Association of dietary niacin and tryptophan intake with the risk of Parkinson´s Disease in the EPIC4ND cohort

Association of dietary niacin and tryptophan intake with the risk of Parkinson´s Disease in the EPIC4ND cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of dietary niacin and tryptophan intake with the risk of Parkinson´s Disease in the EPIC4ND cohort Sina-Isabel Warz, Jutta Dierkes, Rudolf Kaaks, Salvatore Panico, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9436550/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Parkinson's disease (PD) is a disabling and currently incurable neurodegenerative disorder with a rapidly increasing global prevalence. Mitochondrial dysfunction is increasingly implicated in PD, with nicotinamide adenine dinucleotide (NAD) playing a crucial role. Given the growing number of clinical trials evaluating NAD augmentation therapies, we investigated whether dietary intake of niacin and tryptophan, major dietary precursors of NAD, is associated with incident PD. Method: We investigated a sub-cohort of the EPIC study, EPIC4ND, comprising 494 incident PD cases among 130,622 participants. Dietary intakes were estimated by Food Frequency Questionnaires. Cox proportional hazards models, both crude and multivariable-adjusted, assessed potential associations between baseline dietary niacin and tryptophan intake and PD risk in all participants and in sex-stratified analyses. Results: No significant associations were found in the unstratified cohort. In men, lower niacin intake (32 mg/day) (HR Q1vsQ4 1.52, 95% CI 1.04-2.24) in the multivariable model. In women, tryptophan intake in the lowest and third quartiles was associated with a lower risk of PD in the non- and age and center-adjusted models (HR Q1vsQ4 : 0.62, 95% CI: 0.41-0.95; HR Q3vsQ4 : 0.66, 95% CI: 0.44-0.97). Conclusion: In the unstratified cohort, no associations were found. While a higher risk was observed in men with the lowest niacin intake, these findings were not dose-dependent nor robust to different censoring windows and should be interpreted with caution. More research is needed to confirm these findings and investigate potential sex-specific effects. Parkinson’s Disease EPIC Niacin Tryptophan Nutrition Figures Figure 1 Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder and one of the most rapidly growing causes of neurological disability worldwide [ 1 , 2 ]. Pathologically, PD is characterized by degeneration of the dopaminergic neurons of the substantia nigra pars compacta, as well as multiple other neuronal populations across the central and autonomic nervous systems, in the presence of intraneuronal α-synuclein-positive inclusions termed Lewy pathology [ 3 , 4 ]. At molecular level, PD is associated with mitochondrial dysfunction, oxidative stress, aberrant proteostasis, and neuroinflammation [ 3 , 5 , 6 ]. Among these processes, mitochondrial impairment has emerged as an integral driver of neuronal vulnerability in PD [ 7 – 10 ]. Mitochondrial function is critically dependent on nicotinamide adenine dinucleotide (NAD), a key redox cofactor that constantly cycles between its oxidized (NAD + ) and reduced (NADH) states. Furthermore, NAD plays a key role in vital signaling processes, including DNA repair, histone and other protein deacylation, calcium homeostasis, and the generation of second messengers [ 11 ]. It has been shown that NAD levels decline with aging, the strongest risk factor for PD, and this age-dependent decline may be more pronounced in men [ 11 – 13 ]. These findings have stimulated considerable interest in NAD augmentation as a therapeutic strategy. Preclinical research indicates that increasing intracellular NAD levels can improve mitochondrial function and confer neuroprotection in models of aging and neurodegeneration [ 14 ]. Multiple clinical studies in healthy individuals have shown that treatment with oral nicotinamide riboside (NR), a biosynthetic precursor for NAD, increases NAD levels in blood and muscle and decreases levels of circulating inflammatory cytokines [ 15 – 18 ]. Moreover, clinical trials with NR in PD have confirmed target penetration and engagement, demonstrating augmentation of NAD metabolism in the patient's central nervous system, accompanied by changes in cerebral metabolism and signals of clinical improvement [ 19 – 21 ]. In humans, NAD is either produced de novo from the essential amino acid tryptophan via the kynurenine pathway or via salvage pathways from three NAD precursor compounds: nicotinamide, nicotinic acid, and NR [ 22 ]. Nicotinamide and nicotinic acid are collectively referred to as niacin, also known as vitamin B3, while NR is considered a vitamin B3-related precursor rather than a part of the classical niacin group. This precursor contribution is only part of the total NAD pool. Endogenous synthesis, salvage pathways, and tissue-specific regulation maintain NAD levels within relatively narrow ranges, which may limit the impact of habitual dietary intake on systemic NAD availability. Despite growing interventional evidence supporting NAD augmentation in PD, the potential role of habitual dietary intake of NAD precursors in PD risk remains largely unexplored. A retrospective case-control study from 1996 suggested an inverse association between niacin intake and PD [ 23 ], but prospective data are lacking. Given the growing biological rationale linking mitochondrial dysfunction, NAD metabolism, and PD, and emerging clinical interest in NAD augmentation therapies, we aimed to investigate whether dietary intake of niacin and tryptophan is associated with incident PD in the large, multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) cohort for neurodegenerative diseases (EPIC4ND), a sub-cohort of EPIC. Because of PD incidence and NAD biology differ by sex, we also prespecified sex stratified analysis. Participants and Method Study Population The EPIC cohort is a multicenter study across ten European countries, which enrolled 521,323 participants between 1992 and 2000. The cohort study aims to investigate the association between nutrition, lifestyle, cancer, and other chronic diseases. At baseline, comprehensive questionnaires covering environmental and behavioral domains were administered, blood samples were collected, and anthropometry was assessed. Participants are actively and/or passively followed up for incident disease occurrence and deaths, with methods varying by study center. The EPIC study was ethically approved by the International Agency for Research on Cancer (IARC) and the respective participating centers, and written informed consent was obtained from the participants at baseline. Details can be found in the EPIC study populations and data collection reference [ 24 ]. To investigate the relationship between potential risk factors and the development of neurodegenerative diseases, including PD, the EPIC4ND was created as a sub-cohort of EPIC. The EPIC4ND cohort comprises 220,492 participants from 13 of the 23 EPIC centers across seven of the ten EPIC countries. For the present study, we included 130,622 participants from the Netherlands (Utrecht), Germany (Heidelberg), the UK (Cambridge), Spain (Navarra, San Sebastian, Murcia), and Italy (Turin, Varese, Florence, Naples), as