Re-conceptualizing Parkinson's disease as a lifelong neurobiological trajectory: A framework for prevention.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder. No disease-modifying therapies exist. This review proposes that PD susceptibility begins with epigenetic changes and neuroimmune activity-factors that alter gene expression and immune responses-during the vulnerable PD lifespan. Human evidence is mostly indirect or contradictory. We present this as a testable trajectory, drawing on diverse epidemiologic, experimental, and mechanistic evidence to identify intervention opportunities. We adopt a life-course perspective focused on the brain's plasticity. We focus on critical developmental periods that increase PD vulnerability by rendering dopaminergic neurons more susceptible to damage. Specifically, we examine two key mechanisms: the induction of a pro-inflammatory epigenetic state and mitochondrial dysfunction, frequently triggered by early-life stress, malnutrition, or neurotoxicant exposure. We discuss how these mechanisms can be studied across epidemiologic, experimental, and mechanistic research. Integrated evidence suggests that early adverse exposures may set the stage for higher PD susceptibility. This occurs through epigenetic, neuroimmune programming, and mitochondrial vulnerabilities in dopaminergic systems. In contrast, endogenous neuroplasticity promotes neuroprotection. Long-term physical activity, cognitive training, and enriched environments build strong neurobiological reserves by enhancing neurogenesis, improving synaptic function, and reducing neuroinflammation. A life course perspective shows how factors interact over time to shape neurobiological pathways of vulnerability or resilience to PD. This review synthesizes current mechanistic understanding, identifies preventive strategies, and aims to apply this knowledge to clinical practice and public health policies to reduce the global burden of PD.