Introduction: Much debate exists about the role of light to moderate alcohol intake and subsequent cognitive function. The apolipoprotein E genotype may modify the relationship. Methods: Using data from the Honolulu-Asia Aging Study, a longitudinal population-based cohort (n = 2,416), Cox proportional hazards regression analyses were performed to measure midlife alcohol intake (average age = 52 years) and later life cognitive function (average age = 87 years) and to explore the role of apolipoprotein E genotype. Results: No protective effect of light drinking (>1 drink/month– 1 drink/day) or moderate drinking (>1–2 drinks/day) was observed in the cohort in adjusted models (HR = 1.013, CI:0.88–1.16; HR = 1.104, CI:0.91–1.34, respectively). Heavy drinking (>2–4 drinks/day) and very heavy drinking (>4 drinks/day) increased the risk for incident moderate cognitive impairment (HR = 1.355, CI:1.09–1.68; HR = 1.462, CI:1.04–2.05, respectively). When examining the relationship by apolipoprotein E ε4 carrier status, a similar dose-response pattern was observed in both groups with higher hazard ratios for those carrying at least one copy of the apolipoprotein E ℇ4 allele. As alcohol level increased, the age at incident moderate cognitive impairment decreased, especially among those with at least one apolipoprotein E ℇ4 allele. Discussion: We did not observe a significant protective effect for light to moderate drinking in midlife and subsequent cognitive impairment in this cohort. Heavy drinking increased the risk for moderate cognitive impairment and decreased the age at incidence, as did carrying at least one allele of the apolipoprotein E ℇ4 gene.
Little consensus exists as to whether there is a level of alcohol consumption that is beneficial or protective for cognitive function. Results from studies examining alcohol consumption and later life cognitive function have been varied and unpredictable, with meta-analyses and reviews showing differing results [[
An additional issue is the role of the apolipoprotein E (APOE) genotype. APOE plays a role in the transport and redistribution of lipids. Of the three common isoforms of this glycoprotein (ℇ2, ℇ3, ℇ4), ℇ4 has been associated with a higher risk of dementia and cognitive decline [[
Using data from the Honolulu-Asia Aging Study (HAAS), a population-based, longitudinal cohort of Japanese-American men, we examined relationships between midlife alcohol consumption and risk of cognitive impairment in later life. A previous study in this cohort found a positive association for moderate alcohol intake and poorer cognitive performance 18 years later [[
Study participants came from HAAS, which evolved from the Honolulu Heart Program (HHP), both of which were reviewed and approved by the Institutional Review Board of Kuakini Medical Center, Honolulu, Hawaii. Beginning in 1965, a large, representative HHP cohort (n = 8,006) of Japanese men born from 1900–1919 and living on the island of Oahu, Hawaii, were followed and examined at three points over time between 1965 and 1975. Starting in 1991, approximately 80% of the surviving cohort (n = 3,734) participated in additional follow-up assessments designed to study cognitive function and diseases of aging, which formed the HAAS cohort [[
For this study, data from HHP exam 1 (1965–1968) and exam 3 (1971–1975) were used for midlife measures, including alcohol consumption. Data from HAAS exams 4-12 (1991-2012) were used for cognitive measures. Respondents were excluded if already had cognitive impairment at baseline (n = 587), if they were missing data for apolipoprotein E ε4 status (n = 74), alcohol intake (n = 159), or if they had data only for the first HAAS exam (exam 4; n = 508) as they added no time to the survival analysis. The remaining sample comprises 2,416 respondents with an average age at HHP exam 1 of 51.7 years (SD = 4.0), an average age at HAAS exam 4 of 77.1 years (SD = 3.9), and an average age at final cognitive assessment of 86.8 (SD = 5.5). The average length of time between baseline and death was 37.6 years (SD = 5.0).
The Cognitive Abilities Screening Instrument (CASI) is a comprehensive screening instrument specifically designed for the cross-cultural assessment of cognitive impairment and dementia [[
At both HHP exams 1 and 3 respondents were asked about their quantity and frequency of consumption of beer, wine, liquor, and sake. Ounces of ethanol per month were calculated based on typical alcohol contents at the time in the following manner: grams of ethanol per month = [(number of bottles/cans of beer per month) * (12 oz per beer) * (0.037 oz ethanol/oz of beer)] + [(number of glasses of wine per month) * (4 oz per glass) * (0.1 oz ethanol/oz of wine)] + [(number of liquor drinks per month) * (1.5 oz per drink) * (0.38 oz ethanol/oz liquor)] + [(number of sake drinks per month) * (6 oz per drink) * (0.16 oz ethanol/oz sake)]. All forms of alcohol were combined to produce a robust sample size. To convert ounces per month to drinks, we used 0.6 oz of ethanol to equal one drink, aligning with the definition given by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). In order to acquire a measure of alcohol consumption that would be more representative of intake over time, we averaged the drinks per month from both midlife HHP exams. This was then converted into a 5-level measure of alcohol consumption: non-drinkers (≤1 drink/month), light drinkers (>1 drink/month to 1 drink per day), moderate drinkers (>1–2 drinks/day), heavy drinkers (>2–4 drinks/day), and very heavy drinkers (>4 drinks/day). For analyses examining APOE genotype, heavy and very heavy drinkers were collapsed into a single category due to sample size limitations.