participants from Greece (n = 27,514) and Sweden (n = 53,813) had to be excluded due to GDPR issues. The cohorts from Naples and Utrecht encompass females, whereas the other centers include both men and women. A total of 8,543 participants were excluded from the current project due to missing data on dietary variables or an implausible energy intake-to-energy requirement ratio (top and bottom 1%), as shown in Fig. 1 . Parkinson´s Disease Ascertainment A PD template was developed for clinical data collection, based on which a final diagnosis of PD and related disorders were made. Ascertainment consisted of two phases. In Phase I, potential cases were identified through record linkage with at least one local source to minimize the likelihood of false negatives. Hospital discharge registries, drug databases, mortality records, questionnaires, and other sources were used for record linkage. Further in phase II, the potential cases were reviewed by specialists in movement disorders, and a final diagnosis was established. Each diagnosis was labelled with an EPIC4ND label (“definite”, “very likely”, “probable” or “possible”), which depended on the amount and data quality (“poor”, “good” or “excellent”) and the extent of confidence of the neurologist expert (“low”, “medium” and “high”). Details can be found in Gallo et al. [ 25 ]. Dietary Intake Assessments At baseline, dietary data were collected using different assessment methods across the centers and countries. In Italy, the UK, the Netherlands, and Germany, semi-quantitative Food Frequency questionnaires (FFQs) were used to estimate intake frequency and individual portion size, which were self-administered. In Spain, a face-to-face dietary history structured by meals was administered [ 26 ]. Energy, Niacin and tryptophan intake were derived from the U.S. Department of Agriculture (USDA) food composition tables, which report on niacin (mg) and not niacin equivalents, and adapted for EPIC according to established ENDB procedures [ 29 ]. If foods were unavailable in the national databases, nutrient values were approximated using recipe calculations, adjusting for weight changes and vitamin/mineral losses [ 28 ]. Non-dietary variables Standardized and validated questionnaires on education, socio-economic status, occupation, previous illness, disorders or surgeries; tobacco use, alcohol consumption, physical activity, menstrual and reproductive history, use of hormone contraception, and postmenopausal replacement therapy were administered. Height, weight, and waist-hip circumference were measured at baseline in all EPIC4ND centers, expect for UK where they were self-reported, and the body mass index (BMI, in kg/m²) derived thereof [ 24 ]. Statistical analysis All statistical analyses were performed using R software version 4.3.1 (R Project for Statistical Computing, RRID: SCR_001905). Statistical significance was set at α = 0.05. Descriptive statistics were separately calculated for non-PD subjects and incident PD cases, with medians and interquartile ranges (IQRs) for continuous variables and proportions for categorical variables. A Cox proportional hazards model with age as the underlying time scale was used to estimate hazard ratios (HRs) for PD risk, with continuous or categorical niacin and tryptophan intake, in crude, basic, and multivariable-adjusted models. Niacin and tryptophan were modeled as continuous per standard deviation (SD) decrease and as categorical, with sex-specific quartiles based on non-cases, with the fourth quartile used as the reference. The ‘basic’ model was adjusted for age at recruitment in years, sex, and center. Covariates for the multivariable model were selected based on epidemiological risk factors from the literature or their relation to niacin and tryptophan. In addition, the fully adjusted model was adjusted for continuous variables, age at recruitment, BMI, coffee consumption (g/day) and energy intake (kcal/day), and dummy-coded variables sex, highest education level (none, primary school, technical/professional school, secondary school, longer education, or not specified), physical activity (inactive, moderately inactive, moderately active, active, or not specified), smoking history (never, current (1-15cig/day), current (16-25cig/day), current (+ 26 cig/day), former (quit 20 + years), current (pipe, cigar/occasionally), current/former missing or unknown), alcohol consumption (g/d). To reduce potential reverse causation bias, PD cases diagnosed within the first five and ten years after baseline were censored. To account for sex differences in associations, we also ran analyses stratified by sex. Results Baseline Characteristics Selected baseline characteristics of EPIC4ND participants are displayed in Table 1 . The median time from baseline to PD diagnosis was 14 years (IQR, 12-16), with a median age at diagnosis of 76 years. Of the 130,622 participants, 494 (0.4%) were diagnosed with PD during that time, 61 had a definite diagnosis, 205 were very likely to have PD, 73 were probable, and 155 had a possible diagnosis. Sixty-six percent of the EPIC4ND study population were women, reflecting the inclusion of two female-only centers. PD cases nevertheless showed a slight male predominance (55%), in line with the diseases known sex distribution. On average, niacin intake met the recommended intake in men (16–18 mg/d) and women (13–14 mg/d). Similarly, tryptophan intake met the daily recommended intake in men (360–450 mg/d) and women (310–385 mg/d). Associations of niacin and tryptophan intake with risk of PD In the unstratified cohort, neither niacin nor tryptophan intake was associated with Parkinson’s disease (PD) risk in the basic or multivariable-adjusted models (Table 2). This null finding was consistent in both the continuous and quartile-based analyses. For niacin, the continuous model showed no association with PD after adjustment. Crude analyses suggested lower PD risk in the first and second quartiles and per‑SD decrease, but these patterns did not persist after accounting for confounders and did not indicate a dose–response relationship. For tryptophan, crude models showed inverse associations across lower quartiles and per‑SD decrease. After adjusting for age, sex, and center, only the lowest quartile and a one‑SD increase remained statistically significant, but all associations disappeared in the fully adjusted model, and the quartile pattern did not suggest a consistent dose–response. Sensitivity analyses excluding PD cases diagnosed within five and ten years after recruitment showed only minimal changes in HR ( Online Resource, Table S1 and S2). Associations of niacin and tryptophan intake with risk of PD, stratified by sex In the sex-stratified analyses, we observed several associations between niacin and tryptophan intake and PD risk in unadjusted models; however, these patterns did not persist after multivariable adjustment, except for a higher PD risk among men in the lowest niacin quartile (Table 3). Among men, the fully adjusted model showed that those in the lowest niacin quartile had a higher PD risk than those in the highest quartile (HRQ1 vs Q4: 1.52; 95% CI, 1.04–2.24), and no dose–response pattern was observed across the intermediate quartiles. No