Critique 262:Changes in alcohol consumption and risk of dementia in a nationwide cohort in South Korea

Authors

Jeon KH, Han K, Jeong SM, Park J, Yoo JE, Yoo J, Lee J, Kim S, Shin DW. 2023. JAMA Network Open, 6(2) Art No e2254771, 14pp.

Author’s abstract

Importance: The impact of serial changes in alcohol consumption on dementia risk has rarely been investigated to date.

Objective: To investigate the association of comprehensive patterns of changes in alcohol consumption with the incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD).

Design, Setting, and Participants: This is a retrospective cohort study. Data were obtained from the Korean National Health Insurance Service database. Adults aged 40 years and older underwent 2 health examinations in 2009 and 2011. The cohort was assessed until December 31, 2018, and statistical analysis was performed in December 2021.

Exposures: Alcohol consumption level was categorized into none (0g per day), mild ( < 15g per day), moderate (15-29.9g per day), and heavy (>/= 30 g per day) drinking. On the basis of changes in alcohol consumption level from 2009 to 2011, participants were categorized into the following groups: nondrinker, quitter, reducer, sustainer, and increaser.

Main Outcomes and Measures: The primary outcome was newly diagnosed AD, VaD, or other dementia.

Results: Among 3,933,382 participants (mean [SD] age, 55.0 [9.6] years; 2,037,948 men [51.8%]), during a mean (SD) follow-up of 6.3 (0.7) years, there were 100,282 cases of all-cause dementia, 79,982 cases of AD, and 11,085 cases of VaD. Compared with sustained nondrinking, sustained mild (adjusted hazard ratio [aHR], 0.79; 95% CI, 0.77-0.81) and moderate (aHR, 0.83; 95% CI, 0.79-0.88) drinking were associated with a decreased risk of all-cause dementia, whereas sustained heavy drinking was associated with an increased risk of all-cause dementia (aHR, 1.08; 95% CI, 1.03-1.12). Compared with sustained levels of drinking, reducing alcohol consumption from a heavy to a moderate level (aHR, 0.92; 95% CI, 0.86-0.99) and the initiation of mild alcohol consumption (aHR, 0.93; 95% CI, 0.90-0.96) were associated with a decreased risk of all-cause dementia. Increasers and quitters exhibited an increased risk of all-cause dementia compared with sustainers. The trends in AD and VaD remained consistent.

Conclusions and Relevance: In this cohort study of a Korean population, decreased risk of dementia was associated with maintaining mild to moderate alcohol consumption, reducing alcohol consumption from a heavy to a moderate level, and the initiation of mild alcohol consumption, suggesting that the threshold of alcohol consumption for dementia risk reduction is low.

Forum Summary

Cognitive dysfunction eventually leads to a loss of independence that becomes a burden on families and society, as the individual requires more intense care and often institutionalisation. In the later stages, the cognitive impairment associated with dementias will create total dependency such that dementia is one the major causes of disability and disability burden overall among older adults globally (WHO 2023)[1].

As there is no cure, identification of factors associated with preservation of cognitive function could lead to substantial improvements in the quality of life in older adults, including simple dietary measures. Recent systematic review of health behaviours which maintain healthy cognitive function suggests that the consumption of fish and vegetables[2],[3], moderate physical activity and moderate alcohol consumption tend to be protective against cognitive decline and dementia.  Studies have shown that alcohol acts directly and indirectly on the brain[4].

Consistent with the systematic review of 28 studies by Rehm et al. (2019)[5] where although causality could not be established, light to moderate alcohol consumption in middle to late adulthood was associated with a decreased risk of cognitive impairment and dementia. Conversely, heavy alcohol consumption was associated with changes in cognitive impairments, and an increased risk of all types of dementia.

Jeon et al. (2023) also showed in their massive retrospective cohort study of four million people followed for six years resulting in 24 million person-years, which is a significantly adds to the strength of the study outcomes that a decreased risk of dementia was associated with maintaining mild to moderate alcohol consumption. The study additionally showed that a decreased risk of dementia was associated with reducing alcohol consumption from a heavy to a moderate level, and with the initiation of mild alcohol consumption; collectively this data suggests that the threshold of alcohol consumption for dementia risk reduction is low.

Genetic profiles, standardized cognition, mood and behavioural assessments, as well as the quantification of structural and functional connectivity brain measures, which are all well established for dementia, if included in this study would have enabled the extrapolation of, and further added to the global relevance of the results from this huge South Korean population.

