# Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women

Mariem Louati-Hajji, Berta Portugal, Emmanuelle Correia, Nasser Laouali, Pei-Chen Lee, Fanny Artaud, Emmanuel Roze, Francesca Romana Mancini, Alexis Elbaz

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Mariem Louati-Hajji, Berta Portugal, Emmanuelle Correia, Nasser Laouali, Pei-Chen Lee, et al. Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women. 2025. hal-05237360

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# Consumption of milk and other dairy products and incidence of Parkinson's disease: a prospective cohort study in French women

Mariem Louati-Hajji

mariem.hajji@inserm.fr

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations https://orcid.org/0009-0006-9112-1423

Berta Portugal

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations

Emmanuelle Correia

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations

Nasser Laouali

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations

Pei-Chen Lee

National Cheng Kung University Department of Public Health

Fanny Artaud

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations

Emmanuel Roze

Hopital Pitie-Salpetriere Departement de Neuropathologie

Francesca Romana Mancini

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations

Alexis Elbaz

INSERM U1018 Equipe 11: Centre de recherche en Epidemiologie et Sante des Populations https://orcid.org/0000-0001-9724-5490

## Research Article

**Keywords:** Parkinson's disease, milk, dairy, cohort, epidemiology

**Posted Date:** March 13th, 2024

**DOI:** https://doi.org/10.21203/rs.3.rs-3955725/v1

**License:** This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

**Version of Record:** A version of this preprint was published at European Journal of Epidemiology on September 18th, 2024. See the published version at https://doi.org/10.1007/s10654-024-01152-2.
## Abstract

Previous studies on dairy products and Parkinson's disease (PD) were inconsistent; a meta-analysis suggested that dairy increased risk in men only. Due to the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in PD. We investigated associations between intake of milk and other dairy products with PD incidence, while considering reverse causation, in the E3N cohort study (1993-2018). PD diagnoses were validated using medical records and drug claim databases. Diet was assessed via a validated dietary questionnaire. Hazard ratios for incident PD were estimated using multivariable Cox regression models. Exposures were lagged by 5y in main analyses and longer lags in sensitivity analyses. We also examined the impact of adjustment for premotor symptoms. During a mean follow-up of 18.8y, 845 of 71,542 women developed PD. PD incidence increased significantly with pure milk consumption (HR/1-SD = 1.08, 95% CI = 1.02-1.14, P-linear = 0.011). A U-shaped relation was observed for milk added to coffee/tea (P-quadratic = 0.036), with lower PD incidence in women with moderate consumption (HR = 0.77 [0.61-0.97], P = 0.029) and no difference between non-drinkers and those with the highest consumption (HR = 0.98 [0.79-1.22], P = 0.878). Findings were similar in analyses using longer lags and adjusted for constipation/depression. Consumption of other dairy products was not associated with PD. Reverse causation is unlikely to explain the association of pure milk intake with increased PD incidence in women. There was a U-shaped relation for added milk, possibly explained by caffeine intake, and no association for other dairy products. Further studies are warranted to elucidate the underlying mechanisms.

## Introduction

Parkinson's disease (PD) is a common neurodegenerative disease due to the loss of dopaminergic neurons in the *substantia nigra pars compacta* [1]. The etiology of PD involves combined effects of ageing, genetic predisposition, and environmental factors [2]. A growing body of evidence suggests that diet may play a role in the development of PD [3].

Among dietary factors, the role of dairy products has been examined in seven cohort studies with inconsistent findings [4-10]. In a meta-analysis of 5 studies (1,083 PD patients; 3 US studies, one from Finland, one from Greece) [11], consumption of dairy products was associated with increased PD risk overall (pooled RR highest vs. lowest category = 1.40, 95% confidence interval [CI] = 1.20-1.63) and in men (RR = 1.66, 95% CI = 1.29-2.14), but not in women (RR = 1.15, 95% CI = 0.85-1.56); however, only 3 studies were available in women (362 PD patients). This association was mainly explained by milk intake, while there was no significant association for butter, cheese, or fermented milk intake [9-11]. PD risk increased by 17% for every 200g/day increment in milk consumption [11].

Reverse causation refers to situations in which the undiagnosed outcome leads to changes in exposures [12], and represents a key issue for the interpretation of the relation between diet and PD [13]. Non-motor symptoms (e.g., constipation, anxiety, depression, sleep disorders) can be present several years prior to PD diagnosis [14, 15]. Constipation may prompt patients to change their diet before PD is diagnosed. It has also been hypothesized that alpha-lactalbumin, one of the main protein components of milk, may have beneficial effects on mood and sleep, and that patients may drink milk during the prodromal phase to improve depressive symptoms or sleep disorders [16]. Hence, cohort studies with a long follow-up and a large number of incident PD patients are needed to rule out reverse causation by performing lagged analyses or adjusting for premotor symptoms. While some of the previous cohort studies excluded PD cases over the first 2 [6], 3 [10], 4 [9], 5 [7], and 6y [4] of the follow-up, longer lags would be necessary to rule out reverse causation given the long prodromal phase of PD in some patients.

We investigated the association between consumption of milk and other dairy products with PD incidence in a large prospective cohort of French women with a 25y follow-up, while considering the potential for reverse causation.

## Methods

### E3N cohort study

The E3N study (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Éducation Nationale, MGEN) is an ongoing French prospective cohort that recruited in 1990 98,995 women born in 1925-1950 who were enrolled in a French national health insurance plan covering mostly teachers [17]. Information on lifestyle and health is collected approximately every 2y through self-administered questionnaires (from Q1 in 1990 to Q11 in 2014, the last questionnaire used for the present analyses). The average
response rate for each questionnaire is ~ 80%, and less than 3% of the participants are lost to follow-up since 1990. Detailed data on outpatient reimbursements of health expenditures, including drug claims, are provided by MGEN since January 1, 2004. Causes of death are available until 2014.

The study protocol was approved by the French National Commission for Computerized Data and Individual Freedom (*Commission Nationale Informatique et Libertés*), and all participants signed informed consent. The protocol is registered at clinicaltrials.gov (NCT03285230).

## Parkinson's disease case ascertainment

The detailed protocol to ascertain PD cases has been described elsewhere [18]. Briefly, all potential cases were identified through self-reported diagnoses of PD/parkinsonism in questionnaires, antiparkinsonian drug claims from the MGEN databases until December 2018, and death certificates. Potential PD patients were contacted by mail to confirm the diagnosis. For participants who confirmed a diagnosis of PD or parkinsonism and for those who could not be contacted, we obtained medical records from their neurologists or general practitioners (GP) and asked them to fill a standardized questionnaire (year of PD onset/diagnosis, cardinal motor signs and other neurologic symptoms, use of neuroleptics, treatment, responsiveness to treatment, diagnosis). Medical records enabled an expert panel to adjudicate PD status (definite, probable, possible, no PD) [19]. Only definite and probable PD cases were retained in the analyses.

For participants without medical records, PD status was adjudicated using a validated algorithm (94% sensitivity, 88% specificity) based on antiparkinsonian drug claims and medical visits [18, 20]. The proportion of PD diagnosis adjudicated using medical records and the algorithm is 62% and 38%, respectively.

We defined year of PD diagnosis as the year of diagnosis according to medical records or, in decreasing order of priority, self-reported year of diagnosis, year of first use of antiparkinsonian drugs, and year of the first questionnaire where PD was self-reported.

We previously showed that PD incidence rates in E3N are in agreement with those observed in women from Western Europe between 1992–2018 according to the Global Burden of Disease [18].

