BMJ  2004;329:539 (4 September), doi:10.1136/bmj.38181.418958.BE (published 10 August 2004)

Paper

Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study

¹ Aging Research Center, Division of Geriatric Epidemiology, Neurotec, Karolinska Institutet, Box 6401, 11382 Stockholm, Sweden, ² Department of Public Health and General Practice, University of Kuopio, Box 1627, 70211 Kuopio, Finland, ³ Division of Geriatric Medicine, Neurotec, Karolinska Institutet, Karolinska University Hospital, Huddinge, 14186 Stockholm, ⁴ Department of Neuroscience and Neurology, University of Kuopio, Kuopio, ⁵ Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland

Abstract

Objective To evaluate the relation between midlife alcohol consumption and mild cognitive impairment and dementia in old age, and the possible modification of this relation by apolipoprotein E.

Design Prospective, population based study.

Setting Populations of Kuopio and Joensuu, eastern Finland.

Participants Of 1464 men and women aged 65-79 years randomly selected from population based samples studied in 1972 or 1977, 1018 (70%) were re-examined in 1998 (after an average follow up of 23 years).

Main outcome measures Mild cognitive impairment and dementia in old age.

Results Participants who drank no alcohol at midlife and those who drank alcohol frequently were both twice as likely to have mild cognitive impairment in old age as those participants who drank alcohol infrequently. The risk of dementia related to alcohol drinking was modified by the presence of the apolipoprotein e4 allele. The carriers of apolipoprotein e4 had an increased risk of dementia with increasing alcohol consumption: compared with non-carriers who never drank, the odds ratio for carriers who never drank was 0.6, for infrequent drinkers it was 2.3, and for frequent drinkers was 3.6 (the overall interaction term "drinking frequency^*apolipoprotein e4" was significant (P = 0.04), as were the interactions "infrequent drinking^*apolipoprotein e4" (P = 0.02) and "frequent drinking^*apolipoprotein e4" (P = 0.03)). Non-carriers of apolipoprotein e4 had similar odds ratios for dementia irrespective of alcohol consumption.

Conclusion Alcohol drinking in middle age showed a U shaped relation with risk of mild cognitive impairment in old age. Risk of dementia increased with increasing alcohol consumption only in those individuals carrying the apolipoprotein e4 allele.

Introduction

Alcohol drinking has been proposed as a possible risk factor for cognitive impairment and dementia, though understanding the association has proved difficult. Some studies have found no association between alcohol drinking and cognitive impairment^1-3 or Alzheimer's disease,^{4 5} whereas others have found an association between heavy drinking and increased risk of dementia.^{6 7} Some have claimed there is a J or U shaped relation between alcohol drinking and cognitive impairment^8-10 or dementia^11-14; that is, light to moderate alcohol drinking might have a protective effect compared with total abstention and heavy drinking. The apolipoprotein e4 allele, which is the only genetic risk factor for dementia with an established risk for the general population, may modify the effects of alcohol on the risk of developing cognitive impairment^{15 16} or dementia.^{12 17} However, the observed pattern of the effect modification has been different across the studies.

The aim of this study was to evaluate the association between midlife alcohol drinking and the risk of mild cognitive impairment and dementia in old age. We also investigated whether the apolipoprotein e4 allele modifies this association.

Participants and methods

Participants
We selected our study participants from those in the cardiovascular risk factors, aging and dementia (CAIDE) study who were first enrolled in 1972 and 1977.¹⁸ A random sample of 1464 individuals aged 65-79 years in 1997 who were still alive and living in the study area were invited for re-examination, and 1018 (70%) were investigated in 1998. These 632 women (62%) and 386 men (38%) had a mean (SD) age of 48.3 (4.8) years at the time of their midlife examination and 71.7 (4.1) years at their follow up examination in 1998.

Surveys
In brief, the survey included a self administered questionnaire on health behaviour, health status, medical history, and socioeconomic factors. A venous blood specimen was taken to determine apolipoprotein E genotypes.

Alcohol consumption
The 1972 and 1977 questionnaire asked for details of the overall frequency of alcohol drinking. For the present study, we classified people as those who never drank alcohol, those who drank "infrequently" (less than once a month), and those who drank "frequently" (several times a month).

Cognitive assessments
Cognitive function was assessed in 1998 with a three step protocol for diagnosing dementia and mild cognitive impairment. Participants who scored 24 on the mini-mental state examination¹⁹ were selected for further examination.

