Is Parkinson’s disease getting older? Demographic and modifiable determinants of age at onset in a large Italian tertiary care cohort

BACKGROUND: Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder, with age at onset (AAO) influenced by genetic and environmental factors. This study aimed to (i) examine temporal trends in PD AAO over the past four decades in a large tertiary care cohort; and (ii) identify independent associations between AAO and a comprehensive set of demographics, cardiovascular/dysmetabolic, lifestyle, and environmental variables. METHODS: We conducted a retrospective observational study of 13,220 individuals diagnosed with PD between 1998 and 2024 at a tertiary referral center in Italy, excluding genetically confirmed cases. Demographic, clinical, and exposure data were collected via questionnaires and interviews. Temporal trends in AAO were analysed in relation to national population ageing. Independent predictors of AAO were identified using multivariable linear regression with cross-validation and multiple imputation. Age- and sex-stratified analyses were also performed. RESULTS: = 0.94), without evidence of additional temporal acceleration (P = 0.852). An earlier AAO was independently associated with a positive family history of PD (β = -2.96, P < 0.0001), pollutant exposure (β = -3.50, P < 0.0001), and higher education level (β = -0.52, P < 0.0001). In contrast, type 2 diabetes mellitus (β = + 2.63, P < 0.0001) and hypertension (β = + 2.24, P < 0.0001) were associated with later onset. Among women, later menarche was linked to delayed AAO (β = + 0.60, P < 0.0001). CONCLUSIONS: While demographic ageing largely accounts for the temporal increase in AAO, modifiable exposures, particularly cardiovascular/dysmetabolic comorbidities and environmental toxins, can significantly influence disease timing, though causal interpretation is limited by accumulation bias.