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How (We Think) Parkinson's disease begins

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 The Authors. 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.

Publication metadata

Author(s): Outeiro TF, Tolosa E

Publication type: Review

Publication status: Published

Journal: Parkinsonism and Related Disorders

Year: 2026

Pages: Epub ahead of print

Online publication date: 18/08/2026

Acceptance date: 15/08/2026

ISSN (print): 1353-8020

ISSN (electronic): 1873-5126

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.parkreldis.2026.108943

DOI: 10.1016/j.parkreldis.2026.108943

PubMed id: 42624662

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