The diagnostic criteria used for diagnosing mild cognitive impairment included (a) memory complaint by patient, family, or physician; (b) normal activities of daily living; (c) normal global cognitive function; (d) objective impairment of memory or one other area of cognitive function, as shown by scores > 1.5 standard deviations below the age appropriate mean; (e) clinical dementia rating score of 0.5; and (f) not demented.^{20 21}

The diagnosis of dementia was based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, with Alzheimer's disease being diagnosed according to standard criteria.²²

Altogether 61 (5.8%) participants met the criteria for mild cognitive impairment, and 48 (4.6%) met the criteria for dementia, of whom 37 (77%) had Alzheimer's disease. The total number of dementia cases increased to 88 (6.0% of the population) when we included information regarding the non-participants from their patient records at the local hospitals and primary healthcare centres.

Statistical analyses
We investigated the association between midlife alcohol and subsequent mild cognitive impairment and dementia by means of multiple logistic regression analyses. Since some studies, as well as our preliminary analyses, indicated that there was a J or U shaped relation between alcohol drinking and mild cognitive impairment and dementia, we used infrequent drinkers as our reference group.

All analyses were adjusted for age, sex, and education. We tested the putative interaction between alcohol drinking and carrier status for apolipoprotein e4 (e4 carrier/non-carrier).

Results

Characteristics of the participants according to their midlife alcohol drinking
About 30% of the participants never drank alcohol, 40% drank it infrequently, and 30% drank frequently (table 1). Among the frequent drinkers, about 68% drank alcohol once or twice a month, 24% once a week, about 8% twice a week, and 1% daily. Among the infrequent drinkers, more than 40% drank alcohol twice a year or less frequently, and about 60% reported drinking three to six times a year.

View this table: [in this window] [in a new window]   Table 1 Sociodemographic and clinical characteristics of 1018 participants from eastern Finland according to their midlife alcohol consumption. Values are means (standard deviations) unless stated otherwise

 

Alcohol consumption in middle age and cognitive impairment in old age
Participants who reported never drinking alcohol and those who reported drinking alcohol frequently were both more than twice as likely to have mild cognitive impairment in old age than those who drank infrequently, even after we controlled for age, sex, and years of education (table 2). The results remained essentially the same when we repeated the analyses with additional adjustment for factors related to alcohol drinking or increased risk of dementia, including follow up time, smoking, total serum cholesterol concentration, body mass index, systolic and diastolic blood pressure, and vascular diseases in old age. The risk of dementia did not significantly differ between alcohol drinking categories (table 2).

View this table: [in this window] [in a new window]   Table 2 Results of multiple logistic regression analyses showing influence of participants' midlife alcohol consumption on their cognitive status in old age. Values are odds ratios (95% confidence intervals)

 

Effect of apolipoprotein e4 allele
We introduced the interaction term "drinking frequency^*apolipoprotein e4" into the logistic regression model together with apolipoprotein e4, drinking frequency, and other covariates. This showed a significant interaction between apolipoprotein E and alcohol drinking frequency, with the overall interaction term being significant (P = 0.04). The figure shows the odds ratios derived from this model for each of the six possible combinations between apolipoprotein e4 and drinking frequency. Compared with the participants who never drank and did not carry the apolipoprotein e4 allele, e4 carriers who drank infrequently were 2.3 times more likely to develop dementia, and carriers who drank frequently were 3.6 times more likely. However, the risk of dementia for e4 carriers who never drank was not different from that for non-carriers who never drank. Among the non-carriers, there was no association between alcohol drinking and the risk of dementia.

View larger version (19K): [in this window] [in a new window]   Combined effect of midlife alcohol drinking and apolipoprotein e4 allele on risk of dementia in old age. Values are odds ratios. Non-carriers of apolipoprotein e4 who never drank were the reference group. P value for the overall interaction "drinking frequency*apolipoprotein e4" is 0.04, for "infrequent drinking*apolipoprotein e4" P=0.02, and for "frequent drinking*apolipoprotein e4" P=0.03

 

The effect modification by apolipoprotein e4 for the association between alcohol drinking and mild cognitive impairment in the interaction model did not reach significance (P = 0.54 for the overall interaction term).

We also analysed how apolipoprotein e4 modified the association between alcohol drinking and cognitive impairment (including both mild cognitive impairment and dementia) and found similar results as those seen for dementia alone (see bmj.com for details).

Alcohol consumption in old age and cognitive impairment
Alcohol consumption in old age was in agreement with midlife consumption ( = 0.36, P < 0.01). We found again that non-drinkers more often had mild cognitive impairment than did infrequent drinkers, even after we adjusted for age, education, and sex (data not shown). However, frequent alcohol drinking was no longer associated with mild cognitive impairment. Old age drinking was not associated with dementia. Further adjustments did not change these results. The apolipoprotein e4 allele did not significantly modify the association between old age drinking and mild cognitive impairment or dementia.