adjusted associations remained for tryptophan. Among women, lower niacin and tryptophan intake were associated with reduced PD risk in crude analyses, both in the continuous and quartile models. These associations weakened after basic adjustment, and in the multivariable model, there was no evidence of independent associations for either nutrient. Sensitivity analyses excluding PD cases diagnosed within five years of baseline abolished the association between niacin intake and PD risk in men ( Online Resource, Table S3) . However, the association re-emerged when excluding cases diagnosed within ten years, with a higher HR compared to the primary analysis ( Online Resource, Table S4 ). Discussion In this large prospective cohort study, we found no significant association between dietary niacin or tryptophan intake and incident PD in the overall population. However, some sex-specific patterns were observed, but these were not fully consistent and should be interpreted with caution and not be viewed as conclusive. In men, lower niacin intake (< 20 mg/day) was associated with a 52% higher risk of PD in fully adjusted models, whereas no consistent associations were observed in women. For tryptophan, associations observed in unadjusted and minimally adjusted models did not survive after multivariable adjustment. To our knowledge, this is the first prospective cohort study to have investigated the association between dietary niacin and tryptophan and the risk of PD. In contrast to the only case-control study from 1996 [ 23 ] reporting a universal association between niacin intake and PD, our study found an association only in men. This discrepancy may reflect differences in study design, as the case-control study relied on retrospective self-reported intake among already-diagnosed participants. A prospective design generally reduces the risk of reverse causality, which is particularly relevant in PD, due to prodromal symptoms, medication use, and disease-related lifestyle changes influencing dietary habits. Furthermore, a prospective assessment minimizes the risk of differential exposure misclassification. Our data suggest that the role of niacin intake in PD may be sex-dependent, preferentially affecting men and that the preventive effect of niacin at standard diet levels may be limited to certain thresholds. The mechanisms underlying this observation remain unknown and merit preclinical and prospective clinical research. It is possible that the absence of estrogen-mediated neuroprotection in men renders them more susceptible to the metabolic benefits of niacin-derived NAD [ 30 , 31 ], a notion supported by experimental evidence indicating that men exhibit a steeper age-related decline in NAD levels and greater oxidative and metabolic stress than women [ 32 – 34 ]. Although associations between tryptophan intake and PD risk were not statistically significant in fully adjusted models, we observed trends in crude analyses suggesting higher risk with higher intake. One potential mechanistic explanation involves the kynurenine pathway and the hypothesis that a high-tryptophan environment may fuel neuroinflammation via increased flux through the kynurenine pathway, leading to accumulation of neurotoxic metabolites, such as quinolinic acid and 3-hydroxykynurenine.Accumulation of such compounds may outweigh the potential neuroprotective benefits of NAD [ 35 , 36 ] At the same time, it is important to note that dietary tryptophan is strongly regulated by intestinal transport, first-pass liver metabolism, and modulation by the gut microbiota. Therefore, dietary intake may be a relatively crude proxy for the relevant central kynurenine dynamics. Strengths and limitations This study provides new prospective evidence on the association between dietary NAD precursors and risk of PD, conducted in a multinational European cohort with over 130,000 participants and ~ 500 incident PD cases. Case ascertainment was based on validated PD diagnoses following standardized procedures [ 25 ], which strengthens confidence in outcome classification. The long follow-up period (median 13.8 years to diagnosis, with up to 30 years of follow-up) enhances temporal separation between exposure assessment and diagnosis, although it does not fully eliminate concerns about prodromal influences. However, this study also has several limitations. First, although the follow-up is long, the prodromal phase of PD may extend 20 years or more, meaning that reverse causation cannot be fully excluded. The prospective design, exclusion of early follow-up, and large sample size reduce these concerns, but do not eliminate them. Second, dietary data were obtained only from the baseline dietary assessment. Dietary habits likely change over time, including due to early nonmotor symptoms of PD, and we were unable to capture such changes. We also lacked information on supplements containing niacin or tryptophan, limiting the analysis to food-derived nutrient intakes. However, given the period of baseline assessment and the limited focus on niacin at that time, we expect supplement use to be low, and amino acid supplements were not widely consumed [ 37 ]. Third, nutrient intake was based on self-reported FFQs, even though they were validated, and the intake was calculated using the USDA database rather than a European database, which may have led to over- or underestimation. Further, dietary intake data may include outliers that distort results, though we have excluded participants with implausible energy intake. Conclusion These findings suggest no overall association between dietary niacin or tryptophan intake and PD risk. However, lower niacin intake was associated with higher PD risk in men, suggesting possible sex-specific effects. Although this finding was neither dose-dependent across quartiles nor robust to different censoring windows, it should be interpreted with caution. Further studies should focus on stratifying by sex and intake levels of niacin and tryptophan, and should account for dietary supplements. Declarations Financial Support Sina-Isabel Warz received funding for her research stay in Heidelberg from the Medical Faculty at the University of Bergen. C.M. Lill was supported by the Heisenberg program of the DFG (DFG; LI 2654/4-1). The coordination of EPIC-Europe is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark);Ligue Nationale Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale (MGEN), Institut National de la Santé et de la Recherche Médicale (INSERM), French National Research Agency (ANR, reference ANR-10-COHO-0006), French Ministry for Higher Education (subsidy 2102918823, 2103236497, and 103586016) (France); German Cancer Aid, German Cancer Research Center(DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Research, Technology and Space (BMFTR) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Italian Ministry of Health, Italian Ministry of University and Research (MUR), Compagnia di San Paolo (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), the Netherlands Organisation for Health Research and Development (ZonMW), World Cancer Research Fund (WCRF), (The Netherlands); UiT The Arctic University of Norway; Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain); Swedish Cancer Society, Swedish Research Council of Region Skåne and Region Västerbotten (Sweden); Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A29017 to EPICOxford), Medical Research Council (MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPICNorfolk (DOI 10.22025/2019.10.105.00004); MR/Y013662/1 to EPIC-Oxford) (United Kingdom). Previous support has come from “Europe against Cancer” Programme of the European Commission (DG SANCO). Financial Interests The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: The studies involving human participants were reviewed and approved by the IARC Ethics Committee (IEC). Consent to participate: The patients/participants provided their written informed consent to participate in this study. Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of International Agency for Research on Cancer / World Health Organization. Data availability EPIC data and biospecimens are available for inves­tigators who seek to answer important questions on health and disease in the context of research projects that are consistent with the legal and ethical standard practices of the International Agency for Research on Cancer (IARC), WHO, and the EPIC centres. The primary responsibil­ity for accessing the data, obtained in the frame of the present publica­tion, belongs to the EPIC centres that provided them. Access to EPIC data can be requested to the EPIC Steering Committee, as detailed in the EPIC-Europe Access Policy. Author contributions Conceptualization: Sina-Isabel Warz, Jutta Dierkes and Charalampos Tzoulis. Methodology: Sina-Isabel Warz, Verena A. Katzke and Jutta Dierkes. Formal analysis and Writing – original draft: Sina-Isabel Warz. Interpretation: Sina-Isabel Warz, Verena A. Katzke, Jutta Dierkes, Christina M. Lill and Charalampos Tzoulis. Supervision: Jutta Dierkes, Verena A. Katzke and Charalampos Tzoulis. Writing – review and editing: All authors Acknowledgments We thank the participants in the EPIC study and the validating personnel for the first round of Parkinson´s disease cases. We acknowledge the use of data and biological samples from the EPIC-Norfolk cohort, PI Nick Wareham and EPIC-Bilthoven cohort, PI Monique Verschuren. We thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study. References Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson's disease. Lancet Neurol. 2021;20(5):385-97.https://doi.org/10.1016/s1474-4422(21)00030-2 Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-80.https://doi.org/10.1016/s1474-4422(18)30499-x Kalia LV, Lang AE. Parkinson's disease. 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PLoS One. 2012;7(7):e42357.https://doi.org/10.1371/journal.pone.0042357 Vina J, Gambini J, Lopez-Grueso R, Abdelaziz KM, Jove M, Borras C. Females live longer than males: role of oxidative stress. Curr Pharm Des. 2011;17(36):3959-65.https://doi.org/10.2174/138161211798764942 Pathak S, Nadar R, Kim S, Liu K, Govindarajulu M, Cook P, et al. The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies. Int J Mol Sci. 2024;25(2).https://doi.org/10.3390/ijms25020853 Török N, Tanaka M, Vécsei L. Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway. International Journal of Molecular Sciences. 2020;21(24):9338 Skeie G, Braaten T, Hjartåker A, Lentjes M, Amiano P, Jakszyn P, et al. Use of dietary supplements in the European Prospective Investigation into Cancer and Nutrition calibration study. European Journal of Clinical Nutrition. 2009;63(4):S226-S38.https://doi.org/10.1038/ejcn.2009.83 Supplementary Files ESM1.docx Supplemental Material Table S1: Sensitivity analysis of association between niacin and tryptophan and the risk of PD in the EPIC4ND cohort excluding cases diagnosed within the first five years of follow-up Table S2 Sensitivity analysis of association between niacin and tryptophan and the risk of PD in the EPIC4ND cohort excluding cases diagnosed within the first ten years years of follow-up Table S3: Sensitivity analysis of association between niacin and tryptophan and the risk of PD in the EPIC4ND cohort excluding cases within the first five years of follow-up after stratified by sex Table S4: Sensitivity analysis of association between niacin and tryptophan and the risk of in the EPIC4ND cohort excluding cases diagnosed within the first ten years of follow-up, stratified by sex Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9436550","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":632573848,"identity":"e818fd5b-15ff-4036-aec9-f6465fc2d484","order_by":0,"name":"Sina-Isabel 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ONLUS","correspondingAuthor":false,"prefix":"","firstName":"Sabina","middleName":"","lastName":"Sieri","suffix":""},{"id":632573862,"identity":"3e6bb7e7-3845-4fce-99fc-d0a48b0213ab","order_by":14,"name":"Susan Peters","email":"","orcid":"","institution":"Utrecht University: Universiteit Utrecht","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"","lastName":"Peters","suffix":""},{"id":632573863,"identity":"491393ef-c98a-447d-a359-c1d9ab98c01a","order_by":15,"name":"Charalampos Tzoulis","email":"","orcid":"","institution":"University of Bergen: Universitetet i Bergen","correspondingAuthor":false,"prefix":"","firstName":"Charalampos","middleName":"","lastName":"Tzoulis","suffix":""},{"id":632573864,"identity":"0b4b16ee-f8d0-4eff-a073-b644edcfff18","order_by":16,"name":"Christina M. Lill","email":"","orcid":"","institution":"Imperial College London Division of Epidemiology Public Health and Primary Care: Imperial College London School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Christina","middleName":"M.","lastName":"Lill","suffix":""},{"id":632573865,"identity":"ccfc14a1-e315-48d6-a9f9-cd344d98e993","order_by":17,"name":"Verena A. Katzke","email":"","orcid":"https://orcid.org/0000-0002-6509-6555","institution":"German Cancer Research Centre: Deutsches Krebsforschungszentrum","correspondingAuthor":false,"prefix":"","firstName":"Verena","middleName":"A.","lastName":"Katzke","suffix":""}],"badges":[],"createdAt":"2026-04-16 10:05:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9436550/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9436550/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108970719,"identity":"8dcff2e9-626d-408d-b267-f0f96bd9dc10","added_by":"auto","created_at":"2026-05-11 10:18:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45665,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of cohort participants included in the study\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9436550/v1/c77f95948f467d2cc7b6bf91.png"},{"id":108996663,"identity":"df3c1f22-f3ae-4a47-b0ad-f975eec17d9c","added_by":"auto","created_at":"2026-05-11 14:15:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":238116,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9436550/v1/58b32f43-8920-4867-b8e1-692aa0f3beb9.pdf"},{"id":108970720,"identity":"91561684-0491-4ad8-834b-0c862c01ad23","added_by":"auto","created_at":"2026-05-11 10:18:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":44797,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable S1: Sensitivity analysis of association between niacin and tryptophan and the risk of PD in the EPIC4ND cohort excluding cases diagnosed within the first five years of