## Assessment of diet and consumption of milk and other dairy products

Dietary intake was assessed using a validated 208-item semi-quantitative dietary questionnaire sent in 1993 (Q3) [21]. Participants were asked to report the frequency of consumption and amount of intakes of 208 food items over the past year on eight occasions throughout the day (breakfast, morning snack, appetizers before lunch, lunch, afternoon snack, appetizers before dinner, dinner, after dinner snack). Portion sizes were assessed using a photo booklet [22]. The validity and reproducibility of this questionnaire has been described elsewhere [21, 23]. Daily intakes of energy (in quartiles), caffeine (in quartiles), and calcium were estimated using food composition databases from the French Information Centre on Food Quality [24].

Daily consumption of dairy products was estimated in milliliters (ml) per day for milk, including pure milk (or with cereals) and milk added to drinks (tea, coffee, chicory), and in grams per day for butter, yogurt, cottage cheese, other cheese, and cream.

We defined a score of adherence to the Mediterranean diet as a 9-unit dietary score based on intake of fruit, vegetables, legumes, cereals, lipids (ratio of monounsaturated fatty acids to saturated fatty acids), fish, dairy products, meat products, and alcohol [25]. The Mediterranean diet score was categorized into approximate tertiles to reflect low (0–3), medium (4, 5), and high (6–9) adherence to the Mediterranean diet [26].

## Covariates

Birth date, region of residence (rural/urban), age at menarche (≤ 11/12–13/≥14y), parity (nulliparous, one child, two children, ≥three children), menopausal status (premenopausal and natural, artificial, or unknown type of menopause), physical activity (metabolic equivalent of task hours per week, MET-h/week, in quartiles), body mass index (BMI, categorized according to the WHO classification: <18.5,18.5–24.9, 25.0–29.9, ≥ 30 kg/m²), and smoking status (never, ex, current) were available at Q3 (1993).
Constipation (no/yes) and history of treated depression (no/yes) were created by combining information collected in Q1 (1990) and Q2 (1992) questionnaires.

**Statistical analysis**

For the present study, we included participants who completed the dietary questionnaire (Q3). We excluded participants with extreme values of the ratio between dietary energy intake and energy requirement (i.e., below the 1st or above the 99th percentiles) and participants who did not complete any follow-up questionnaire after Q3. We also excluded participants with prevalent PD at Q3, PD patients with missing age of diagnosis, and patients with possible PD.

In order to consider the potential for reverse causation, we included an exposure lag of 5y in our main analyses; this cutoff was chosen for main analyses because it is generally considered that loss of dopaminergic neurons in the substantia nigra starts on average 5y before diagnosis[14]. Thus, we excluded women who developed PD over the first 5y of follow-up and those with a follow-up shorter than 5y after Q3.

Baseline characteristics of the study population were described overall, and by quartiles of total (pure and added) milk consumption and PD status.

Hazards ratios (HRs) and 95% CI were estimated from Cox proportional hazards regression models with age as the time scale. Given the 5y-lag, participants were followed since 5y after they filled the dietary questionnaire (Q3, 1993) until PD diagnosis or end of follow-up (maximum of the date of the last questionnaire and last drug reimbursement).

Milk consumption was modelled as a dichotomous variable (yes/no) and as a 5-level categorical variable (according to quartiles of the distribution among drinkers compared to non-drinkers as the reference group). We tested for linear dose-effect relations by including milk consumption as a continuous variable (divided by one standard deviation, SD); we also tested for linear trend among drinkers by including in the same model milk consumption as a linear variable and the dichotomous variable. As some analyses showed evidence of U-shaped relations across quartiles of milk consumption, we used orthogonal polynomial contrasts to test for quadratic trend. The proportional hazards assumption was verified based on Schoenfeld residuals.

We first performed analyses for total milk, and then included pure and added milk in a mutually adjusted model; interactions between pure and added milk intake were tested by including a multiplicative term in the model but were not significant, and were therefore not retained.

Four models were fitted. The first model was adjusted for age (time scale). The second model was adjusted for known PD risk factors, including rural residence [27], smoking [18], parity [28], age at menarche [28], menopausal status [28], physical activity [29], caffeine intake [30], and Mediterranean dietary score [31]. The third model was further adjusted for total energy intake (quartiles). The fourth model was further adjusted for BMI. According to observational and Mendelian randomization studies, milk intake is associated with higher BMI [32], and higher BMI or obesity are associated with lower PD incidence [29, 33]. Therefore, BMI may be in the causal pathway between milk consumption and PD (mediator), and we examined whether adjusting for BMI changed the association between milk intake and PD. Interactions between BMI and milk intake were not significant in any model, and were therefore not retained.

For dairy products other than milk, we estimated the HR for an increase of 1-SD using the same adjustments as described above, except that Model 4 was a multi-adjusted model, including all categories of dairy products, total energy intake, as well as pure and added milk.

Missing values of covariates were coded as specific categories in order to retain the same number of participants in all analyses.

Statistical analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC). Two tailed P-values ≤ 0.05 were considered statistically significant.

**Sensitivity analyses**

Several sensitivity analyses were performed. First, we repeated the analyses using longer lag times of 10, 15 and 20y.
Second, we further adjusted Model 3 for premotor symptoms that may lead to changes in dietary habits (constipation, depression); interactions between constipation/depression and milk intake were not significant in any model, and were therefore not retained.

Third, we examined the association between calcium intake (per 1-SD increase of total, from milk and dairy products, from non-dairy products calcium) and PD incidence using the same adjustment strategy. Previous studies showed an association between dietary calcium and PD incidence that was restricted to calcium intake from dairy products [4, 9].

Fourth, as dairy products intake is included in the definition of the score of adherences to the Mediterranean diet, we repeated the analyses with an alternative definition of the score that does not take dairy intake into account.

# Results

## Study population

Of 74,529 participants who answered the dietary questionnaire at Q3, we excluded 1,499 participants with extreme values of the ratio between dietary energy intake and energy requirement, 316 participants who did not complete follow-up questionnaires after Q3, 40 prevalent PD patients at Q3, 7 PD patients with missing age of diagnosis, and 36 possible PD patients, leaving 72,631 participants of whom 908 developed PD (Supplementary Fig. 1). For our main survival analysis (5y-lag), we further excluded 1026 women with a follow-up shorter than 5y after Q3 and 63 prevalent PD patients, leaving 71,542 women followed up to 20y (mean = 18.8, SD = 3.3), of whom 845 developed PD (incidence rate = 63.0/100,000 person-years). The number of participants available for survival analyses decreased with increasing lags (Supplementary Fig. 1).

