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BackgroundCombined effects of multiple risk factors on incident late-onset Parkinson's disease (PD; LOPD) remain poorly characterized.ObjectiveThe objective of this study was to quantify the impact of joint risk exposures and estimate the contribution of potentially modifiable factors to incident LOPD risk.MethodsIn this prospective cohort study, 311,261 UK Biobank participants aged ≥50 years and free of PD at baseline were followed for up to 15 years. During follow-up, 2769 individuals developed incident LOPD. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) for 65 candidate risk factors. Combinations of two (pairs) or three (triplets) risk factors were evaluated for additive interaction. Population-attributable fractions (PAFs) were estimated for potentially modifiable risk factors.ResultsEighteen risk factors (mean HR, 1.43) were independently associated with incident LOPD and subsequently evaluated as joint exposures. Thirteen pairs (mean HR, 2.00) and 14 triplets (mean HR, 4.21) demonstrated significant positive additive interaction and larger effect sizes than individual factors alone. A limited set of modifiable factors-loneliness, low handgrip strength, epilepsy, hearing loss, and diabetes-within the highest-risk pairs (HR range, 2.55-2.93) and triplets (HR range, 5.28-12.24) emerged as major contributors to elevated LOPD risk. Removing modifiable exposures from additive pairs and triplets was associated with reduction in mean HRs of 30% and 49%, respectively (P = 0.001). At the population level, removal of modifiable risk factors accounted for an estimated 34.4% reduction in LOPD incidence.ConclusionsIntegrating traditional single-factor approaches with high-risk additive joint exposure profiles may improve risk stratification and inform targeted prevention strategies for incident PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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