Forum members agreed with the conclusions of the authors which, simply stated, suggest that ‘sustained’ drinking up to 30 g/day is good for the brain, but non-drinkers who went from zero to moderate or heavy drinking did not show the same improvement as those who increased only to mild drinking.  These observations are not new and indeed are generally consistent of those of past studies on alcohol consumption and cognitive decline, but the subject size is almost more significant than the sum of participants in past studies.

Forum comments

Background including previous research

The Global Burden of Disease Study has predicted that the number of adults (aged 40 years and older) living with dementia worldwide is expected to nearly triple, from an estimated 57 million in 2019 to 153 million in 2050, due primarily to population growth and population ageing[6].  Approximately 3% of adults aged 70 to 74 had dementia in 2019, compared with 22% of adults aged 85 to 89 and 33% of adults aged 90 and older. Alzheimer’s disease is the most common dementia diagnosis among older adults. More aggressive prevention efforts to reduce dementia risk through lifestyle factors, such as education, diet, and exercise, as well as by expanding much-needed health and social care resources are thus required.

Forum member Stockley states that there have been few systematic reviews on the effects of light to moderate alcohol consumption on cognitive dysfunction and dementias in elderly adults[7]. Cognitive health can be considered as a continuum of cognitive function ranging from optimal to decline to impairment and dementia[8]. It was cautiously concluded from a meta-analysis of 23 studies that there was evidence to suggest that alcohol consumption in earlier adult life may be protective against incident dementia later[9]. An examination of epidemiological studies published between 1998 and 2008 also suggested that light to moderate alcohol consumption may be associated with a 38% reduced risk of unspecified dementias and with a 32% reduced risk specifically for Alzheimer’s disease. From a meta-analysis of 15 studies, Anstey et al. (2009) also concluded that light to moderate alcohol consumers later in life have a 47% reduced risk of any dementias compared with abstainers[10]. In addition, Neafsey and Collins (2011) concluded that in 14 of 19 countries for which data was available, light to moderate alcohol consumption significantly reduced the risk of cognitive decline and in the remaining countries there were non-significant reductions in risk as well[11]. Heavy drinking was, however, associated with an increased risk of cognitive decline and dementias. Their meta-analysis of 143 studies also differentiated between the different types of alcoholic beverages and found that wine was more protective than beer or spirits although this finding was based on a relatively small number of studies.  The SU.VI.MAX2 cohort study also found that heavy beer but not wine consumption was associated with impaired cognitive function[12]. Long-term light to moderate alcohol consumption of any alcoholic beverage does not appear to exacerbate age-related cognitive impairment[13]. Yet another recent meta-analysis assessed the association between alcohol consumption and the risk of Alzheimer’s disease using a dose–response meta-analysis. When compared with abstainers, individuals who drink alcohol had a 32% reduced risk of Alzheimer’s disease. Subgroup analysis by region and sex showed similar summary relative risks. The association between alcohol consumption and Alzheimer’s disease risk was significant only in cohort studies. When stratified by the type of alcoholic beverages, a lower risk of Alzheimer’s disease was found for wine consumption. No protective effects were found for beer and spirits[14].

She also noted that from prospective population-based studies, there is a clear J-shaped relationship between the consumption of alcoholic beverages such as wine, and the risk of cardiovascular diseases including myocardial infarction, which has been extended to a reduced risk of certain cancers, type 2 diabetes and ischaemic stroke[15]. Over the last decade, evidence has accumulated which suggests that this J-shaped relationship could also be extended to the risk of cognitive dysfunction and dementias such as Alzheimer’s disease and vascular dementia[16]. Mild cognitive dysfunction or impairment is an early symptom of Alzheimer’s disease.

While the literature consistently defines light to moderate consumption as 20 to 40 g ethanol per day[17], several studies have defined moderate consumption as up to 80 g ethanol per day for men[18], which may reflect country and cultural differences in alcohol consumption; 10 g ethanol approximates one drink or 100 mL wine. For amounts above moderate consumption the risk of alcohol-related diseases increases dose-dependently[19]. Interestingly, cognition has been observed to decline in individuals who ceased consuming alcoholic beverages[20] and similarly declined with heavier consumption compared to light to moderate consumption[21].

Study design and Discussion comments

Forum member Hendriks suggested that one of the limitations of this study may be its retrospective aspect. The study was not originally designed with the purpose to detect the association between alcohol consumption and risk of dementia. The authors, however, had been excluding adults with underlying diseases such as cardiovascular disease, cancer and dementia, either occurring between the two routine check-ups (2009 and 2011) or within one year after the second screening. The latter resulted in excluding an additional 104,310 persons.