follow-up\u003c/p\u003e\n\u003cp\u003eTable S2 Sensitivity analysis of association between niacin and tryptophan and the risk of PD in the EPIC4ND cohort excluding cases diagnosed within the first ten years years of follow-up\u003c/p\u003e\n\u003cp\u003eTable S3: Sensitivity analysis of association between niacin and tryptophan and the risk of PD in the EPIC4ND cohort excluding cases within the first five years of follow-up after stratified by sex\u003c/p\u003e\n\u003cp\u003eTable S4: Sensitivity analysis of association between niacin and tryptophan and the risk of in the EPIC4ND cohort excluding cases diagnosed within the first ten years of follow-up, stratified by sex\u003c/p\u003e","description":"","filename":"ESM1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9436550/v1/6c63a9f108f0a431fbb2ba6e.docx"}],"financialInterests":"","formattedTitle":"Association of dietary niacin and tryptophan intake with the risk of Parkinson´s Disease in the EPIC4ND cohort","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson’s disease (PD) is the second most common neurodegenerative disorder and one of the most rapidly growing causes of neurological disability worldwide [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. Pathologically, PD is characterized by degeneration of the dopaminergic neurons of the substantia nigra pars compacta, as well as multiple other neuronal populations across the central and autonomic nervous systems, in the presence of intraneuronal α-synuclein-positive inclusions termed Lewy pathology [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. At molecular level, PD is associated with mitochondrial dysfunction, oxidative stress, aberrant proteostasis, and neuroinflammation [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among these processes, mitochondrial impairment has emerged as an integral driver of neuronal vulnerability in PD [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMitochondrial function is critically dependent on nicotinamide adenine dinucleotide (NAD), a key redox cofactor that constantly cycles between its oxidized (NAD\u003csup\u003e+\u003c/sup\u003e) and reduced (NADH) states. Furthermore, NAD plays a key role in vital signaling processes, including DNA repair, histone and other protein deacylation, calcium homeostasis, and the generation of second messengers [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. It has been shown that NAD levels decline with aging, the strongest risk factor for PD, and this age-dependent decline may be more pronounced in men [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings have stimulated considerable interest in NAD augmentation as a therapeutic strategy. Preclinical research indicates that increasing intracellular NAD levels can improve mitochondrial function and confer neuroprotection in models of aging and neurodegeneration [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Multiple clinical studies in healthy individuals have shown that treatment with oral nicotinamide riboside (NR), a biosynthetic precursor for NAD, increases NAD levels in blood and muscle and decreases levels of circulating inflammatory cytokines [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. Moreover, clinical trials with NR in PD have confirmed target penetration and engagement, demonstrating augmentation of NAD metabolism in the patient's central nervous system, accompanied by changes in cerebral metabolism and signals of clinical improvement [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn humans, NAD is either produced de novo from the essential amino acid tryptophan via the kynurenine pathway or via salvage pathways from three NAD precursor compounds: nicotinamide, nicotinic acid, and NR [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. Nicotinamide and nicotinic acid are collectively referred to as niacin, also known as vitamin B3, while NR is considered a vitamin B3-related precursor rather than a part of the classical niacin group. This precursor contribution is only part of the total NAD pool. Endogenous synthesis, salvage pathways, and tissue-specific regulation maintain NAD levels within relatively narrow ranges, which may limit the impact of habitual dietary intake on systemic NAD availability. Despite growing interventional evidence supporting NAD augmentation in PD, the potential role of habitual dietary intake of NAD precursors in PD risk remains largely unexplored. A retrospective case-control study from 1996 suggested an inverse association between niacin intake and PD [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], but prospective data are lacking.\u003c/p\u003e \u003cp\u003eGiven the growing biological rationale linking mitochondrial dysfunction, NAD metabolism, and PD, and emerging clinical interest in NAD augmentation therapies, we aimed to investigate whether dietary intake of niacin and tryptophan is associated with incident PD in the large, multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) cohort for neurodegenerative diseases (EPIC4ND), a sub-cohort of EPIC. Because of PD incidence and NAD biology differ by sex, we also prespecified sex stratified analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e "},{"header":"Participants and Method","content":"\u003cp\u003eStudy Population\u003c/p\u003e\u003cp\u003eThe EPIC cohort is a multicenter study across ten European countries, which enrolled 521,323 participants between 1992 and 2000. The cohort study aims to investigate the association between nutrition, lifestyle, cancer, and other chronic diseases. At baseline, comprehensive questionnaires covering environmental and behavioral domains were administered, blood samples were collected, and anthropometry was assessed. Participants are actively and/or passively followed up for incident disease occurrence and deaths, with methods varying by study center. The EPIC study was ethically approved by the International Agency for Research on Cancer (IARC) and the respective participating centers, and written informed consent was obtained from the participants at baseline. Details can be found in the EPIC study populations and data collection reference [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo investigate the relationship between potential risk factors and the development of neurodegenerative diseases, including PD, the EPIC4ND was created as a sub-cohort of EPIC. The EPIC4ND cohort comprises 220,492 participants from 13 of the 23 EPIC centers across seven of the ten EPIC countries. For the present study, we included 130,622 participants from the Netherlands (Utrecht), Germany (Heidelberg), the UK (Cambridge), Spain (Navarra, San Sebastian, Murcia), and Italy (Turin, Varese, Florence, Naples), as participants from Greece (n = 27,514) and Sweden (n = 53,813) had to be excluded due to GDPR issues. The cohorts from Naples and Utrecht encompass females, whereas the other centers include both men and women. A total of 8,543 participants were excluded from the current project due to missing data on dietary variables or an implausible energy intake-to-energy requirement ratio (top and bottom 1%), as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eParkinson´s Disease Ascertainment\u003c/p\u003e\u003cp\u003eA PD