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 , a cumulative amount , or amount per week based on typical consumption patterns during most of the subject's adult life . 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 .
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 . Several epidemiologic studies found that beer [11, 28, 29], spirits , wine  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 . 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 . 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 . 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 . 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.