Baseline characteristics of the study population, overall and according to total milk consumption are shown in Table 1; 57.2% of the women reported any milk intake (pure milk, 22.8%; added milk, 47.2%); 10.0% women drank pure milk only, 34.4% drank added milk only, and 12.8% drank both. Participants' mean (SD) age was 52.9y (6.7). Compared to women in the lowest quartile, women in the highest quartile of total milk consumption were more often postmenopausal, had more children, had higher physical activity level, were less likely to be ex/current smokers and to consume caffeine, and had lower adherence to Mediterranean diet; no differences were observed for place of residence, age at menarche and BMI.
<table><caption>Table 1
Participant's characteristics at baseline (1993-Q3) overall and according to total milk consumption.</caption><thead><tr><th rowspan="2">Characteristics, N (%)</th><th colspan="5">Total milk consumption (ml/day)</th></tr><tr><th>No</th><th>Q1</th><th>Q2</th><th>Q3</th><th>Q4</th></tr></thead><tbody><tr><td></td><td></td><td colspan="4">&lt; 60</td></tr><tr><td></td><td></td><td colspan="4">60-149</td></tr><tr><td></td><td></td><td colspan="4">150-269</td></tr><tr><td></td><td></td><td colspan="4">≥ 270</td></tr><tr><td>Age (y), M (SD)</td><td>52.9 (6.7)</td><td>52.7 (6.6)</td><td>52.8 (6.6)</td><td>53.0 (6.7)</td><td>53.0 (6.7)</td></tr><tr><td>Place of residence</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Rural</td><td>9,874 (15.0)</td><td>4,352 (15.4)</td><td>1,298 (14.2)</td><td>1,338 (14.0)</td><td>1,356 (15.4)</td></tr><tr><td>Urban</td><td>56,125 (85.0)</td><td>23,916 (84.6)</td><td>7,846 (85.8)</td><td>8,195 (86.0)</td><td>7,474 (84.6)</td></tr><tr><td>Missing</td><td>5543</td><td>2343</td><td>801</td><td>785</td><td>729</td></tr><tr><td>Menopausal status</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Premenopausal</td><td>30,447 (43.0)</td><td>13,144 (43.5)</td><td>4,315 (43.9)</td><td>4,283 (42.0)</td><td>4,026 (42.5)</td></tr><tr><td>Natural menopause</td><td>34,449 (48.7)</td><td>14,536 (48.1)</td><td>4,771 (48.5)</td><td>5,034 (49.3)</td><td>4,681 (49.4)</td></tr><tr><td>Artificial menopause</td><td>5,402 (7.6)</td><td>2,356 (7.8)</td><td>686 (7.0)</td><td>826 (8.1)</td><td>724 (7.6)</td></tr><tr><td>Unknown type of menopause</td><td>463 (0.7)</td><td>213 (0.7)</td><td>68 (0.7)</td><td>65 (0.6)</td><td>41 (0.4)</td></tr><tr><td>Missing</td><td>781</td><td>362</td><td>105</td><td>110</td><td>87</td></tr><tr><td>Parity</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Nulliparous</td><td>8,450 (11.9)</td><td>3,841 (12.6)</td><td>1,247 (12.6)</td><td>1,175 (11.4)</td><td>1,030 (10.8)</td></tr><tr><td>One child</td><td>11,187 (15.7)</td><td>5,111 (16.8)</td><td>1,518 (15.4)</td><td>1,538 (15.0)</td><td>1,456 (15.3)</td></tr><tr><td>Two children</td><td>30,666 (43.2)</td><td>13,191 (43.4)</td><td>4,372 (44.2)</td><td>4,428 (43.1)</td><td>4,002 (42.1)</td></tr><tr><td>≥ Three children</td><td>20,762 (29.2)</td><td>8,232 (27.1)</td><td>2,752 (27.8)</td><td>3,124 (30.4)</td><td>3,007 (31.7)</td></tr><tr><td>Missing</td><td>477</td><td>236</td><td>56</td><td>53</td><td>64</td></tr><tr><td>Age at menarche (y), M (SD)</td><td>12.8 (1.4)</td><td>12.8 (1.4)</td><td>12.8 (1.4)</td><td>12.8 (1.4)</td><td>12.8 (1.4)</td></tr><tr><td>≤ 11</td><td>14,566 (20.8)</td><td>6,339 (21.1)</td><td>2,025 (20.8)</td><td>2,072 (20.5)</td><td>1,878 (20.0)</td></tr><tr><td>12-13</td><td>35,672 (50.9)</td><td>15,136 (50.5)</td><td>4,997 (51.2)</td><td>5,176 (51.2)</td><td>4,857 (51.8)</td></tr><tr><td>≥ 14</td><td>19,886 (28.4)</td><td>8,499 (28.4)</td><td>2,735 (28.0)</td><td>2,863 (28.3)</td><td>2,644 (28.2)</td></tr><tr><td>Missing</td><td>1418</td><td>637</td><td>188</td><td>207</td><td>180</td></tr></tbody><tfoot><tr><td colspan="6">Q, quartile; M, mean; SD, standard deviation, MET, metabolic equivalent of task.</td></tr><tr><td colspan="6">Baseline characteristics are shown for participants available for survival analyses with a 5-year exposure lag.</td></tr></tfoot></table>
<table><thead><tr><th colspan="7">Total milk consumption (ml/day)</th></tr><tr><th></th><th>No</th><th>Q1</th><th>Q2</th><th>Q3</th><th>Q4</th><th></th></tr><tr><th></th><th></th><th>&lt; 60</th><th>60-149</th><th>150-269</th><th>&ge; 270</th><th></th></tr></thead><tbody><tr><td><strong>Smoking</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Never</td><td>38,225<br>(53.5)</td><td>15,997<br>(52.4)</td><td>5,113 (51.5)</td><td>5,466 (53.1)</td><td>5,273<br>(55.3)</td><td>6,376<br>(57.5)</td></tr><tr><td>Ex</td><td>23,531<br>(33.0)</td><td>10,191<br>(33.4)</td><td>3,422 (34.5)</td><td>3,485 (33.8)</td><td>3,042<br>(31.9)</td><td>3,391<br>(30.6)</td></tr><tr><td>Current</td><td>9,651 (13.5)</td><td>4,359 (14.3)</td><td>1,392 (14.0)</td><td>1,346 (13.1)</td><td>1,228<br>(12.9)</td><td>1,326<br>(12.0)</td></tr><tr><td>Missing</td><td>135</td><td>64</td><td>18</td><td>21</td><td>16</td><td>16</td></tr><tr><td><strong>Body mass index (kg/m<sup>2</sup>), M<br>(SD)</strong></td><td>22.9 (3.3)</td><td>22.8 (3.3)</td><td>23.0 (3.3)</td><td>23.2 (3.4)</td><td>23.1 (3.3)</td><td>23.1 (3.4)</td></tr><tr><td>&lt; 18.5</td><td>2,405 (3.4)</td><td>1,204 (3.9)</td><td>312 (3.1)</td><td>311 (3.0)</td><td>262 (2.7)</td><td>316 (2.8)</td></tr><tr><td>18.5-24.9</td><td>54,127<br>(75.7)</td><td>23,297<br>(76.1)</td><td>7,581 (76.2)</td><td>7,650 (74.1)</td><td>7,185<br>(75.2)</td><td>8,414<br>(75.7)</td></tr><tr><td>25.0-29.9</td><td>12,303<br>(17.2)</td><td>5,051 (16.5)</td><td>1,688 (17.0)</td><td>1,915 (18.6)</td><td>1,711<br>(17.9)</td><td>1,938<br>(17.4)</td></tr><tr><td>&ge; 30.0</td><td>2,707 (3.8)</td><td>1,059 (3.5)</td><td>364 (3.7)</td><td>442 (4.3)</td><td>401 (4.2)</td><td>441 (4.0)</td></tr><tr><td><strong>Physical activity (MET-h/week)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 22.8</td><td>17,675<br>(24.9)</td><td>7,835 (25.8)</td><td>2,447 (24.8)</td><td>2,536 (24.7)</td><td>2,297<br>(24.2)</td><td>2,560<br>(23.2)</td></tr><tr><td>22.8-37.9</td><td>17,804<br>(25.0)</td><td>7,605 (25.0)</td><td>2,501 (25.3)</td><td>2,576 (25.1)</td><td>2,416<br>(25.4)</td><td>2,706<br>(24.5)</td></tr><tr><td>38.0-61</td><td>17,855<br>(25.1)</td><td>7,499 (24.7)</td><td>2,549 (25.8)</td><td>2,580 (25.1)</td><td>2,389<br>(25.1)</td><td>2,838<br>(25.7)</td></tr><tr><td>&gt; 61</td><td>17,743<br>(25.0)</td><td>7,447 (24.5)</td><td>2,382 (24.1)</td><td>2,567 (25.0)</td><td>2,406<br>(25.3)</td><td>2,941<br>(26.6)</td></tr><tr><td>Missing</td><td>465</td><td>225</td><td>66</td><td>59</td><td>51</td><td>64</td></tr><tr><td><strong>Caffeine intake (mg/day), M<br>(SD)</strong></td><td>202.1<br>(149.7)</td><td>221.8<br>(161.6)</td><td>206.4<br>(137.1)</td><td>199.2<br>(135.6)</td><td>180.6<br>(131.0)</td><td>165.1<br>(144.3)</td></tr><tr><td>&lt; 93.5</td><td>17,806<br>(24.9)</td><td>6,840 (22.3)</td><td>2,160 (21.7)</td><td>2,181 (21.1)</td><td>2,579<br>(27.0)</td><td>4,046<br>(36.4)</td></tr><tr><td>93.5-174.1</td><td>17,984<br>(25.1)</td><td>6,522 (21.3)</td><td>2,527 (25.4)</td><td>3,056 (29.6)</td><td>2,883<br>(30.2)</td><td>2,996<br>(27.0)</td></tr><tr><td>174.2-271.3</td><td>17,924<br>(25.1)</td><td>8,083 (26.4)</td><td>2,696 (27.1)</td><td>2,759 (26.7)</td><td>2,267<br>(23.7)</td><td>2,119<br>(19.1)</td></tr><tr><td>&gt; 271.4</td><td>17,828<br>(24.9)</td><td>9,166 (29.9)</td><td>2,562 (25.8)</td><td>2,322 (22.5)</td><td>1,830<br>(19.1)</td><td>1,948<br>(17.5)</td></tr><tr><td><strong>Adherence to Mediterranean diet</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&le; 3</td><td>20,967</td><td>7,176 (23.4)</td><td>2,474 (24.9)</td><td>3,052 (29.6)</td><td>3,671</td><td>4,594</td></tr></tbody><tfoot><tr><td colspan="7">Q, quartile; M, mean; SD, standard deviation, MET, metabolic equivalent of task.</td></tr><tr><td colspan="7">Baseline characteristics are shown for participants available for survival analyses with a 5-year exposure lag.</td></tr></tfoot></table>
<table><thead><tr><th colspan="6">Total milk consumption (ml/day)</th></tr><tr><th></th><th>No</th><th>Q1</th><th>Q2</th><th>Q3</th><th>Q4</th></tr></thead><tbody><tr><td></td><td>(29.3)</td><td></td><td></td><td>(38.4)</td><td>(41.4)</td></tr><tr><td>4-5</td><td>32,301<br>(45.1)</td><td>14,059<br>(45.9)</td><td>4,513 (45.4)</td><td>4,712 (45.7)</td><td>4,798<br>(43.2)</td></tr><tr><td>≥ 6</td><td>18,274<br>(25.5)</td><td>9,376 (30.6)</td><td>2,958 (29.7)</td><td>2,554 (24.8)</td><td>1,717<br>(15.5)</td></tr><tr><td>Total energy intake (Kcal/day), M (SD)</td><td>2210.8<br>(560.2)</td><td>2159.6<br>(556.7)</td><td>2178.0<br>(548.4)</td><td>2219.7<br>(552.5)</td><td>2243.0<br>(551.5)</td><td>2345.6<br>(570.2)</td></tr><tr><td>&lt; 1812.6</td><td>17,853<br>(25.0)</td><td>8,682 (28.4)</td><td>2,637 (26.5)</td><td>2,439 (23.6)</td><td>2,175<br>(22.8)</td><td>1,920<br>(17.3)</td></tr><tr><td>1812.6-2156.6</td><td>17,902<br>(25.0)</td><td>7,769 (25.4)</td><td>2,550 (25.6)</td><td>2,642 (25.6)</td><td>2,384<br>(24.9)</td><td>2,557<br>(23.0)</td></tr><tr><td>2156.7-2551.2</td><td>17,893<br>(25.0)</td><td>7,282 (23.8)</td><td>2,474 (24.9)</td><td>2,675 (25.9)</td><td>2,486<br>(26.0)</td><td>2,976<br>(26.8)</td></tr><tr><td>≥ 2551.3</td><td>17,894<br>(25.0)</td><td>6,878 (22.5)</td><td>2,284 (23.0)</td><td>2,562 (24.8)</td><td>2,514<br>(26.3)</td><td>3,656<br>(32.9)</td></tr><tr><td colspan="6"><strong>Constipation</strong></td></tr><tr><td>No</td><td>53,499<br>(75.4)</td><td>22,715<br>(74.9)</td><td>7,520 (76.2)</td><td>7,771 (75.9)</td><td>7,222<br>(76.2)</td><td>8,271<br>(75.1)</td></tr><tr><td>Yes</td><td>17,453<br>(24.6)</td><td>7,628 (25.1)</td><td>2,353 (23.8)</td><td>2,470 (24.1)</td><td>2,256<br>(23.8)</td><td>2,746<br>(24.9)</td></tr><tr><td>Missing</td><td>590</td><td>268</td><td>72</td><td>77</td><td>81</td><td>92</td></tr><tr><td colspan="6"><strong>Depression</strong></td></tr><tr><td>No</td><td>56,148<br>(78.5)</td><td>24,086<br>(78.7)</td><td>7,838 (78.8)</td><td>8,137 (78.9)</td><td>7,552<br>(79.0)</td><td>8,535<br>(76.8)</td></tr><tr><td>Yes</td><td>15,394<br>(21.5)</td><td>6,525 (21.3)</td><td>2,107 (21.2)</td><td>2,181 (21.1)</td><td>2,007<br>(21.0)</td><td>2,574<br>(23.2)</td></tr><tr><td>Calcium intake, M (SD)</td><td>1066.0<br>(367.0)</td><td>942.2<br>(319.8)</td><td>973.2<br>(301.9)</td><td>1057.8<br>(311.3)</td><td>1154.8<br>(302.7)</td><td>1421.7<br>(389.5)</td></tr><tr><td colspan="6"><strong>Pure milk consumption</strong></td></tr><tr><td>No</td><td>55,259<br>(77.2)</td><td>30,611<br>(100.0)</td><td>6,496 (65.3)</td><td>6,933 (67.2)</td><td>5,860<br>(61.3)</td><td>5,359<br>(48.2)</td></tr><tr><td>Yes</td><td>16,283<br>(22.8)</td><td>0</td><td>3,449 (34.7)</td><td>3,385 (32.8)</td><td>3,699<br>(38.7)</td><td>5,750<br>(51.8)</td></tr><tr><td colspan="6"><strong>Added milk consumption</strong></td></tr><tr><td>No</td><td>37,764<br>(52.8)</td><td>30,611<br>(100.0)</td><td>2,745 (27.6)</td><td>1,501 (14.5)</td><td>1,267<br>(13.3)</td><td>1,640<br>(14.8)</td></tr><tr><td>Yes</td><td>33,778<br>(47.2)</td><td>0</td><td>7,200 (72.4)</td><td>8,817 (85.5)</td><td>8,292<br>(86.7)</td><td>9,469<br>(85.2)</td></tr></tbody></table>