template was developed for clinical data collection, based on which a final diagnosis of PD and related disorders were made. Ascertainment consisted of two phases. In Phase I, potential cases were identified through record linkage with at least one local source to minimize the likelihood of false negatives. Hospital discharge registries, drug databases, mortality records, questionnaires, and other sources were used for record linkage. Further in phase II, the potential cases were reviewed by specialists in movement disorders, and a final diagnosis was established. Each diagnosis was labelled with an EPIC4ND label (“definite”, “very likely”, “probable” or “possible”), which depended on the amount and data quality (“poor”, “good” or “excellent”) and the extent of confidence of the neurologist expert (“low”, “medium” and “high”). Details can be found in Gallo et al. [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDietary Intake Assessments\u003c/p\u003e\u003cp\u003eAt baseline, dietary data were collected using different assessment methods across the centers and countries. In Italy, the UK, the Netherlands, and Germany, semi-quantitative Food Frequency questionnaires (FFQs) were used to estimate intake frequency and individual portion size, which were self-administered. In Spain, a face-to-face dietary history structured by meals was administered [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEnergy, Niacin and tryptophan intake were derived from the U.S. Department of Agriculture (USDA) food composition tables, which report on niacin (mg) and not niacin equivalents, and adapted for EPIC according to established ENDB procedures [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. If foods were unavailable in the national databases, nutrient values were approximated using recipe calculations, adjusting for weight changes and vitamin/mineral losses [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNon-dietary variables\u003c/p\u003e\u003cp\u003eStandardized and validated questionnaires on education, socio-economic status, occupation, previous illness, disorders or surgeries; tobacco use, alcohol consumption, physical activity, menstrual and reproductive history, use of hormone contraception, and postmenopausal replacement therapy were administered. Height, weight, and waist-hip circumference were measured at baseline in all EPIC4ND centers, expect for UK where they were self-reported, and the body mass index (BMI, in kg/m²) derived thereof [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using R software version 4.3.1 (R Project for Statistical Computing, RRID: SCR_001905). Statistical significance was set at \u003cem\u003eα\u003c/em\u003e = 0.05. Descriptive statistics were separately calculated for non-PD subjects and incident PD cases, with medians and interquartile ranges (IQRs) for continuous variables and proportions for categorical variables.\u003c/p\u003e\u003cp\u003eA Cox proportional hazards model with age as the underlying time scale was used to estimate hazard ratios (HRs) for PD risk, with continuous or categorical niacin and tryptophan intake, in crude, basic, and multivariable-adjusted models. Niacin and tryptophan were modeled as continuous per standard deviation (SD) decrease and as categorical, with sex-specific quartiles based on non-cases, with the fourth quartile used as the reference.\u003c/p\u003e\u003cp\u003eThe ‘basic’ model was adjusted for age at recruitment in years, sex, and center. Covariates for the multivariable model were selected based on epidemiological risk factors from the literature or their relation to niacin and tryptophan. In addition, the fully adjusted model was adjusted for continuous variables, age at recruitment, BMI, coffee consumption (g/day) and energy intake (kcal/day), and dummy-coded variables sex, highest education level (none, primary school, technical/professional school, secondary school, longer education, or not specified), physical activity (inactive, moderately inactive, moderately active, active, or not specified), smoking history (never, current (1-15cig/day), current (16-25cig/day), current (+ 26 cig/day), former (quit \u0026lt; = 10years), former (quit 11-20years), former (quit \u0026gt; 20 + years), current (pipe, cigar/occasionally), current/former missing or unknown), alcohol consumption (g/d).\u003c/p\u003e\u003cp\u003eTo reduce potential reverse causation bias, PD cases diagnosed within the first five and ten years after baseline were censored. To account for sex differences in associations, we also ran analyses stratified by sex.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eBaseline Characteristics\u003c/h2\u003e\n\u003cp\u003eSelected baseline characteristics of EPIC4ND participants are displayed in \u003cstrong\u003eTable 1\u003c/strong\u003e. The median time from baseline to PD diagnosis was 14 years (IQR, 12-16), with a median age at diagnosis of 76 years. Of the 130,622 participants, 494 (0.4%) were diagnosed with PD during that time, 61 had a definite diagnosis, 205 were very likely to have PD, 73 were probable, and 155 had a possible diagnosis. Sixty-six percent of the EPIC4ND study population were women, reflecting the inclusion of two female-only centers. PD cases nevertheless showed a slight male predominance (55%), in line with the diseases known sex distribution. On average, niacin intake met the recommended intake in men (16\u0026ndash;18 mg/d) and women (13\u0026ndash;14 mg/d). Similarly, tryptophan intake met the daily recommended intake in men (360\u0026ndash;450 mg/d) and women (310\u0026ndash;385 mg/d).\u003c/p\u003e\n\u003ch2\u003eAssociations of niacin and tryptophan intake with risk of PD\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eIn the unstratified cohort, neither niacin nor tryptophan intake was associated with Parkinson\u0026rsquo;s disease (PD) risk in the basic or multivariable-adjusted models (Table 2). This null finding was consistent in both the continuous and quartile-based analyses.\u003c/p\u003e\n\u003cp\u003eFor niacin, the continuous model showed no association with PD after adjustment. Crude analyses suggested lower PD risk in the first and second quartiles and per‑SD decrease, but these patterns did not persist after accounting for confounders and did not indicate a dose\u0026ndash;response relationship.\u003c/p\u003e\n\u003cp\u003eFor tryptophan, crude models showed inverse associations across lower quartiles and per‑SD decrease. After adjusting for age, sex, and center, only the lowest quartile and a one‑SD increase remained statistically significant, but all associations disappeared in the fully adjusted model, and the quartile pattern did not suggest a consistent dose\u0026ndash;response.\u003c/p\u003e\n\u003cp\u003eSensitivity analyses excluding PD cases diagnosed within five and ten years after recruitment showed only minimal changes in HR (\u003cstrong\u003eOnline Resource, Table S1 and S2).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAssociations of niacin and tryptophan intake with risk of PD, stratified by sex\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eIn the sex-stratified analyses, we observed several associations between niacin and tryptophan intake and PD risk in unadjusted models; however, these patterns did not persist after multivariable adjustment, except for a higher PD risk among men in the lowest niacin quartile (Table 3).