers with nondrinkers were based on very broad categories, it showed again that alcohol consumption was associated with reduced risk of dementia. The strengths of this study are the strict selection criteria such as the exclusion of studies that did not screen for dementia at baseline, the inclusion of both dementia and cognitive decline as outcome variables, and the reduction of publication bias by including studies from article reference lists, as well as those studies that included alcohol as a covariate, not just the main predictor. The results were consistent across comparisons of light to moderate drinkers and the broad range analysis of alcohol consumption versus no alcohol consumption. The study of alcohol drinking as a risk factor for health outcomes is complicated by issues such as beverage type, standard measurements of quantity, and other individual characteristics or behaviors that may interact with alcohol consumption to affect cognitive performance.69 With the exception of one study, all publications included in this review adjusted for multiple confounders. Nearly all studies adjusted for smoking status, which has been shown to increase the risk of dementia14 and in people with alcohol use disorders to compound the effects of chronic alcohol consumption.70,71 Where studies re-
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Alcohol, Dementia, and Cognitive Decline ported results for adjusted and unadjusted analyses, the ORs increased after adjustment in most studies. Definitions of mild to moderate drinking varied across studies in terms of number of units or drinks, and the definition of a unit or drink. This reflects the problem of comparing alcohol consumption data generally. However, all studies excluded very heavy drinkers from these categories. The different criteria for moderate drinking means that there is a lack of specificity of the results in relation to the upper end of the moderate drinking category. If some studies did include harmful drinkers and heavy drinking is a risk factor for dementia, then this would weaken the observed effect. This would occur particularly with women, because the level of harmful alcohol consumption for women is lower than for men. A limitation of the review was the pooling of men and women in most analyses, which was required because most studies did not report results separately for men and women. However, all studies adjusted for gender and separate results for men and women were pooled from three studies. The fact that reduced risk of all dementia outcomes were found for both men and women light to moderate drinkers shows that the overall effects observed in analyses including both genders were not specific to men or women. It is notable that the reduced risks of dementia associated with light to moderate drinking in men were larger than those observed in women. This may have been due to the same number of drinks being used to classify men and women in two of the studies46,47 that were included in the subanalyses of men and women. A limitation of the review was that there were too few studies within consistent outcome criteria to enable analysis according to beverage type. Furthermore, there is a lack of published data on how ethnicity interacts with alcohol to effect brain development and dementia. Overall, our findings suggest that among older adults participating in cohort studies, light to moderate alcohol consumption is associated with reduced risk of dementia in older adults over 2– 8 years of follow-up. As no studies included follow-up of individuals from early or mid-adulthood, it is unknown how selection effects may have biased the results. For example, very heavy drinkers may have already had cognitive impairment or dementia and hence been screened out of these studies or analyses.
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Alternatively, participants with neurological conditions or dementia may have ceased drinking as a consequence of their disease. The low prevalence of heavy drinkers in population-based studies of older adults may have reduced the likelihood of this review identifying significant associations between harmful alcohol use and dementia or cognitive decline. Hence, the null result reported here must be taken as a preliminary finding, with further analyses on larger samples of hazardous drinkers required to fully assess this potential association. Research has shown that even young adult alcohol abstainers have lower cognitive test scores,72 so it is possible that the findings in late life reflect individual differences associated with drinking patterns across the entire lifespan. It is also possible that other health conditions, life style behaviors, and medications may explain the associations found between alcohol consumption and dementia and cognition because the studies reviewed did not adjust for the same covariates. Our results are for the most part consistent with another systematic review of the association between alcohol consumption and dementia.73 That review also found a protective effect of alcohol consumption for AD and dementia, but unlike our study, did not find a protective effect for VaD. The present review pooled data on the basis of level of alcohol consumption and conducted analyses separately for AD, VaD, Any dementia, and cognitive decline. The previous review pooled results on the basis of outcome but not the level of alcohol consumption. If the direction of effects of alcohol on dementia risk vary according to the level of consumption, then pooling across different levels of consumption may obfuscate findings. Compared with the previous review, our review included a wider list of search terms, and did not have a minimum date for inclusion of articles. Our review also excluded articles, where the sample had not been screened for dementia at baseline. This is particularly important because incipient dementia may affect alcohol drinking patterns and cognitive performance and is likely to be prevalent samples of older adults. The mechanisms underlying a putative protective effect of alcohol on cognition remain unclear. It is widely accepted that moderate alcohol consumption increases high-density cholesterol, which helps lower risk for cardiovascular events.74 –76 Alcohol in moderation also increases cerebral blood flow,77 de-
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Anstey et al. creases blood coagulation, increases antithrombotic activity (especially red wine), increases endothelial relaxation, and increases insulin sensitivity.75,78 Such effects are protective against atheroma, vascular occlusion, and cerebral hypoperfusion. The Northern Manhattan Study’s evaluation of inflammatory markers and Mini-Mental State Examination scores suggested that light to moderate alcohol consumption may modify inflammation as participants with a history of moderate alcohol consumption had lower IL-6 levels than abstainers nondrinkers or those who drank intermediate and heavy amounts.79 An antiinflammatory effect maybe one reason for the apparent protective effects moderate alcohol consumption has on cardiovascular disease, which may in turn reduce the risk of dementia.80,81 We conclude that light to moderate alcohol consumption in older adults is associated with reduced risk of dementia. Further research is required to clarify the mechanisms underlying the observed association between alcohol and brain function, to determine how this may be affected by cardiovascular disease. Importantly, further research is required to determine whether the results reported here will remain over longer follow-up intervals and how alcohol consumption (including binge drinking) in early
and midlife affects later dementia risk. Finally, the extent to which alcohol consumption interacts with other risk factors such as apolipoprotein E to moderate dementia risk needs to be evaluated before making recommendations on alcohol consumption to protect against dementia in the population. The clinical implications of this review are that low levels of alcohol may be beneficial for cognitive function in late life. However, these findings do not address broader potential adverse drinking outcomes associated with other clinical conditions or medication use. Hence, the overall safety of alcohol use in later life needs to be evaluated in relation to all of the available evidence regarding its associations with health and disease outcomes.
The authors thank Richard Burns, Haley Caldwell, and Jennifer Young. They also thank the authors who kindly provided data for the meta-analyses. This work was supported by Dementia Collaborative Research Centres, an Australian Government Initiative (to HAM), NHMRC Research Fellowship No. 366756 (to KJA), Alzheimer’s Australia Research and the Centre for Mental Health Research at the Australian National University (to NC).
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