Objective: To determine whether greater physical activity could modify the negative association of APOE ε4 with longitudinal cognitive changes in early Parkinson’s disease (PD) and to uncover the disease-specific mechanism for explaining such benefits of physical activity.

Methods: We used data from the Parkinson’s Progression Markers Initiative cohort. Because self-reported physical activity, measured by the Physical Activity Scale of the Elderly, was initiated at 2 years after enrollment, this longitudinal analysis was based on assessments performed at years 2, 3, and 4. Cognitive function was measured annually with the Montreal Cognitive Assessment (MoCA). Dopamine transporter (DAT) imaging was performed at years 2 and 4. We assessed the interactive associations between physical activity and the APOE ε4 allele on the longitudinal changes in MoCA scores and striatal DAT activities.

Results: A total of 173 early PD patients (age 63.3±10.0 years; 27% APOE ε4 carriers) were included. The APOE ε4 allele showed a steeper rate of cognitive decline than the non-APOE ε4 allele (estimate -1.33; 95% CI, -2.12 to -0.47; p=0.002). However, there was a significant interaction between physical activity and APOE ε4, such that higher physical activity was related to slower APOE ε4-related cognitive decline (estimate 0.007; 95% CI, 0.003 to 0.011; p=0.001). No significant interaction was found between physical activity and the APOE ε4 allele regarding the change in striatal DAT activities.

Conclusion: Increased physical activity attenuated APOE ε4-related vulnerability to early cognitive decline in PD patients. This protective effect did not appear to be mediated by striatal dopaminergic function.

Classification of evidence: This study provides Class II evidence that increased physical activity was associated with decreased APOE ε4-related early cognitive decline in PD patients.