\u003c/p\u003e\n\u003cp\u003eAmong men, the fully adjusted model showed that those in the lowest niacin quartile had a higher PD risk than those in the highest quartile (HRQ1 vs Q4: 1.52; 95% CI, 1.04\u0026ndash;2.24), and no dose\u0026ndash;response pattern was observed across the intermediate quartiles. No adjusted associations remained for tryptophan.\u003c/p\u003e\n\u003cp\u003eAmong women, lower niacin and tryptophan intake were associated with reduced PD risk in crude analyses, both in the continuous and quartile models. These associations weakened after basic adjustment, and in the multivariable model, there was no evidence of independent associations for either nutrient.\u003c/p\u003e\n\u003cp\u003eSensitivity analyses excluding PD cases diagnosed within five years of baseline abolished the association between niacin intake and PD risk in men (\u003cstrong\u003eOnline Resource, Table S3)\u003c/strong\u003e. However, the association re-emerged when excluding cases diagnosed within ten years, with a higher HR compared to the primary analysis (\u003cstrong\u003eOnline Resource, Table S4\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this large prospective cohort study, we found no significant association between dietary niacin or tryptophan intake and incident PD in the overall population. However, some sex-specific patterns were observed, but these were not fully consistent and should be interpreted with caution and not be viewed as conclusive. In men, lower niacin intake (\u0026lt;\u0026thinsp;20 mg/day) was associated with a 52% higher risk of PD in fully adjusted models, whereas no consistent associations were observed in women. For tryptophan, associations observed in unadjusted and minimally adjusted models did not survive after multivariable adjustment.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first prospective cohort study to have investigated the association between dietary niacin and tryptophan and the risk of PD. In contrast to the only case-control study from 1996 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] reporting a universal association between niacin intake and PD, our study found an association only in men. This discrepancy may reflect differences in study design, as the case-control study relied on retrospective self-reported intake among already-diagnosed participants. A prospective design generally reduces the risk of reverse causality, which is particularly relevant in PD, due to prodromal symptoms, medication use, and disease-related lifestyle changes influencing dietary habits. Furthermore, a prospective assessment minimizes the risk of differential exposure misclassification.\u003c/p\u003e \u003cp\u003eOur data suggest that the role of niacin intake in PD may be sex-dependent, preferentially affecting men and that the preventive effect of niacin at standard diet levels may be limited to certain thresholds. The mechanisms underlying this observation remain unknown and merit preclinical and prospective clinical research. It is possible that the absence of estrogen-mediated neuroprotection in men renders them more susceptible to the metabolic benefits of niacin-derived NAD [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], a notion supported by experimental evidence indicating that men exhibit a steeper age-related decline in NAD levels and greater oxidative and metabolic stress than women [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough associations between tryptophan intake and PD risk were not statistically significant in fully adjusted models, we observed trends in crude analyses suggesting higher risk with higher intake. One potential mechanistic explanation involves the kynurenine pathway and the hypothesis that a high-tryptophan environment may fuel neuroinflammation via increased flux through the kynurenine pathway, leading to accumulation of neurotoxic metabolites, such as quinolinic acid and 3-hydroxykynurenine.Accumulation of such compounds may outweigh the potential neuroprotective benefits of NAD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] At the same time, it is important to note that dietary tryptophan is strongly regulated by intestinal transport, first-pass liver metabolism, and modulation by the gut microbiota. Therefore, dietary intake may be a relatively crude proxy for the relevant central kynurenine dynamics.\u003c/p\u003e \u003cp\u003eStrengths and limitations\u003c/p\u003e \u003cp\u003eThis study provides new prospective evidence on the association between dietary NAD precursors and risk of PD, conducted in a multinational European cohort with over 130,000 participants and ~\u0026thinsp;500 incident PD cases. Case ascertainment was based on validated PD diagnoses following standardized procedures [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], which strengthens confidence in outcome classification. The long follow-up period (median 13.8 years to diagnosis, with up to 30 years of follow-up) enhances temporal separation between exposure assessment and diagnosis, although it does not fully eliminate concerns about prodromal influences.\u003c/p\u003e \u003cp\u003eHowever, this study also has several limitations. First, although the follow-up is long, the prodromal phase of PD may extend 20 years or more, meaning that reverse causation cannot be fully excluded. The prospective design, exclusion of early follow-up, and large sample size reduce these concerns, but do not eliminate them.\u003c/p\u003e \u003cp\u003eSecond, dietary data were obtained only from the baseline dietary assessment. Dietary habits likely change over time, including due to early nonmotor symptoms of PD, and we were unable to capture such changes. We also lacked information on supplements containing niacin or tryptophan, limiting the analysis to food-derived nutrient intakes. However, given the period of baseline assessment and the limited focus on niacin at that time, we expect supplement use to be low, and amino acid supplements were not widely consumed [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThird, nutrient intake was based on self-reported FFQs, even though they were validated, and the intake was calculated using the USDA database rather than a European database, which may have led to over- or underestimation. Further, dietary intake data may include outliers that distort results, though we have excluded participants with implausible energy intake.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThese findings suggest no overall association between dietary niacin or tryptophan intake and PD risk. However, lower niacin intake was associated with higher PD risk in men, suggesting possible sex-specific effects. Although this finding was neither dose-dependent across quartiles nor robust to different censoring windows, it should be interpreted with caution. Further studies should focus on stratifying by sex and intake levels of niacin and tryptophan, and should account for dietary supplements.