Q, quartile; M, mean; SD, standard deviation, MET, metabolic equivalent of task.

Baseline characteristics are shown for participants available for survival analyses with a 5-year exposure lag.
Participants with incident PD were older, more likely to live in urban areas, were more often postmenopausal, had more often menarche between 12-14y and more children, were less frequently current smokers and less likely to consume caffeine, were less often obese, and had lower physical activity levels at baseline than those who did not develop PD; they tended to have higher adherence to Mediterranean diet (Supplementary Table 1). The frequency of constipation and depression was higher in PD patients than in those who did not develop PD (Supplementary Table 1).

**Association between total milk consumption and PD incidence**

Table 2 shows the association between the consumption of total milk and PD incidence with a 5y exposure lag. In Model 3 adjusted for confounders and total energy intake, PD incidence was lower in total milk drinkers than in non-drinkers, but the difference was not statistically significant (HR = 0.93, 95% CI = 0.81–1.07, P = 0.305). There was no evidence of a linear relationship between total milk consumption and PD incidence overall (P-linear = 0.198). There was a trend towards a U-shaped relationship across quartiles of total milk intake in relation to PD incidence (P-quadratic = 0.0982; Fig. 1), with a significant positive linear trend among drinkers (HR per 1-SD increase = 1.09, 95% CI = 1.01–1.18, P = 0.022). This association remained unchanged after further adjustment for BMI (Model 4). We observed a similar pattern in analyses with longer lags of 10 to 20y (Fig. 1; Supplementary Tables 2–4).
<table><caption>Table 2
Hazards ratios (HRs) and 95% confidence intervals (CIs) of incident Parkinson's disease according to total milk consumption: analyses with a 5-year exposure lag.</caption><thead><tr><th rowspan="2">Total milk<br>consumption<br>(ml/day)</th><th rowspan="2">Cases</th><th rowspan="2">IR</th><th colspan="2">Model 1</th><th colspan="2">Model 2</th><th colspan="2">Model 3</th><th colspan="2">Model 4</th></tr><tr><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td>No</td><td>369</td><td>64.3</td><td>1.00<br>(Reference)</td><td></td><td>1.00<br>(Reference)</td><td></td><td>1.00<br>(Reference)</td><td></td><td>1.00<br>(Reference)</td><td></td></tr><tr><td>Yes</td><td>476</td><td>61.9</td><td>0.94 (0.83-1.08)</td><td>0.414</td><td>0.94 (0.82-1.08)</td><td>0.387</td><td>0.93 (0.81-1.07)</td><td>0.305</td><td>0.93 (0.81-1.07)</td><td>0.320</td></tr><tr><td>No</td><td>369</td><td>64.3</td><td>1.00<br>(Reference)</td><td></td><td>1.00<br>(Reference)</td><td></td><td>1.00<br>(Reference)</td><td></td><td>1.00<br>(Reference)</td><td></td></tr><tr><td>&lt; 60</td><td>108</td><td>57.7</td><td>0.89 (0.72-1.10)</td><td>0.288</td><td>0.89 (0.72-1.10)</td><td>0.288</td><td>0.89 (0.72-1.10)</td><td>0.276</td><td>0.89 (0.72-1.10)</td><td>0.280</td></tr><tr><td>60-149</td><td>114</td><td>58.8</td><td>0.89 (0.72-1.10)</td><td>0.274</td><td>0.88 (0.72-1.09)</td><td>0.248</td><td>0.88 (0.71-1.08)</td><td>0.216</td><td>0.88 (0.71-1.09)</td><td>0.229</td></tr><tr><td>150-269</td><td>112</td><td>62.3</td><td>0.95 (0.77-1.17)</td><td>0.618</td><td>0.95 (0.76-1.17)</td><td>0.616</td><td>0.94 (0.75-1.16)</td><td>0.542</td><td>0.94 (0.76-1.16)</td><td>0.555</td></tr><tr><td>≥ 270</td><td>142</td><td>68.3</td><td>1.05 (0.86-1.27)</td><td>0.657</td><td>1.05 (0.86-1.27)</td><td>0.666</td><td>1.03 (0.84-1.25)</td><td>0.802</td><td>1.03 (0.84-1.26)</td><td>0.792</td></tr><tr><td>P-quadratic<br>trend</td><td></td><td></td><td></td><td>0.105</td><td></td><td>0.096</td><td></td><td>0.098</td><td></td><td>0.104</td></tr><tr><td>per SD<sup>a</sup></td><td>845</td><td>63.0</td><td>1.05 (0.98-1.11)</td><td>0.147</td><td>1.05 (0.98-1.12)</td><td>0.145</td><td>1.05 (0.98-1.12)</td><td>0.198</td><td>1.05 (0.98-1.12)</td><td>0.191</td></tr><tr><td>per SD<br>among<br>drinkers<sup>a</sup></td><td>845</td><td>63.0</td><td>1.10 (1.02-1.18)</td><td>0.016</td><td>1.10 (1.02-1.18)</td><td>0.016</td><td>1.09 (1.01-1.18)</td><td>0.022</td><td>1.09 (1.01-1.18)</td><td>0.022</td></tr></tbody><tfoot><tr><td colspan="11">IR, crude incidence rate of Parkinson's disease per 100,000 person-years; SD, standard deviation.</td></tr><tr><td colspan="11">Hazard ratios (HR) and 95% confidence intervals (CI) calculated using Cox proportional hazards models with age as the time scale.</td></tr><tr><td colspan="11">Model 1: adjusted for age (as the timescale).</td></tr><tr><td colspan="11">Model 2: further adjusted for baseline place of residence (rural/urban), age at menarche (≤ 11/12-13/≥14y), parity (nulliparous/one child/two children/≥three children), smoking (never/ex/current), menopausal status (premenopausal/natural/artificial/unknown type), physical activity (quartiles), caffeine intake (quartiles) and adherence to Mediterranean diet (≤ 3/ 4-5 /≥6).</td></tr><tr><td colspan="11">Model 3: further adjusted for total energy intake (quartiles).</td></tr><tr><td colspan="11">Model 4: further adjusted for BMI (&lt; 18.5,18.5-24.9, 25.0-29.9, ≥ 30.0 kg/m<sup>2</sup>).</td></tr><tr><td colspan="11">a SD, 162 ml/day.</td></tr></tfoot></table>

