Alcohol drinking and risk of Parkinson's disease: a case-control study in Japan

While smoking has been consistently associated with a decreased risk of Parkinson's disease (PD), a relationship between alcohol intake and PD still remains controversial. Some epidemiological studies reported that alcohol drinking was inversely associated with PD [1‐4]. Conversely, the vast majority of investigations failed to find significant associations between alcohol intake and PD [5‐13]. In a meta-analysis comparing drinkers with non-drinkers, the pooled odds ratio (OR) for PD risk was 0.81 (95% confidence interval (CI): 0.70-0.92) or 0.73 (95% CI: 0.57-0.92) when 13 case-control studies or 4 cohort studies, respectively, were included [14].

Alcohol drinking status, including frequency and amount, can be influenced by activities of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). ALDH2, a key enzyme in the elimination of acetaldehyde, has a polymorphism that is prevalent in East Asians, but rare in Caucasians or Africans [15]. Those with inactive ALDH2 are likely to experience facial flushing responses due to acetaldehydemia after drinking alcohol, resulting in reduced alcohol intake with respect to both frequency and amount [16‐19]. It has been reported that those with flushing responses drank significantly less hard liquor than those without [19]. Because aldehydes may react with dopamine both in vitro and in vivo [20, 21], it might be hypothesized that relations between alcohol and PD risk vary according to flushing status. To our knowledge, only one study, a case-control study from Japan, investigated a possible effect modification by ALDH2 activity and found that average alcohol consumption was significantly lower among cases than controls regardless of ALDH2 genotype [3].

In the present study, we examined the association between alcohol drinking and PD risk using data from a hospital-based case-control study among Japanese. We also investigated whether flushing status, as a proxy variable of ALDH2 activity, modified the association.

Thirty-five percent of the subjects were male and the mean age was approximately 70 years (Table 1). Compared with control subjects, cases were more likely to be older and thinner, report never having smoked, report never having medication histories for hypertension, hypercholesterolemia, or diabetes, and have a low intake of caffeine. There were no differences with respect to both the status of current drinking and alcohol flushing status, as well as sex, region of residence, education, and the other dietary variables.

In crude analyses, neither frequency nor amount of alcohol intake during the peak drinking period was significantly associated with the risk of PD among all subjects (Table 2). After adjustment for several potential confounders including sex, age, region of residence, pack-years of smoking, years of education, body mass index, flushing status, and presence of selected medication history, the association between weekly alcohol intake and PD was strengthened. Compared with non-drinkers, the OR of those who drank ≥219.4 g ethanol per week was 2.09 (95% CI: 1.13-3.91, P for trend = 0.03). The confounding was primarily due to smoking, not flushing status (data not shown). This positive relationship disappeared, however, when caffeine, cholesterol, vitamin E, vitamin B6, iron, and the dietary glycemic index were further included as confounders (OR: 1.79, 95% CI: 0.95-3.39, P for trend = 0.11). Likewise, no significant associations were observed between frequency or daily ethanol intake and the risk of PD in the fully adjusted model: the adjusted OR of the highest category (≥6 days per week and ≥66.0 g ethanol per day) was 0.96 for the frequency (95% CI: 0.50-1.81, P for trend = 0.96) and 1.46 for the daily amount (95% CI: 0.79-2.71, P for trend = 0.26).

When we assessed daily ethanol intake separately for each type of alcohol, there were no significant associations with PD, except for Japanese sake (Table 3). The OR of the highest category (≥66.0 g ethanol per day) in the fully adjusted model was 2.13 for beer (95% CI: 0.80-5.82, P for trend = 0.39), 3.39 for Japanese sake (95% CI: 1.10-11.0, P for trend = 0.001), 1.29 for shochu (95% CI: 0.59-2.78, P for trend = 0.58), 6.11 for wine (95% CI: 0.67-134, P for trend = 0.36) and 2.25 for whisky (95% CI: 0.67-7.83, P for trend = 0.06). We could not examine the frequency or weekly amount of alcohol intake for the individual types of alcohol because we did not ask information on drinking frequency separately for each type of alcohol.

In the stratified analysis according to flushing status, former and current flushers were combined due to small numbers of former flushers (Table 4). We did not find any significant interactions between alcohol drinking and flushing status with regard to the risk of PD (P for interaction = 0.22, 0.37, and 0.18 for the highest category of frequency, daily amount, and weekly amount of alcohol intake, respectively). With respect to the separate types of alcohol, no interactions with flashing status were observed.