He also suggested that another limitation may be that adults with occurring type 2 diabetes have not been excluded from their analysis. Type 2 diabetes and cardiovascular disease are well-known risk factors for cognitive impairment[22] and dementia[23], and so exclusion of diabetics or pre-diabetics may have been interesting to consider. In model #2, however, the authors corrected for type 2 diabetes and fasting glucose levels, so that diabetes probably did not confound the observed association.

Alcohol consumption was derived from a questionnaire asking for drinking habits over the last 12 months, that is self-reported. It may have been useful to see some validation of the questionnaire derived data on alcohol consumption. Some epidemiological studies compare data from the drinking questionnaires with HDL cholesterol levels assuming that alcohol consumption is associated with increased HDL cholesterol levels. Thus, by comparing questionnaire data with other biomarkers for alcohol consumption, the validity of these self-reported data may have improved.

Conversely, the study is very interesting because of its huge population base. The study monitored almost 4 million people. Follow-up time was approximately six years resulting in 24 million person-years, which is considerable and adds to the strength of the study outcome.

The authors converted drinking data into four drinking categories; first non-drinkers (of course a control group is essential), mild drinkers, moderate drinkers and heavy drinkers categorized according to the American Dietary Guidelines (2015). Drinkers totalled approximately 1,700,000 (with a majority of sustainers) and abstainers about 1,800,000, which suggests a mainly nondrinking population with a large control group. This control group is not easily confounded since it is large and most likely is a good representation of the South Korean population.

The main effect is that those who sustained a mild-moderate level of drinking throughout the follow-up period and those who initiated a mild-moderate level of drinking at the 2011 screening and maintained a mild-moderate level were found to have a lower risk of all-cause dementia compared with sustained non-drinkers:  aHR, 0.75 (95% CI, 0.72-0.77) and aHR, 0.82 (95% CI, 0.77-0.88), respectively.

Forum member Hendriks also reminds that the authors subsequently analysed the risk for dementia for sustained non-drinkers, quitters, reducers, sustainers and increasers, whom reduced, sustained or increased their level of alcohol consumption. This nicely allows for the analysis of the associations between changes in drinking habits and Alzheimer’s disease incidence, in addition to the more classical analysis of the association between drinking habit and Alzheimer’s disease incidence. These analyses showed that starting to drink reduced the risk, reducing drinking also reduced the risk for dementia and increasing drinking (mainly from moderate to heavy) increased the risk. Such analysis really adds to the value of the study.

Forum member Hendriks noted that there no differentiation in drink type may have been interesting in the light of the previous meta-analyses on beverage types and Alzheimer’s disease incidence.

The use of a selected group of health-conscious people participating in screening may also be a limitation, although the total group was quite considerable where in a population of 52 million South Koreans, about 4 million persons participated and not all were particularly health conscious given that many smoked and were not regularly physically active.

Another limitation mentioned was, as in all epidemiological studies, unmeasured confounding. The authors mentioned the genetic factor ApoE4 and ethnicity which they interpret as genetics and drinking culture. Of these unmeasured factors, drinking culture and, therefore, drinking pattern may be the most relevant one in term of confounding. Unfortunately, the paper does not describe the current prevailing drinking habits in South Korea. The authors do acknowledge that alcohol consumption may be considered as a marker for several lifestyle factors, such as social activities. Several studies suggest that more frequent social contact decreases the risk of dementia[24].

The authors comment on the various mechanisms that may contribute to the protective effect of mild to moderate alcohol consumption to Alzheimer’s disease. Protective effects may involve the promotion of pro-survival pathways and decrease of neuroinflammation. These pro-survival pathways are not further specified but the beneficial effects on the vascular system, with beneficial effects on platelet function and increased serum concentration of high-density lipoprotein, are mentioned. Beneficial effects of moderate alcohol consumption on glucose homeostasis may be an additional protective pathway.

What does this study add to current knowledge

Forum member Stockley states that it is difficult to directly compare findings across different studies on cognitive decline and impairment, because of the use of different cognitive assessment tests to measure and assess various components of cognitive function[25],[26].

Jeon et al. (2023), however, support and strengthen previous findings that the introduction and maintenance of even light alcohol consumption, as well as moderate alcohol consumption in studies of middle-aged and older persons is associated with a decreased risk of both all-cause dementia and specifically, Alzheimer’s disease.

