Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study

Abstract Objective To examine the association between alcohol consumption and risk of dementia. Design Prospective cohort study. Setting Civil service departments in London (Whitehall II study). Participants 9087 participants aged 35-55 years at study inception (1985/88). Main outcome measures Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. Measures of alcohol consumption were the mean from three assessments between 1985/88 and 1991/93 (midlife), categorised as abstinence, 1-14 units/week, and >14 units/week; 17 year trajectories of alcohol consumption based on five assessments of alcohol consumption between 1985/88 and 2002/04; CAGE questionnaire for alcohol dependence assessed in 1991/93; and hospital admission for alcohol related chronic diseases between 1991 and 2017. Results 397 cases of dementia were recorded over a mean follow-up of 23 years. Abstinence in midlife was associated with a higher risk of dementia (hazard ratio 1.47, 95% confidence interval 1.15 to 1.89) compared with consumption of 1-14 units/week. Among those drinking >14 units/week, a 7 unit increase in alcohol consumption was associated with a 17% (95% confidence interval 4% to 32%) increase in risk of dementia. CAGE score >2 (hazard ratio 2.19, 1.29 to 3.71) and alcohol related hospital admission (4.28, 2.72 to 6.73) were also associated with an increased risk of dementia. Alcohol consumption trajectories from midlife to early old age showed long term abstinence (1.74, 1.31 to 2.30), decrease in consumption (1.55, 1.08 to 2.22), and long term consumption >14 units/week (1.40, 1.02 to 1.93) to be associated with a higher risk of dementia compared with long term consumption of 1-14 units/week. Analysis using multistate models suggested that the excess risk of dementia associated with abstinence in midlife was partly explained by cardiometabolic disease over the follow-up as the hazard ratio of dementia in abstainers without cardiometabolic disease was 1.33 (0.88 to 2.02) compared with 1.47 (1.15 to 1.89) in the entire population. Conclusion The risk of dementia was increased in people who abstained from alcohol in midlife or consumed >14 units/week. In several countries, guidelines define thresholds for harmful alcohol consumption much higher than 14 units/week. The present findings encourage the downward revision of such guidelines to promote cognitive health at older ages.

. Mortality and dementia incidence rates over time. Table S2. Association between detailed categories of midlife alcohol consumption with incident dementia. Table S3. Estimation of trajectories of alcohol consumption: model fit statistics (group based trajectory models). Table S4. ICD codes for identification of chronic diseases 100% attributable to alcohol consumption. Table S5. Association between alcohol consumption at age 50, 60, and 70 and risk of dementia up to March 31 st , 2017. Table S6. Association between midlife alcohol consumption and risk of mortality. Table S7. Sensitivity analysis to assess the impact of dementia misclassification on the association between alcohol consumption in midlife and dementia.  Figure S2. Trajectories of cognitive function before dementia diagnosis.* *To assess trajectories of cognitive function before dementia diagnosis, we used data from a cognitive test battery administered in 1997/99, 2002/04, 2007/09, 2012/13, and 2015/16. It consisted of tests of memory (20-word free recall test), reasoning (Alice Heim 4-I test composed of a series of 65 verbal and mathematical reasoning items of increasing difficulty), and verbal fluency (measures of phonemic (words starting with s) and semantic (animal names) fluency). A global cognitive score was created using all tests described above by first standardising the raw scores for each domain to z-scores (mean=0; standard deviation (SD)=1) using the distribution of the first wave of cognitive data. These zscores were summed and restandardised to yield the global score. To compare trajectories of global cognition in those with dementia compared to those free of dementia, a mixed model was used with a backward timescale such that Year=0 in the analysis was the year of dementia diagnosis for cases, year of death for those who died during the follow-up, and end of follow-up (March 31 st 2017) for all others. The analysis was adjusted for age at time 0, sex, education, 5-year cohort of birth and dementia status and their interaction with time and time².  HRs correspond to an increment of 7 alcohol units per week. Analysis based on 2232 participants; N dementia=70; N death=360 (among which 39 had dementia before death). Analysis adjusted for age, sex, ethnicity, education, occupational position, and marital status.

A. B.
*Cox regression analysis adjusted for socio-demographic factors.

Figure S5. Association between midlife alcohol consumption and dementia by type of alcohol* (left panel) and corresponding distribution of types of alcohol consumed (right panel).
A. Association between wine and risk of dementia B. Distribution of wine consumption C. Association between beer and risk of dementia D. Distribution of beer consumption E. Association between spirit and risk of dementia F. Distribution of spirit consumption *Cox regression analysis adjusted for socio-demographic factors. Table S1. Mortality and dementia incidence rates over time.

Incidence of Mortality
Rate per 1000 person-years

Incidence of Dementia
Rate per 1000 person-years

Analysis on midlife alcohol consumption
Included: N = 9087 7.2 (6.9 to 7.6) 1.9 (1.7 to 2.1) 13.8 (11.8 to 16.1) 4.6 (3.5 to 6.1) Additionally adjusted for physical activity, smoking status, and fruit and vegetable consumption. § Additionally adjusted for systolic blood pressure, total cholesterol, diabetes, BMI, GHQ score, CVD, and CVD medication.   *Simulated data were generated assuming sensitivity range between 60% and 90% and specificity range between 97% and 100% with a trapezoidal probability density function. This simulation makes the hypothesis of differential dementia misclassification (i.e. the hypothesis that probability of dementia misclassification depends on alcohol consumption). We first analysed the impact of potential differential misclassification on the risk in abstainers compared to those drinking 1-14 alcohol units/week. We simulated two scenarios: first where the correlation between the sensitivity distribution in those following recommendations and the sensitivity distribution in all others was 0.8 and then 0.6 (and similarly for the correlations of the specificity distributions); note that a correlation of 1 corresponds to non-differential misclassification. We then repeated these analyses for alcohol consumption >14 units/week compared to 1-14 units/week. † Adjusted for sociodemographic variables Abbreviation: NA, not applicable.