In this study, alcohol intake during the peak drinking period was not associated with PD when ethanol intake was combined from all types of alcohol. There was no significant interaction of alcohol drinking with flushing status in relation to PD risk. Similarly to the present study, a substantial body of previous case-control studies failed to find significant associations between alcohol and PD. In each study, alcohol as an exposure variable was assessed differently, including as a binary category of "ever vs. never" [5‐8, 12, 13], an average amount [12], a cumulative amount [10], or amount per week based on typical consumption patterns during most of the subject's adult life [9]. A large prospective cohort study, including two cohorts from the Nurses' Health Study and Health Professionals' Study, found no significant relationship between average alcohol intake at baseline and subsequent PD incidence [11].

Our finding is not in agreement with previous studies that observed significant inverse associations between alcohol intake and PD [1‐4]. A meta-analysis reported a reduced risk of PD among drinkers compared with non-drinkers: the pooled OR (95% CI) was 0.81(0.70-0.92) or 0.73 (0.57-0.92) when 13 case-control studies or 4 cohort studies, respectively, were included [14]. Several epidemiologic studies found that beer [11, 28, 29], spirits [28], wine [29] and liquor [2, 29], but not ethanol intake [11, 28], were inversely associated with PD. The high content of urate in beer or niacin in alcoholic beverages were reported as plausible protective agents [30, 31]. Another hypothesis is that PD patients have a premorbid personality to avoid alcohol drinking. Two previous case-control studies showed that PD patients were significantly less likely to have been diagnosed with alcoholism or to have a previous history of alcohol use disorder [8, 13].

When we examined daily ethanol intake separately for each type of alcohol, only Japanese sake was positively associated with PD. To our knowledge, there has been no report that Japanese sake increased the risk of PD. Although our finding could be due to chance, it has been shown that relationships between alcohol intake and PD varied according to different kinds of alcohol [11, 28, 29].

In vitro studies showed that aldehydes might react with dopamine. Ethanol enhanced the toxicity of 6-hydroxydopamin (6-OHDA) when ethanol and 6-OHDA were simultaneously applied to cultured cells [20]. In an attempt to create a mouse version of the rat model of PD, developed using a synthetic proteasome inhibitor (PSI), decreased levels of nigrostriatal dopamine were observed both in the mice treated with PSI in an ethanol-vehicle and in control mice with ethanol-vehicle alone [21]. By contrast, it was reported that ADHs, and not ALDHs, play important roles in the synthesis of retinoic acid, which may influence the proper development and maintenance of the dopaminergic system [32]. These inconsistent findings may explain the lack of significant interaction we observed between alcohol drinking and flushing status in relation to PD risk.

A strength of the present study is that cases were identified using strict diagnostic criteria, minimizing disease misclassification as much as possible. We also designed our study with extensive data collection, based on comprehensive literature review, allowing us to adjust for several potential confounders, including dietary factors. However, residual confounding cannot be ruled out. In contrast to previous studies that looked at average drinking habits, we examined subjects' peak drinking status as exposure variables. Some PD patients experience several gastrointestinal symptoms as non-motor manifestations. It was shown that constipation, occurring as early as 20 or more years before the onset of motor symptoms, was associated with an increased risk of PD [33]. Given that some gastrointestinal symptoms such as constipation affect alcohol drinking status even before the onset of disease, average or cumulative drinking amounts might be decreased in PD patients compared with healthy subjects. Thus the peak drinking status may be another reasonable indicator to avoid underestimation of alcohol consumption among PD patients.

Our study was limited by our failure to collect information on peak drinking from former drinkers (approximately 10% of the subjects initially recruited for the present study). A comparison of the 541 subjects included in the final analysis with 69 former drinkers revealed that former drinkers were more likely to be male (63.8 vs. 34.6%, P <0.0001), older (mean age: 70.2 vs. 67.0, P = 0.003), smokers (those with ≥30.0 pack-years: 36.2 vs. 15.3%, P <0.0001), more educated (those with ≥13 years: 34.8 vs. 31.6%, P = 0.006), and have a medication history for diabetes (15.9 vs. 7.0%, P = 0.01). We previously revealed an inverse association between smoking habits or medication history for diabetes and PD in this study population [22, 23]. By contrast, ageing is known to be strong positive risk factor for PD; therefore, selection bias might not be negligible, although we cannot precisely speculate on either the direction or the magnitude of the bias.