The beneficial effects of alcoholic beverages such as wine on the risk of cardiovascular and cerebrovascular diseases have been partly attributed to changes in lipid and haemostatic or blood flow factors. Among older persons without cerebrovascular and neurodegenerative diseases, for example, those who moderately consume alcoholic beverages have been shown to have fewer white-matter abnormalities and infarcts on magnetic resonance imaging than abstainers[27], where pronounced reductions in the risk of both vascular dementia and Alzheimer’s disease have been shown among persons consuming one to six standard drinks per week[28].  Thus, this study also suggests that that consistent with cardio-protection, an optimal amount of an alcoholic beverage for neuro-protection appears to be up to 30 g alcohol/day[29]. Further, Jeon et al. (2003) is also consistent with Solfrizzi et al. (2007), in observing that even consuming up to 15 g alcohol/day, that is, mild consumption appears to also significantly decrease the rate of progression of cognitive dysfunction to dementia[30].

Comments by specific Forum members

Forum Member Ellison suggests thatthe main weaknesses may relate to having to base effects on dementia only from the amount of alcohol reported, with very little information on the pattern of drinking.  Although they apparently made some adjustments for socio-economic factors, it not sure if this really separates the ‘drink to enhance meal’ group from the ‘drink to get drunk’ group.  As the importance of alcohol consumption with food is now known, it is unfortunate that such information was not available.

Another potential weakness is that they had only two assessments of consumption two years apart to assess ‘changes’ in drinking, and is would have been useful to see changes later during the six plus years of follow-up.

Ellison comments that It is ‘amazing’ that all of the changes showed results ‘in the right direction’.  Sustained mild or moderate drinkers did best, and those who reduced heavy drinking or even those who went from non-drinking to mild drinking (but not to moderate or heavy drinking) showed decreases in risk of dementia.  A nagging question that is always unanswered is ‘why did they stop drinking?’  At least, these authors suggested that many may have been ‘sick quitters’.

A key factor giving importance for this study is the HUGE number of subjects, as while only 7.5% of subjects were baseline heavy drinkers, there were about 300,000 people in that group.

Forum Member Skovenborg states that he has 180 studies of the association of moderate alcohol intake and risk of dementia with a total of 624.000 participants in his files. It is almost surreal that this new study has 6.3-times the number of participants than the previous 180 studies together.  In relation to Curt’s comment that the main weaknesses relate to having to base effects on dementia only from the amount of alcohol reported, with very little information on the pattern of drinking.

One of the specific differences concerning the Korean drinking culture and thus pattern of drinking, is that is used to help create and form ties between family members and friends. Drinking is very present throughout traditional family rituals such as honouring ancestors. Aside from traditional holiday and family ritual drinking, alcohol consumption has modernized and become a huge part of socialization in Korean culture. Regardless of the setting, drinking has become a major part of modern Korean socialization. A large majority of Korean people have regarded drinking as a necessary element of social life.  Soju is the most popular Korean liquor and “the common people’s”. The drink is usually served in a shot glass; it has a smooth, clean taste, and pairs well with a variety of Korean dishes. Soju is inexpensive and typically has an alcohol content of 20 percent alcohol by volume.

A Korean standard drink is defined as a specialized cup for each type of alcohol such as beer, soju, or whisky. Each cup has a different volume but is able to hold a similar amount of alcohol (8 g). The fast-paced “bottoms-up” approach to drinking translates to drinking one shot at a time rather than drinking a little sip each time. Whether it’s during a time of joy, happiness, or stress, Koreans often drink until they are drunk. Furthermore, with 8 g alcohol as standard drink and fast-paced drinking as the common drinking pattern, the categorization of alcohol consumption (none, < 15 g/day, 15-29 g/day and ≥ 30 g/day) does not make sense. Not none, < 16 g/day, 16-24 g/day and ≥ 24 g/day would make more sense.

According to a 2018 WHO report, citizens of the Republic of Korea (15+ years) drink 16 L of alcohol per capita per year: males 21.7 L; and females 6.6 L[31].

•   The Nationwide Cohort in South Korea: 3 933 382 participants.

•   Males: 2 037 948; 25.7% nondrinkers = 477 073. (According to WHO 23.0% males are abstainers the past 12 months.) Drinkers = 1 560 875.

•   21.7 litres = 17 360 g alcohol/year = 47.5 g/day per male drinker according to WHO

•   Sustainers <15 g/day (59.9% of drinkers), 15-29 g/day (21.5 %), ≥ 30 g/day (18.6%)

•   A large underreporting among male Korean drinkers is plausible.

