Michele Matarazzo, Per Borghammer, Inas Elsayed, Jennifer G. Goldman, Yue Huang, Katja Lohmann, Per Svenningsson, Lorraine V. Kalia, Daniela Berg, Jeffrey H. Kordower
Parkinson's disease (PD) has been historically defined as a disease of striatal dopamine deficiency secondary to degeneration of dopaminergic neurons in the substantia nigra pars compacta, related to the presence of Lewy bodies and Lewy neurites. Since the discovery of pathogenic variants in the gene encoding α-synuclein, as well as the finding that α-synuclein is a major constituent of Lewy pathology, PD is considered as a prototypical synucleinopathy. However, neuropathological studies consistently show that most people with PD display copathologies, many of which are linked to specific clinical features and outcomes. In this review, we summarize the spectrum and frequency of these co- and multi-pathologies in idiopathic and genetic PD and their impact on disease initiation and progression. Additionally, we also discuss how this multi-pathological landscape may impact biomarker research and the implementation of emerging disease-modifying therapies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.