Discussion

This study showed that midlife alcohol drinking was related to the risk of old age mild cognitive impairment in a U shaped manner, with both non-drinkers and frequent drinkers having a higher risk than infrequent drinkers. In contrast, no U shaped relation was found for dementia. However, the apolipoprotein E genotype seemed to modify the relation, with risk of old age dementia increasing with increasing midlife alcohol consumption only among carriers of the apolipoprotein e4 allele.

Strengths and limitations of study
Our study design, a large population based prospective study with a long follow up time, increases the credibility of our findings. In studies with shorter follow up times and where alcohol consumption is assessed only in old age, subclinical dementia may affect consumption—but this kind of bias is unlikely in our study, where alcohol consumption was assessed at middle age.

The limitation of most studies of alcohol consumption is the reliability of the alcohol drinking data. However, errors in reporting of consumption are in general linearly related irrespective of how one tries to assess drinking,²³ and so ranking of individuals into different alcohol drinking categories, as we did, should be possible. It was obvious that some of our participants drank more alcohol than they reported, but this would bias our results only if the difference between actual and reported alcohol drinking was dependent on participants' cognitive function. This might be so in analyses of alcohol drinking in old age—people with impaired cognitive abilities might forget how much they have drunk—but at the time of our midlife assessment most of our subjects were probably cognitively intact.

We investigated the possibility of selection bias in terms of non-participation (see bmj.com). Non-participants were more likely to have dementia than the participants, but, since the non-participants did not differ significantly from the participants in their midlife alcohol consumption, their non-participation was not likely to have biased the associations between midlife alcohol drinking and mild cognitive impairment or dementia. There is also the possibility of selective survival related to apolipoprotein E polymorphism. Heavy acute loads of alcohol, which are known to increase vascular morbidity,²⁴ more probably occurred in the frequent drinkers of alcohol than in the other groups. If the presence of the apolipoprotein e4 allele was related to increased mortality in this group, then our results would underestimate the relation between alcohol drinking and dementia.

What is already known on this topic A J shaped or U shaped relation between alcohol consumption and cognitive impairment and dementia has been reported The apolipoprotein e4 allele may modify the effect of alcohol on cognitive impairment and dementia, but the few studies conducted produced conflicting results What this study adds This is the first population based study that prospectively evaluated the effects of midlife alcohol drinking on the development of mild cognitive impairment and dementia in old age, taking into account genetic susceptibility Midlife alcohol drinking had a U shaped association with mild cognitive impairment in old age, but no such association emerged in relation to dementia Apolipoprotein E seemed to modify the association between alcohol consumption and dementia; the risk of dementia increased with increasing frequency of alcohol drinking among carriers of the e4 allele

Conclusions
Our results suggest that frequent alcohol drinking in middle age is associated with cognitive impairment in later life. For frequent drinking to be associated with increased risk of dementia, however, the presence of the apolipoprotein e4 allele may be necessary. This observation that apolipoprotein e4 may modify the effect of alcohol is in agreement with the concept that cognitive status is the consequence of both genetic and environmental factors. However, the mechanism by which moderate alcohol drinking could preserve cognitive function remains to be clarified. Is it alcohol as such or some other social and lifestyle factors that co-associate with certain drinking habits? Until all such factors and their associations with cognitive functioning have been identified, we must be careful in how we interpret results relating to alcohol consumption. Our current data indicate that frequent alcohol drinking has harmful effects on the brain, and this may be more pronounced if there is genetic susceptibility. We therefore do not want to encourage people to drink more alcohol in the belief that they are protecting themselves against dementia.

---

This is the abridged version of an article that was posted on bmj.com on 10 August 2004: http://bmj.com/cgi/doi/10.1136/bmj.38181.48958.BE

We thank the colleagues in the CAIDE study group for their cooperation in data collection and management.

Contributors: See bmj.com

Funding: Supported by the Aging Program of the Academy of Finland, EVO-grants of Kuopio University Hospital (5772708, 5772720) and Academy of Finland grants 103334 and 206951, SADF (Insamligsstiftelsen för Alzheimeroch Demensforskning), and the Gamla Tjänarinnor Foundation.

Competing interests: None declared.

Ethical approval: The ethics committees of the University of Kuopio and the Kuopio University Hospital, Kuopio, Finland, approved the study protocol.

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(Accepted 6 July 2004)

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