Data were collected on a range of health status measures and lifestyle behaviors at all exams. Laboratory measures included systolic blood pressure (SBP), total blood cholesterol, height, and weight (for body mass index (BMI) calculation). Self-reported health measures at the baseline HAAS exam included history of coronary heart disease, diabetes, and demographic variables (age, educational attainment, marital status, home ownership, and smoking status). Stroke was measured by self-report and medical record review. APOE genotyping was performed by PCR amplification followed by restriction enzyme digest as described in detail previously [[
For comparisons across levels of alcohol consumption, Pearson chi-square and ANOVA tests were performed based on the variable classification. Tukey's post-hoc tests were used to identify differing categories. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for cognitive impairment by alcohol consumption. Age was used as the time-scale [[
Table 1 displays demographic and health status variables across levels of alcohol intake from exams 1–3. At midlife, 31% of respondents reported no or very little (≤1 drink/month) alcohol intake. The majority of respondents (44%) reported light drinking (>1 drink/month- 1 drink/day), while 13% reported moderate (>1–2 drinks/day), 9% reported heavy (>2–4 drinks/day), and 3% reported very heavy (>4 drinks/day) alcohol consumption. Non-drinkers were older at baseline than light drinkers. Non-drinkers died at an older age than heavy and very heavy drinkers. Non-drinkers and light drinkers had a lower average SBP than moderate and heavy drinkers, while very heavy drinkers had the highest proportion of current smokers. Among those who ultimately developed moderate or severe cognitive impairment, very heavy drinkers had an age at onset approximately 2.1 years earlier than non-drinkers.
Graph
Table 1 Comparison of HAAS characteristics across level of alcohol consumption in midlife.
Parameter Midlife Alcohol Intake (average of exams 1 and 3) Non-Drinker (≤1 drink/month) Light (>1 drink/month–1 drink/day) Moderate (>1–2 drinks/day) Heavy (>2–4 drinks/day) Very Heavy (>4 drinks/day) % (#), Mean (SD) TOTALS 30.9% (747) 44.1% (1066) 12.5% (302) 9.2% (223) 3.2% (78) Demographics Age at E1 52.0 (4.2) 51.4 (3.9) 51.6 (3.8) 51.5 (4.1) 51.7 (3.9) 0.0381 Age at death 89.3 (5.2) 89.0 (5.1) 88.5 (5.1) 88.0 (5.0) 87.2 (5.2) 0.0004 Years of education 11.0 (3.2) 11.2 (3.1) 10.7 (3.2) 10.4 (2.9) 9.9 (3.1) <.0001 Ever married 97.6% (729) 98.3% (1048) 98.0% (296) 99.1% (221) 97.4% (76) 0.6107 Own home 80.2% (599) 83.5% (889) 78.8% (238) 79.8% (178) 74.4% (58) 0.0945 APOE ε4 18.2% (136) 18.3% (195) 20.9% (63) 18.8% (42) 23.1% (18) 0.7122 Midlife Health Status (E1-3) Average BMI, E1,3 23.9 (2.8) 24.0 (2.7) 24.1 (2.8) 24.0 (2.8) 24.0 (2.9) 0.8858 Average SBP, E1-3 128.3 (15.2) 129.3 (15.6) 131.9 (15.8) 135.4 (16.6) 132.7 (16.1) <.0001 Average cholesterol, E1-3 217.8 (35.3) 212.4 (29.0) 217.6 (28.3) 209.5 (26.5) 210.3 (29.5) 0.1924 Current smoker, E1 26.1% (195) 34.4% (367) 38.4% (116) 48.0% (107) 65.4% (51) <.0001 Later Life Health Status (E4) Heart attack, ever 7.4% (54) 6.8% (72) 6.0% (18) 6.3% (14) 5.1% (4) 0.9022 Coronary heart disease 29.2% (218) 27.7% (295) 25.5% (77) 22.4% (50) 30.8% (24) 0.2883 Stroke, ever 6.6% (49) 7.8% (83) 8.6% (26) 10.3% (23) 9.0% (7) 0.4073 Diabetes 18.2% (134) 16.4% (173) 12.8% (38) 14.5% (32) 18.0% (14) 0.2542 Cancer, ever 9.3% (69) 8.1% (85) 8.9% (27) 7.8% (17) 9.0% (7) 0.8882 CES-D score >9 14.5% (98) 14.1% (136) 17.2% (47) 16.3% (32) 16.4% (11) 0.2895 Cognitive Function Baseline CASI, E4 88.0 (6.1) 88.6 (6.0) 88.2 (5.9) 86.9 (6.3) 86.5 (6.4) 0.0006 Final CASI 70.3 (21.3) 71.1 (21.1) 70.6 (22.3) 69.1 (22.2) 70.8 (17.1) 0.7864 Incident CASI <74 47.4% (354) 46.6% (497) 48.0% (145) 51.1% (114) 50.0% (39) 0.7854 Among those with CASI <74 Average age at incident 84.7 (5.1) 84.4 (5.1) 83.7 (5.6) 83.2 (4.8) 82.6 (4.9) 0.0095 Final CASI 55.1 (21.8) 55.4 (21.2) 55.2 (23.2) 54.3 (21.9) 58.8 (15.8) 0.9482
1 Note. Dichotomous measures are shown as percentage and sample size while continuous measures are displayed as mean and standard deviation (SD).