## Association between pure and added milk consumption and PD incidence

Table 3 shows the association between pure and added milk consumption and PD incidence. In Model 3 adjusted for confounders and total energy intake, pure milk drinkers tended to have higher PD incidence than non-drinkers, but the difference was not statistically significant (HR = 1.16, 95% CI = 0.99-1.36, P = 0.063). PD incidence increased significantly with pure milk consumption (HR per 1-SD increase = 1.08, 95% CI = 1.02-1.14, P-linear = 0.011); PD incidence was 28% higher for women in the top quartile compared to non-drinkers (HR = 1.28, 95% CI = 0.98-1.67). Adjustment for BMI (Model 4) did not change this association.
<table><caption>Table 3
Hazards ratios (HRs) and 95% confidence intervals (CIs) of incident Parkinson's disease according to intake of pure and added milk: analyses with a 5-year exposure lag.</caption><thead><tr><th rowspan="2">Milk consumption (ml/day)</th><th rowspan="2">Cases</th><th rowspan="2">IR</th><th colspan="2">Model 1</th><th colspan="2">Model 2</th><th colspan="2">Model 3</th><th colspan="2">Model 4</th></tr><tr><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td colspan="11"><strong>Pure milk</strong></td></tr><tr><td>No</td><td>637</td><td>61.5</td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td></tr><tr><td>Yes</td><td>208</td><td>67.9</td><td>1.16 (0.99-1.36)</td><td>0.061</td><td>1.17 (1.00-1.37)</td><td>0.052</td><td>1.16 (0.99-1.36)</td><td>0.063</td><td>1.16 (0.99-1.36)</td><td>0.063</td></tr><tr><td>No</td><td>637</td><td>61.5</td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td></tr><tr><td>&lt; 28.6</td><td>48</td><td>60.3</td><td>1.08 (0.80-1.45)</td><td>0.613</td><td>1.09 (0.81-1.46)</td><td>0.575</td><td>1.08 (0.81-1.46)</td><td>0.594</td><td>1.08 (0.81-1.46)</td><td>0.593</td></tr><tr><td>28.6-85.6</td><td>45</td><td>67.8</td><td>1.18 (0.87-1.60)</td><td>0.280</td><td>1.20 (0.89-1.63)</td><td>0.239</td><td>1.20 (0.88-1.62)</td><td>0.246</td><td>1.20 (0.89-1.63)</td><td>0.241</td></tr><tr><td>85.7-200</td><td>56</td><td>66.1</td><td>1.11 (0.85-1.46)</td><td>0.452</td><td>1.11 (0.85-1.46)</td><td>0.445</td><td>1.11 (0.84-1.46)</td><td>0.467</td><td>1.11 (0.84-1.46)</td><td>0.466</td></tr><tr><td>≥ 201.0</td><td>59</td><td>77.9</td><td>1.29 (0.98-1.68)</td><td>0.066</td><td>1.29 (0.99-1.69)</td><td>0.063</td><td>1.28 (0.98-1.67)</td><td>0.073</td><td>1.28 (0.98-1.67)</td><td>0.075</td></tr><tr><td>per SD<sup>a</sup></td><td>845</td><td>63.0</td><td>1.08 (1.02-1.14)</td><td>0.010</td><td>1.08 (1.02-1.15)</td><td>0.009</td><td>1.08 (1.02-1.14)</td><td>0.011</td><td>1.08 (1.02-1.14)</td><td>0.012</td></tr><tr><td>per SD among drinkers<sup>a</sup></td><td>845</td><td>63.0</td><td>1.07 (0.99-1.16)</td><td>0.088</td><td>1.07 (0.99-1.16)</td><td>0.091</td><td>1.07 (0.99-1.16)</td><td>0.096</td><td>1.07 (0.99-1.07)</td><td>0.099</td></tr><tr><td colspan="11"><strong>Added milk</strong></td></tr><tr><td>No</td><td>460</td><td>64.9</td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td></tr><tr><td>Yes</td><td>385</td><td>60.7</td><td>0.89 (0.78-1.02)</td><td>0.096</td><td>0.88 (0.77-1.01)</td><td>0.074</td><td>0.87 (0.76-1.00)</td><td>0.055</td><td>0.88 (0.76-1.01)</td><td>0.059</td></tr><tr><td>No</td><td>460</td><td>64.9</td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td><td>1.00 (Reference)</td><td></td></tr><tr><td>&lt; 52.7</td><td>93</td><td>57.9</td><td>0.85 (0.68-1.06)</td><td>0.143</td><td>0.84 (0.67-1.05)</td><td>0.131</td><td>0.84 (0.67-1.05)</td><td>0.124</td><td>0.84 (0.67-1.05)</td><td>0.127</td></tr><tr><td>52.7-122.8</td><td>84</td><td>53.6</td><td>0.79 (0.62-0.99)</td><td>0.043</td><td>0.78 (0.61-0.98)</td><td>0.034</td><td>0.77 (0.61-0.97)</td><td>0.029</td><td>0.77 (0.61-0.98)</td><td>0.031</td></tr><tr><td>122.9-231.3</td><td>101</td><td>64.2</td><td>0.94 (0.76-1.17)</td><td>0.589</td><td>0.93 (0.75-1.16)</td><td>0.534</td><td>0.92 (0.74-1.15)</td><td>0.466</td><td>0.93 (0.74-1.15)</td><td>0.483</td></tr><tr><td>≥ 231.4</td><td>107</td><td>67.3</td><td>1.00 (0.81-1.24)</td><td>0.993</td><td>1.00 (0.80-1.24)</td><td>0.980</td><td>0.98 (0.79-1.22)</td><td>0.878</td><td>0.99 (0.79-1.22)</td><td>0.893</td></tr><tr><td>P-quadratic trend</td><td></td><td></td><td></td><td>0.040</td><td></td><td>0.033</td><td></td><td>0.034</td><td></td><td>0.035</td></tr><tr><td>per SD<sup>b</sup></td><td>845</td><td>63.0</td><td>1.00 (0.94-1.07)</td><td>0.964</td><td>1.00 (0.94-1.07)</td><td>0.971</td><td>1.00 (0.93-1.07)</td><td>0.923</td><td>1.00 (0.93-1.07)</td><td>0.945</td></tr><tr><td>per SD among drinkers<sup>a</sup></td><td>845</td><td>63.0</td><td>1.06 (0.97-1.44)</td><td>0.198</td><td>1.06 (0.97-1.15)</td><td>0.189</td><td>1.05 (0.97-1.14)</td><td>0.218</td><td>1.05 (0.97-1.14)</td><td>0.216</td></tr></tbody></table>
<table><thead><tr><th rowspan="2">Milk<br>consumption<br>(ml/day)</th><th rowspan="2">Cases</th><th rowspan="2">IR</th><th colspan="2">Model 1</th><th colspan="2">Model 2</th><th colspan="2">Model 3</th><th colspan="2">Model 4</th></tr><tr><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td colspan="11"><strong>Pure milk</strong></td></tr><tr><td colspan="11">drinkers<sup>b</sup></td></tr><tr><td colspan="11">IR, crude incidence rate of Parkinson's disease per 100,000 person-years; SD, standard deviation.</td></tr><tr><td colspan="11">Hazard ratios (HR) and 95% confidence intervals (CI) calculated using Cox proportional hazards models with age as the time scale.</td></tr><tr><td colspan="11">Model 1: adjusted for age (as the timescale).</td></tr><tr><td colspan="11">Model 2: further adjusted for baseline place of residence (rural/urban), age at menarche (≤ 11/12–13/≥14y), parity (nulliparous/one child/two children/≥three children), smoking (never/ex/current), menopausal status (premenopausal/natural/artificial/unknown type), physical activity (quartiles), caffeine intake (quartiles) and adherence to Mediterranean diet (≤ 3/ 4–5 /≥6).</td></tr><tr><td colspan="11">Model 3: further adjusted for total energy intake (quartiles).</td></tr><tr><td colspan="11">Model 4: further adjusted for BMI (< 18.5,18.5–24.9, 25.0–29.9, ≥ 30.0 kg/m<sup>2</sup>).</td></tr><tr><td colspan="11"><sup>a</sup> SD, 85 ml/day.</td></tr><tr><td colspan="11"><sup>b</sup> SD, 136 ml/day.</td></tr></tbody></table>

We observed a similar positive and significant linear trend in analyses lagged by 10, 15, and 20y; women in the top quartile had significantly increased PD incidence compared to non-drinkers in analyses lagged by 10 and 15y (Fig. 1; Supplementary Tables 5–7); HRs were of a similar size in analyses lagged by 20y, but with larger confidence intervals due to a smaller number of PD patients. HRs per 1-SD of pure milk intake were comparable overall and in drinkers.

Added milk drinkers tended to have lower PD incidence than non-drinkers, but the difference was not statistically significant (HR = 0.87, 95% CI = 0.76-1.00, P = 0.055). There was no evidence of a linear relationship between added milk consumption and PD incidence, neither overall nor in drinkers. Alternatively, there was a U-shaped association (P-quadratic = 0.034), with significantly reduced PD incidence in the second quartile compared to non-drinkers (HR = 0.77, 95% CI = 0.61–0.97, P = 0.029) and no difference between the top quartile and non-drinkers (HR = 0.98, 95% CI = 0.79–1.22, P = 0.878; Fig. 1). Results remained unchanged after further adjustment for BMI (Model 4). Findings were similar in analyses lagged by 10, 15 and 20y (Fig. 1; Supplementary Tables 5–7).

