Multimodal Imaging and Molecular Biomarkers of Co-Pathology Across the Parkinson’s Disease–Dementia with Lewy Bodies Continuum

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are increasingly viewed as regions of a single α-synuclein continuum rather than separate entities. Neuropathology shows that Lewy pathology rarely occurs alone: Alzheimer-type amyloid-β and tau, transactive response DNA-binding protein 43 kDa (TDP-43) inclusions, and cerebrovascular lesions accompany it as the rule rather than the exception, and this co-pathology contributes to the clinical heterogeneity observed across the continuum without mapping onto its clinical divisions. The open problem is no longer whether co-pathology matters but how to measure it in living patients and integrate that information for individualized care. This review is organized by proteinopathy (α-synuclein as the primary lesion, then amyloid-β, tau, and TDP-43/vascular co-pathology) and, within each, follows the modalities that interrogate it: molecular imaging, fluid and tissue biomarkers, and their downstream structural, metabolic, functional, and electrophysiological correlates. No single technique captures the co-pathological landscape. Profiling an individual’s proteinopathy burden in vivo requires a deliberate combination of methods, and precision management of the PD–DLB continuum depends on this multimodal integration.