Another possible limitation is that our controls were not fully representative of the population from which our cases arose, as they were selected from only 3 of the 11 collaborating hospitals where cases were recruited. The results of a sensitivity analysis restricted to cases who were recruited from the three hospitals associated with control recruitment (n = 130) were similar to those in the overall analysis: the adjusted OR in the highest category was 0.78 (95% CI: 0.36-1.63, P for trend = 0.59) for frequency, 1.17 (95% CI: 0.58-2.36, P for trend = 0.71) for daily amount, and 1.66 (95% CI: 0.81-3.42, P for trend = 0.26) for weekly amount. Furthermore, cases in the present study were prevalent rather than incident cases. When we conducted a sensitivity analysis confined to cases less than 3 years from onset (n = 88), interpretation of our results was not markedly changed. The adjusted OR in the highest category was 0.60 (95% CI: 0.24-1.42, P for trend = 0.32) for frequency, 1.28 (95% CI: 0.58-2.82, P for trend = 0.69) for daily amount, and 1.50 (95% CI: 0.67-3.36, P for trend = 0.51) for weekly amount. We were also concerned that medication history might affect alcohol drinking habits, so we performed a sensitivity analysis among subjects without medication history for hypertension, hypercholesterolemia, or diabetes (152 cases and 173 controls). The associations between alcohol intake and PD were not considerably altered. The adjusted OR in the highest category was 0.91 (95% CI: 0.41-2.00, P for trend = 0.94) for frequency, 1.34 (95% CI: 0.62-2.93, P for trend = 0.47) for daily amount, and 1.61 (95% CI: 0.75-3.50, P for trend = 0.27) for weekly amount. Thus, the possible influence of medication history on alcohol intake was, if any, likely to be minimal. Finally, all the information in this study relied on self-reports rather than on interviews by trained investigators, and information on alcohol intake and non-dietary factors was collected via a non-validated questionnaire, which could affect the present results.

We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed. The present study, however, is the first to assess the effects of alcohol on PD risk using peak drinking status as an exposure variable and alcohol flushing status as a potential confounder. To better understand the role of alcohol drinking in the pathogenesis of PD, it may be helpful to take into consideration many aspects of alcohol.

Other members of the Fukuoka Kinki Parkinson's Disease Study Group are as follow: Yasuhiko Baba and Tomonori Kobayashi (Department of Neurology, Faculty of Medicine, Fukuoka University); Hideyuki Sawada, Eiji Mizuta, and Nagako Murase (Clinical Research Institute and Department of Neurology, Utano National Hospital); Tsuyoshi Tsutada and Hiroyuki Shimada (Department of Geriatrics and Neurology, Osaka City University Graduate School of Medicine); Jun-ichi Kira (Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University); Tameko Kihira and Tomoyoshi Kondo (Department of Neurology, Wakayama Medical University); Hidekazu Tomimoto (Department of Neurology, Kyoto University Graduate School of Medicine); Takayuki Taniwaki (Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine); Hiroshi Sugiyama and Sonoyo Yoshida (Department of Neurology, Minami-Kyoto National Hospital); Harutoshi Fujimura and Tomoko Saito (Department of Neurology, Toneyama National Hospital); Kyoko Saida and Junko Fujitake (Department of Neurology, Kyoto City Hospital); Naoki Fujii (Department of Neurology, Neuro-Muscular Center, National Omuta Hospital); Masatoshi Naito and Jun Arimizu (Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University); Takashi Nakagawa, Hirofumi Harada, and Takayuki Sueta (Department of Otorhinolaryngology, Faculty of Medicine, Fukuoka University); Toshihiro Kikuta and George Umemoto (Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Fukuoka University); Eiichi Uchio and Hironori Migita (Department of Ophthalmology, Faculty of Medicine, Fukuoka University); Kenichi Kazuki, Yoichi Ito, and Hiroyoshi Iwaki (Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine); Kunihiko Siraki and Shinsuke Ataka (Department of Ophthalmology and Visual Sciences, Osaka City University Graduate School of Medicine); Hideo Yaname and Rie Tochino (Department of Otolaryngology and Head and Neck Surgery, Osaka City University Graduate School of Medicine); Teruichi Harada (Plastic and Reconstructive Surgery, Osaka City University Graduate School of Medicine); Yasushi Iwashita, Motoyuki Shimizu, Kenji Seki, and Keiji Ando (Department of Orthopedic Surgery, Utano National Hospital).