How (We Think) Parkinson's disease begins.

Parkinson's disease (PD) is a complex heterogeneous neurodegenerative syndrome that is clinically defined. However, how it begins at the molecular and systems level remains unresolved. In this review, we cover selected evidence from neuropathology, imaging, genetics, microbiome and immune studies to examine competing and complementary models of PD initiation. We discuss classical pathology-staging concepts alongside brain-first and periphery-first subtypes, olfactory and gut routes, and threshold and multifocal models that posit parallel central and peripheral involvement. Emerging work on microbiome dysbiosis, endotoxin exposure, environmental toxicants at the nose-brain interface, genetically defined cellular vulnerabilities, and neuroinflammation, suggest these factors may act as potential upstream drivers of alpha-synuclein (aSyn) aggregation and spread. This supports a view in which PD comprises multiple initiating biologies leading to phenotypes that converge on a shared degenerative cascade. Altogether, we posit that understanding how PD starts impacts on our ability for performing biology-based subtyping, prodromal stratification, and for devising mechanism-based early preventive strategies.