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial Support\u0026nbsp;\u003c/strong\u003eSina-Isabel Warz received funding for her research stay in Heidelberg from the Medical Faculty at the University of Bergen. C.M. Lill was supported by the Heisenberg program of the DFG (DFG; LI 2654/4-1).\u003c/p\u003e\n\u003cp\u003eThe coordination of EPIC-Europe is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark);Ligue Nationale Contre le \u0026nbsp;Cancer, Institut Gustave Roussy, Mutuelle G\u0026eacute;n\u0026eacute;rale de l\u0026rsquo;Education Nationale (MGEN), Institut National \u0026nbsp;de la Sant\u0026eacute; et de la Recherche M\u0026eacute;dicale (INSERM), French National Research Agency (ANR, reference \u0026nbsp;ANR-10-COHO-0006), French Ministry for Higher Education (subsidy 2102918823, 2103236497, and 103586016) (France); German Cancer Aid, German Cancer Research Center(DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Research, Technology and Space (BMFTR) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Italian Ministry of Health, Italian Ministry of University and Research (MUR), Compagnia di San Paolo (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), the Netherlands Organisation for Health Research and Development (ZonMW), World Cancer Research Fund (WCRF), (The Netherlands); UiT The Arctic University of Norway; Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional \u0026nbsp;Governments of Andaluc\u0026iacute;a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain); Swedish Cancer Society, Swedish Research Council of Region Sk\u0026aring;ne and Region V\u0026auml;sterbotten (Sweden); Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A29017 to EPICOxford), Medical Research Council (MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPICNorfolk (DOI 10.22025/2019.10.105.00004); MR/Y013662/1 to EPIC-Oxford) (United Kingdom). Previous support has come from \u0026ldquo;Europe against Cancer\u0026rdquo; Programme of the European Commission (DG SANCO).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Interests\u003c/strong\u003e The authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u0026nbsp;\u003c/strong\u003eThe studies involving human participants were reviewed and approved by the IARC Ethics Committee (IEC).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u0026nbsp;\u003c/strong\u003eThe patients/participants provided their written informed consent to participate in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclaimer:\u0026nbsp;\u003c/strong\u003eWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of International Agency for Research on Cancer / World Health Organization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eEPIC data and biospecimens are available for inves\u0026shy;tigators who seek to answer important questions on health and disease in the context of research projects that are consistent with the legal and ethical standard practices of the International Agency for Research on Cancer (IARC), WHO, and the EPIC centres. The primary responsibil\u0026shy;ity for accessing the data, obtained in the frame of the present publica\u0026shy;tion, belongs to the EPIC centres that provided them. Access to EPIC data can be requested to the EPIC Steering Committee, as detailed in the EPIC-Europe Access Policy.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eConceptualization: Sina-Isabel Warz, Jutta Dierkes and Charalampos Tzoulis. Methodology: Sina-Isabel Warz, Verena A. Katzke and Jutta Dierkes. Formal analysis and Writing \u0026ndash; original draft: Sina-Isabel Warz. Interpretation: Sina-Isabel Warz, Verena A. Katzke, Jutta Dierkes, Christina M. Lill and Charalampos Tzoulis. Supervision: Jutta Dierkes, Verena A. Katzke and Charalampos Tzoulis. Writing \u0026ndash; review and editing: All authors\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eWe thank the participants in the EPIC study and the validating personnel for the first round of Parkinson\u0026acute;s disease cases. We acknowledge the use of data and biological samples from the EPIC-Norfolk cohort, PI Nick Wareham and EPIC-Bilthoven cohort, PI Monique Verschuren. We thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson\u0026apos;s disease. 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European Journal of Clinical Nutrition. 2009;63(4):S226-S38.https://doi.org/10.1038/ejcn.2009.83\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s Disease, EPIC, Niacin, Tryptophan, Nutrition","lastPublishedDoi":"10.21203/rs.3.rs-9436550/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9436550/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Parkinson's disease (PD) is a disabling and currently incurable neurodegenerative disorder with a rapidly increasing global prevalence. Mitochondrial dysfunction is increasingly implicated in PD, with nicotinamide adenine dinucleotide (NAD) playing a crucial role. Given the growing number of clinical trials evaluating NAD augmentation therapies, we investigated whether dietary intake of niacin and tryptophan, major dietary precursors of NAD, is associated with incident PD.\u003c/p\u003e\n\u003cp\u003eMethod: We investigated a sub-cohort of the EPIC study, EPIC4ND, comprising 494 incident PD cases among 130,622 participants. Dietary intakes were estimated by Food Frequency Questionnaires. Cox proportional hazards models, both crude and multivariable-adjusted, assessed potential associations between baseline dietary niacin and tryptophan intake and PD risk in all participants and in sex-stratified analyses.\u003c/p\u003e\n\u003cp\u003eResults: No significant associations were found in the unstratified cohort. In men, lower niacin intake (\u0026lt;20 mg/day) was associated with an increased risk of PD compared to higher intake (\u0026gt;32 mg/day) (HR\u003csub\u003eQ1vsQ4\u003c/sub\u003e 1.52, 95% CI 1.04-2.24) in the multivariable model. In women, tryptophan intake in the lowest and third quartiles was associated with a lower risk of PD in the non- and age and center-adjusted models (HR\u003csub\u003eQ1vsQ4\u003c/sub\u003e: 0.62, 95% CI: 0.41-0.95; HR\u003csub\u003eQ3vsQ4\u003c/sub\u003e: 0.66, 95% CI: 0.44-0.97).\u003c/p\u003e\n\u003cp\u003eConclusion: In the unstratified cohort, no associations were found. While a higher risk was observed in men with the lowest niacin intake, these findings were not dose-dependent nor robust to different censoring windows and should be interpreted with caution. More research is needed to confirm these findings and investigate potential sex-specific effects.\u003c/p\u003e","manuscriptTitle":"Association of dietary niacin and tryptophan intake with the risk of Parkinson´s Disease in the EPIC4ND cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 10:18:34","doi":"10.21203/rs.3.rs-9436550/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9b2aed7a-b62f-456b-8d26-3db173f08a18","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Reject without review","date":"2026-05-11T08:52:47+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-30T15:46:21+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T14:14:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 10:18:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9436550","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9436550","identity":"rs-9436550","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}