## Association between dairy products consumption and PD incidence

Table 4 shows the association between intake of dairy products other than milk (per 1-SD) and PD incidence. There was no significant association of butter, yoghurt, cheese, cream and total dairy products (including milk) with PD incidence.
Table 4

Hazards ratios (HRs) and 95% confidence intervals (CIs) of incident Parkinson's disease for one standard deviation (SD) increment in intake of dairy products other than milk: analyses with a 5-year exposure lag.

<table><thead><tr><th rowspan="2">Dairy products</th><th colspan="2">N cases</th><th colspan="2">Model 1</th><th colspan="2">Model 2</th><th colspan="2">Model 3</th><th colspan="2">Model 4</th></tr><tr><th>(non-consumers/consumers)</th><th>SD (g/d)</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th><th>HR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td>Butter</td><td>185/660</td><td>9.4</td><td>1.03 (0.96-1.10)</td><td>0.395</td><td>1.03 (0.96-1.10)</td><td>0.385</td><td>1.02 (0.95-1.10)</td><td>0.522</td><td>1.03 (0.96-1.10)</td><td>0.468</td></tr><tr><td>Yoghurt</td><td>117/728</td><td>82.9</td><td>0.98 (0.91-1.05)</td><td>0.491</td><td>0.97 (0.91-1.04)</td><td>0.456</td><td>0.97 (0.91-1.04)</td><td>0.425</td><td>0.97 (0.91-1.04)</td><td>0.442</td></tr><tr><td>Cottage cheese</td><td>237/608</td><td>54.2</td><td>0.98 (0.92-1.05)</td><td>0.624</td><td>0.98 (0.92-1.05)</td><td>0.557</td><td>0.98 (0.91-1.05)</td><td>0.529</td><td>0.98 (0.91-1.05)</td><td>0.529</td></tr><tr><td>Other cheese</td><td>41/804</td><td>40.4</td><td>1.03 (0.97-1.11)</td><td>0.320</td><td>1.03 (0.97-1.11)</td><td>0.323</td><td>1.03 (0.95-1.10)</td><td>0.498</td><td>1.03 (0.96-1.11)</td><td>0.452</td></tr><tr><td>Cream</td><td>271/574</td><td>33.6</td><td>1.00 (0.94-1.07)</td><td>0.959</td><td>1.00 (0.94-1.07)</td><td>0.970</td><td>0.99 (0.93-1.06)</td><td>0.845</td><td>1.00 (0.93-1.07)</td><td>0.934</td></tr></tbody><tfoot><tr><td colspan="11">Hazard ratios (HR) and 95% confidence intervals (CI) calculated using Cox proportional hazards models with age as the time scale.</td></tr><tr><td colspan="11">Model 1: adjusted for age (as the timescale).</td></tr><tr><td colspan="11">Model 2: further adjusted for baseline place of residence (rural/urban), age at menarche (≤ 11/12-13/≥14y), parity (nulliparous/one child/two children/≥three children), smoking (never/ex/current), menopausal status (premenopausal/natural/artificial/unknown type), physical activity (quartiles), caffeine intake (quartiles) and adherence to Mediterranean diet (≤ 3/4-5/≥6).</td></tr><tr><td colspan="11">Model 3: further adjusted for total energy intake (quartiles).</td></tr><tr><td colspan="11">Model 4: multi-adjusted model, including all categories of dairy products, total energy intake, as well as pure and added milk.</td></tr></tfoot></table>

## Sensitivity analyses

Supplementary Table 8 shows the association between calcium intake (per 1-SD) and PD incidence. There was no significant association between total calcium intake and PD. In analyses by source of calcium, PD incidence increased with increasing calcium intake from pure milk (HR = 1.08, 95% CI = 1.02-1.15, P = 0.009), while there was no association for other sources.

Results did not change in analyses adjusted for constipation and depression (Supplementary Table 9) and when using an alternative definition of the score of adherences to the Mediterranean diet that did not include dairy products (data not shown).

## Discussion

In this large prospective study of women, PD incidence increased with pure milk consumption, even when milk intake was assessed more than 20y before PD diagnosis. Alternatively, there was a U-shaped relation for added milk consumption, with lower incidence in women with moderate consumption and no difference between non-drinkers and those with the highest consumption. These two different patterns of association explained that PD incidence increased with total milk consumption in analyses restricted to drinkers. There was no association with consumption of dairy products other than milk.

Our finding of increased PD incidence with increasing pure milk intake is in agreement with previous cohort studies showing that milk intake was associated with increased PD risk [4-6, 8-10], with the exception of one study based on a small number of PD patients (N = 85). [7] In a meta-analysis of cohort studies, the association was present in men, without any association in women,
but only few studies performed analyses restricted to women [34]. Our study is by far the largest to have examined the role of milk
consumption in relation to PD in women and suggests that the association between milk and PD is not restricted to men.

We found a different pattern of association for pure and added milk, with evidence in favor of a U-shaped relationship across quartiles of added milk intake. Studies have shown that women tend to drink more frequently coffee with milk than men [35, 36]. Several studies have demonstrated a decreased risk of developing PD with increasing caffeine consumption [30]. A possible explanation for our findings is that caffeine in coffee or tea that is consumed alongside added milk may attenuate the effect of milk for those who add small or moderate quantities of milk, with PD risk increasing again for those who add large amounts of milk. Adjustment for caffeine intake may be insufficient to disentangle the effect of milk and caffeine in this situation. It is also possible that specific compounds from milk and coffee or tea may interact, leading to changes in their bioavailability or chemical properties; for instance, milk proteins can strongly bind to phenolic compounds of coffee and impact their antioxidant properties [37], and it has been shown that addition of milk prevents vascular protective effects of tea [38, 39]. A similar pattern has been identified whereby the deleterious effects on acrylamide on health (e.g., cancer) are counterbalanced by the beneficial effects of coffee, an important source of acrylamide [40, 41]. Our study is the first to have distinguished pure from added milk. It is possible that inconsistent findings from previous studies may be partly explained by the facts that they performed analyses with men and women combined and that did not distinguish pure milk from added milk. Further studies are needed to confirm these findings. If confirmed, previous studies may have underestimated the association between milk intake and PD.

In agreement with previous studies, we did not show any association for dairy products other than milk, such as yogurt, butter, cream, and cheese [10, 34].

Reverse causation represents a key issue for the interpretation of the relation between diet and PD due to non-motor symptoms (e.g., constipation, anxiety, depression, sleep disorders) that could lead to changes in diet [13]. The annual number of medical contacts is also higher in PD patients than in matched controls in the years before diagnosis [42], which could also lead to changes in diet following medical recommendations. Hence cohort studies with a long follow-up and a large number of incident PD patients are needed to rule out reverse causation by performing lagged analyses or adjusting for premotor symptoms. Previous studies used lags shorter than 6y, while we were able to confirm our main findings in analyses with a 20y-lag. In addition, our conclusions remained unchanged in analyses adjusted for non-motor symptoms (constipation, depression).

Mendelian randomization (MR) uses genes associated with an exposure to estimate an association between the exposure and an outcome that, under a set of assumptions, is not biased by unmeasured confounding or reverse causation. Three studies showed a positive association between genetically-predicted milk intake and PD risk using as a genetic instrument the rs4988235 single nucleotide polymorphism in the lactase gene (whose T-allele is associated with lactase persistence and the ability to digest lactose) [32, 43, 44]. MR assumptions are not easily verifiable, and it has been argued that triangulation of evidence allows to obtain more reliable answers to research questions through the integration of results from several different approaches, where each approach has different key sources of potential bias that are unrelated to each other [45]. Altogether, MR and observational studies converge to suggest that high milk intake is associated with increased PD risk.