- 2 Abbreviations: APOE ε4, apolipoprotein E ε4 allele; BMI, body mass index; CASI, Cognitive Abilities Screening Instrument; CES-D, Center for Epidemiologic Studies-Depression scale; E, exam; SBP, systolic blood pressure; SD, standard deviation.
- 3
a p value for Pearson chi-square or F test. - 4 *p <.05
- 5 **p <.01
- 6 ***p <.001.
The crude and adjusted HRs estimating the impact of midlife drinking on later life cognitive function are shown in Table 2. Light and moderate midlife drinkers had no difference in risk of moderate or severe cognitive impairment compared to non-drinkers in both crude and adjusted models. However, heavy drinkers at midlife had a 36% increase in risk compared to non-drinkers (HR = 1.355, CI = 1.09–1.68) and very heavy drinkers had a 46% increase in risk compared to non-drinkers (HR = 1.462, CI = 1.04–2.05) after adjusting for covariates. Running the analysis among respondents with no history of heart attack or stroke at exam 4 resulted in the same observed pattern.
Graph
Table 2 Hazard ratios and confidence intervals for moderate cognitive impairment across levels of alcohol intake at midlife.
Moderate Cognitive Impairment Midlife Alcohol Intake (average of exams 1 and 3) Non-drinker (≤1 drink/month) Light (>1 drink/month–1 drink/day) Moderate (>1–2 drinks/day) Heavy (>2–4 drinks/day) Very heavy (>4 drinks/day) Hazard Ratio (95% Confidence Intervals) Crude 1 0.963 (0.84–1.10) p = 0.5843 1.088 (0.90–1.32) p = 0.3933 1.515 (1.23–1.88) p = 0.0001 1.700 (1.22–2.37) p = 0.0017 n = 747 n = 1,066 n = 302 n = 223 n = 78 Adjusted 1 1.013 (0.88–1.16) p = 0.8515 1.104 (0.91–1.34) p = 0.3217 1.355 (1.09–1.68) p = 0.0060 1.462 (1.04–2.05) p = 0.0270 n = 743 n = 1,062 n = 302 n = 223 n = 78
- 7 Note. Bolding indicates significant results at p <.05; Abbreviations: E, exam.
- 8
a Adjusted for education, apolipoprotein E ε4 allele status, average body mass index (E1,3), average systolic blood pressure (E1-3), history of stroke (E4), and smoking status (E1).
Although the interaction term between alcohol consumption and APOE ℇ4 carrier status was not significant, we stratified the results to more closely examine this relationship. The HRs for level of alcohol intake at midlife, APOE ℇ4 carrier status, and later life cognitive impairment (moderate or severe) are shown in Table 3. Among those who do not carry any APOE ℇ4 alleles, a similar relationship is seen as above. Light and moderate drinkers have no difference in risk of moderate or severe cognitive impairment in life (HR = 1.042, CI = 0.89–1.22; HR = 1.009, CI = 0.81–1.26, respectively) while heavy-to-very-heavy drinkers show a 47% increased risk as compared to non-drinkers (HR = 1.473, CI = 1.18–1.83). Compared to respondents without an APOE ℇ4 allele, those with at least one copy showed an increased risk of cognitive impairment at all levels of midlife alcohol consumption. However, the risk grows with growing alcohol intake, reflecting a similar dose-dependent relationship observed among those without the APOE ℇ4 allele. Non-drinkers with at least one APOE ℇ4 allele demonstrated a 35% increased risk of later life moderate cognitive impairment as compared to non-drinkers with no copies of the ℇ4 allele (HR = 1.352, CI = 1.04-1.75). The risk for cognitive impairment increases with alcohol consumption as seen in moderate (HR = 2.039, CI = 1.45–2.87) and heavy-to-very-heavy (HR = 1.544, CI = 1.07–2.23) drinkers. Although the HR is greater for moderate drinkers than heavy-to-very-heavy drinkers, it is important to note the confidence intervals overlap, suggesting no statistical difference between the HR estimates.