•   Females: 1 895 434; 74.3% nondrinkers = 1 380 847. (According to WHO 48.8% females are abstainers the past 12 months) Drinkers = 514 587.

•   7.6 litres = 7 600 g alcohol/year = 16.6 g/day per female drinker according to WHO

•   Sustainers <15 g/day (93% of female drinkers).

•   Relevant underreporting among female Korean drinkers is not plausible.

Forum Member Skovenborg continues that the mechanisms underlying a putative protective effect of alcohol on cognition remain unclear and not well understood. There may be a number of different mechanisms and as one of the possible mechanisms I suggest the role of low to moderate levels of alcohol consumption as a social lubricant to be a possible variable of interest on the causal path between exposure (alcohol consumption) and outcome (risk of dementia).

He suggests that a number of studies have reported experimental findings to explain the risk reduction through alcohol consumption for vascular dementia: elevation of HDL cholesterol, down-regulation of fibrinogen and inhibition of platelet aggregation. Data regarding effects on Alzheimer’s disease related pathology is scarce and contradictory. He also suggests the role of low to moderate levels of alcohol consumption as a social lubricant to be a possible variable of interest on the causal path between exposure (alcohol consumption) and outcome (risk of dementia).

The 2020 report of the Lancet Commission found the weighted relative risk for incident dementia associated with less frequent social contact is 1·57 (95% CI 1·32–1·85)[32]. The human brain appears to require a great deal of stimulation to maintain its cognitive efficacy as people age and environmental enrichment, like social engagement with friends, may aid in the brain’s maintenance[33]. In this context, alcohol may be instrumental in facilitating social engagement in social activities for some older people[34]. Older people appreciate the role of alcohol in sustaining social and leisure activities important to health and well-being in later life[35].

Forum member Skovenborg also emphasises that Dunbar et al. (2017) combined data from a national survey with data from more detailed and observational studies to show that social drinkers have more friends on whom they can depend for emotional and other support, and feel more engaged with, and trusting of, their local community[36]. Furthermore, fewer social occasions are among the most common reasons for decreasing alcohol consumption, while more social occasions and fewer responsibilities are common reasons for increases in later life[37].

Forum Member McEvoy considers that this is a well-done study, where the enormous sample size and repeated assessment of alcohol allow them to examine associations with changes in amount of drinking, which is novel and important. The finding that dementia risk associated with heavy drinking is reduced when heavy drinkers reduce their amount of alcohol consumption is reassuring.

Weaknesses include having entry age of 40 years. Dementia is almost unheard of in individuals in their 40s, so I do not know why they would include individuals who have almost zero chance of experiencing the outcome. They do present age-stratified analyses in the supplement, with similar results for those younger and older than 65 years, but they did not present information on rates of dementia in the younger and older groups, which would have been informative.

Although they tried to address reverse causation by eliminating individuals who developed dementia in the first year of follow-up, this is insufficient since Alzheimer’s disease pathology begins to accumulate a decade or more prior to onset of dementia, and there is typically a prodromal stage in the years preceding dementia diagnosis where cognition is measurably impaired. Additionally, dementia is under-diagnosed, so using health records to identify dementia likely missed many cases of early-stage disease. It is thus plausible that latent disease impacted change in alcohol use.

Self-report of alcohol use within a health screening assessment is also likely to be associated with under-reporting.

Bearing these limitations in mind, this is an important study that adds to our knowledge base of alcohol associations with dementia, providing additional evidence that mild to moderate alcohol use has protective associations for cognitive health in aging.

Concluding comments

Forum members agreed with the conclusions of the authors which simply stated suggest that ‘sustained’ drinking up to 30 g/day is good for the brain, but non-drinkers who went from zero to moderate or heavy drinking did not show the same improvement as those who increased only to mild drinking.  These observations are not new and indeed are general consistent of those of past studies on alcohol consumption and cognitive decline, but the subject size is almost more significant than the sum of participants in past studies.

While there are always concerns about a recommendation that ‘all non-drinkers should consider starting to drink’, the data is consistent that if people do not have contraindications to alcohol, a glass of wine with dinner would not compromise and indeed could improve their health.

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Comments on this paper were provided by the International Scientific Forum on Alcohol Research and specifically by the following members:

R. Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Linda McEvoy, PhD, Department of Radiology, University of California at San Diego (UCSD), La Jolla, CA, USA

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

David van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia

Henk Hendriks, PhD, Netherlands  

Giovanni Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

Fulvio Mattivi, MSc, Head of the Department Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, in San Michele all’Adige, Italy