The mechanisms underlying the association between milk and PD are not well understood. First, calcium is unlikely to be involved because previous studies, as well as the present one, showed that only calcium from milk/dairy products, and not from other sources, was associated with increased PD incidence [4–6]. In addition, MR studies do not support a causal association between calcium levels and PD [46]. Second, milk is associated with reduced serum urate levels [47, 48], and serum urate has been hypothesized to be protective against PD by preventing oxidative damage caused by reactive nitrogen and oxygen species [34]. However, MR studies are not in favor of a causal relation between urate levels and PD [49]. Nevertheless, milk could alter the absorption of other neuroprotective compounds that remain to be identified. Third, dairy products may be contaminated with neurotoxic chemicals, including pesticides, associated with PD risk. In the Honolulu-Asia Aging Study, milk intake was associated with substantia nigra neuronal loss and heptachlor epoxide residues in brains of deceased participants without PD [50]. Pesticide use strongly varies by location and time, and contamination by pesticides is unlikely to fully explain the association between milk and PD because it has now been reported in different countries and periods. Pesticides are also present in dairy products other than milk and are unlikely to explain different findings for milk and other dairy products. In addition, the association between rs4988235 and PD has been reported to be similar in different parts of the world [43]. Nevertheless, other neurotoxic chemicals could be involved. Fourth, MR studies support a causal effect of milk intake on BMI [51]. Therefore, BMI could be a mediator of the
dairy intake-PD association if BMI had an effect on PD (vertical pleiotropy). However, because MR and observational studies suggest that higher BMI is associated with lower PD risk [29, 33], the positive association between milk intake and PD cannot be explained by a negative indirect effect of dairy intake on PD mediated by BMI. Fifth, high milk consumption is associated with oxidative stress and inflammation [52], two mechanisms that play an important role in PD etiology [53, 54]. Finally, other mechanisms could involve changes in microbiota [55] or lipid levels [51] related to milk consumption.

Our study has several strengths. The prospective design ensured the collection of dietary data before PD was diagnosed. Moreover, the long follow-up and large sample size enabled us to perform analyses with lags of increasing size in order to reduce the risk of reverse causation. Our approach to identify PD patients yielded incidence rates similar to those in women from Western Europe, in favor of its validity; this suggests that the selected nature of the cohort did not result in lower PD rates. Our models were adjusted for several potential non-dietary and dietary confounders. Finally, ours is the largest study to have examined the relation between milk and PD incidence in women.

Our study also has limitations. First, although we used a validated dietary questionnaire, we cannot rule out some degree of misclassification of diet. Given that dietary intake was self-reported, we are unable to exclude some degree of measurement error leading to non-differential exposure misclassification that would bias associations towards the null. Second, diet was assessed once, so dietary changes during the follow-up were not taken into account; however, this approach allowed us to perform lagged analyses while retaining a significant number of PD patients in order to rule out reverse causation. Finally, participants are mostly health-conscious women who are not representative of the general population. However, selection into the study did not lead to lower PD incidence rates, since they were similar to expected rates [18]. We acknowledge that analyses restricted to women hampers generalizability to men; however, women represent an understudied population in PD research, in whom additional studies are needed, especially given that few studies on the relation between dairy intake and PD were available among them [56]. Because the study was restricted to French women, it is also possible that these findings are not directly generalizable to other countries, due to differences in dietary patterns and contaminants that may different in other countries.

In conclusion, pure milk consumption was associated with increased PD risk in women, whereas there was a U-shaped relation for added milk and there was no association for other dairy products. Additional studies are warranted to examine the potentially differential roles of pure and added milk, as well as the mechanisms underlying their association with PD.

## Abbreviations

BMI: Body Mass Index

E3N: Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Éducation Nationale.

CI: Confidence Intervals

HR: Hazard ratios

MET: Metabolic equivalent

MGEN: Mutuelle Générale de l'Éducation Nationale

MR: Mendelian randomization

PD: Parkinson's disease

Q: Questionnaire

RR: Relative Risk

SD: Standard Deviation

## Declarations
## Funding

This work was realized with data of the E3N cohort (Inserm) and supported by the Mutuelle Générale de l'Education Nationale (MGEN), Gustave Roussy Institute, and French League against Cancer for the constitution and maintenance of the cohort. This work has benefited from State aid managed by the National Research Agency (ANR) under the program "Investment in the future" bearing the reference ANR-10-COH0-0006 and under the program "Young researcher" bearing the reference ANR-18-CE36-0006-01, as well as a subsidy from the Ministry of Higher Education, Research and Innovation for public service charges bearing the reference N°2102918823, 2103236497, and 2103586016, and from Iresp (Institut de recherche en santé publique). M. Hajji is funded a post-doctoral grant from the France Parkinson patient group.

## Competing interests

M. Hajji is funded a post-doctoral grant from the France Parkinson patient group. F. Artaud, Berta Portugal, Emmanuelle Correia, Francesca Romana Mancini and Nasser Laouali report no competing interests. E. Roze received honorarium for speech from Orkyn, Aguettant, Elivie and for participating in an advisory board from Allergan and Merz-Pharma; additionally, he received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Allergan, Everpharma, Fondation Desmarest, AMADYS, ADCY5.org, Agence Nationale de la Recherche, Société Française de Médecine Esthétique, and Dystonia Medical Research Foundation. A. Elbaz has obtained research grants from the Michael J Fox foundation, Plan Ecophyto (French ministry of agriculture), and France Parkinson.

## Author Contributions

Alexis Elbaz designed and conducted the research. Berta Portugal, Emmanuelle Correia, Nasser Laouali, Pei-Chen Lee, Fanny Artaud, Emmanuel Roze and Francesca Romana Mancini provided essential materials. Mariem Hajji-Louati and Alexis Elbaz performed the statistical analysis and wrote the first version of the manuscript. Mariem Hajji-Louati and Alexis Elbaz had primary responsibility for the final content. All authors read and approved the final manuscript.

## Data availability

Data on E3N cohort participants are available to bona fide researchers for all type of health-related research, which is in the public interest. Data are made available under managed access owing to governance constraints and need to protect the privacy of study participants. Raw data requests should be submitted through the E3N website (www.e3n.fr) or sent to contact@e3n.fr; requests will be reviewed by the E3N Access Committee. Further information is available at https://www.e3n.fr/node/78.

## Acknowledgements

The authors sincerely thank all participants of the E3N study for their continued participation. They are also grateful to all members of the E3N study group. The authors thank the neurologists and general practitioners who contributed medical records for the validation of diagnoses.

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## Figures

<figure><img src="image_3.png" /><figcaption>Figure 1</figcaption></figure>

Hazards ratios (HRs) and 95% confidence intervals (CIs) of incident Parkinson's disease according to milk consumption (total, pure, added): analyses with increasing exposure lags.

Q, quartile. Hazard ratios (HR) and 95% confidence intervals (CI) computed using a Cox proportional hazards models with age as the time scale.

Model adjusted for age (as the timescale), baseline place of residence (rural/urban), age at menarche (≤11/12-13/≥14y), parity (nulliparous/one child/two children/≥three children), smoking (never/ex/current), menopausal status (premenopausal/natural/artificial/unknown type), physical activity (quartiles), caffeine intake (quartiles), adherence to Mediterranean diet (≤3/4-5/≥6) and total energy intake (quartiles).
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