Graph
Table 3 Hazard ratios and confidence intervals for moderate cognitive impairment across levels of alcohol intake at midlife by APOE ε4 status.
Midlife Alcohol Intake (average of exams 1 and 3) Moderate Cognitive Impairment Non-drinker (≤1 drink/month) Light (>1 drink/month–1 drink/day) Moderate (>1–2 drinks/day) Heavy/Very Heavy(>2 drinks/day) Hazard Ratio APOE ε4 Negative 1 1.042 (0.89–1.22) 0.5492 1.009 (0.81–1.26) p = 0.9431 1.473 (1.18–1.83) p = 0.0006 n = 608 n = 868 n = 239 n = 241 APOE ε4 Positive 1.352 (1.04–1.75) p = 0.0209 1.196 (0.95–1.51) p = 0.1095 2.039 (1.45–2.87) p = <.0001 1.544 (1.07–2.23) p = 0.0260 n = 135 n = 194 n = 63 n = 60
- 9 Note. Bolding indicates significant results at p <.05; Abbreviations: APOE ε4 apolipoprotein E ε4 allele; E, exam.
- 10
a Hazard ratios are adjusted for education, average body mass index (E1,3), average systolic blood pressure (E1-3), history of stroke (E4), and smoking status (E1).
Fig 1. shows the age at which the participants' CASI test score is estimated to have fallen below 74, indicating the onset of decline or age of incident moderate cognitive impairment. Among the decedents who developed moderate cognitive impairment, the age at onset appears to decrease with increasing alcohol consumption and with APOE ℇ4 status. Nondrinkers have approximately the same age at onset regardless of APOE ℇ4 status. The age at onset decreases as alcohol consumption increases but appears to decrease faster among respondents with the APOE ℇ4 allele. Although the difference by APOE ℇ4 status for light alcohol intake was marginally significant (p = 0.08), there were no statistically significant differences between the ages at onset. The small sample size may not lend enough strength to observe statistical differences.
Graph: Fig 1 Age of onset of moderate cognitive impairment by midlife alcohol intake (exams 1,3) and apolipoprotein E ℇ4 status.Bars represent standard errors of the estimates and numbers above the bars reflect sample size for the total sample.
The results from the current all-male cohort do not support the suggestion that moderate midlife drinking is beneficial or protective for cognitive function later in life. Discrepant findings in the literature may be due to differences in alcohol classification, study design, follow-up time, and bias. In a recent systematic review of 27 cohort studies, Brennan et al. [[
We found an increased risk for cognitive impairment among the heavy (>2–4 drinks/day) and very heavy (>4 drinks/day) drinkers, a result supported by many studies [[
The presence of at least one APOE ℇ4 allele increased the risk for moderate cognitive impairment in an approximately additive manner. That is, a similar relationship between alcohol and cognition was observed among those with the APOE ℇ4, only the risk was shifted higher (Table 3). This finding is supported by several other studies [[
Harwood et al. [[
As with other research of similar design, there are limitations to be considered when interpreting the results of this study. Any information collected via self-report is subject to recall bias that may affect the accuracy of the results. Particularly alcohol intake has been observed to be underestimated in self-reports [[
Some may argue that measuring alcohol at only two points in midlife does not accurately reflect alcohol consumption over the lifespan. While this may be true, we observed a great deal of correlation between the two points in midlife (r = 0.521, p <.0001) and between the later point in midlife and the measurement taken in later life (r = 0.455, p <.0001). This suggests drinking habits remained relatively constant over time in this cohort. This does not necessarily reflect consumption as young adults, but we did not have access to those data.
The current study has many strengths, including the longitudinal study design, large cohort size, and high participation rates. Data were collected prospectively, reducing bias, and there was a long follow-up period for monitoring cognition, up to 48 years. Lastly, collecting data on alcohol intake at two time points allowed us to create a measure of alcohol that better reflected consumption over midlife rather than at a single time point.
We did not observe a protective effect on later life cognitive function for light to moderate consumption of alcohol in midlife. Heavy alcohol consumption increased the risk for cognitive impairment later in life. The presence of at least one APOE ℇ4 allele increased the risk for moderate cognitive impairment with increasing alcohol consumption. As alcohol level increased, the age at incident moderate cognitive impairment decreased, especially among those with at least one APOE ℇ4 allele.
All authors contributed to the manuscript.
By E. Julia Chosy; Steven Edland; Lenore Launer and Lon R. White
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