Biological effects of pathologies in Lewy body diseases: why timing matters

The emergence of promising biomarkers of α-synuclein Lewy pathology has led to new biological definitions and staging systems for Parkinson's disease and dementia with Lewy bodies. These research frameworks aim to enhance patient selection for studies of biomarkers and disease-modifying therapies. Building on approaches developed for Alzheimer's disease, these new frameworks focus on hallmark neuropathological findings in Lewy body diseases, including abnormal α-synuclein aggregates and neurodegeneration, particularly nigrostriatal dopaminergic loss. Understanding the temporal inter-relationships between Lewy pathology, Alzheimer's disease, and other co-pathologies and symptom manifestation is central to any biological staging system. Neuropathological and in vivo evidence demonstrates substantial temporal and biological heterogeneity in the progression of clinical and pathological events across Lewy body disorders, highlighting knowledge gaps. Staging systems must incorporate this evidence into a nuanced conceptual framework of biological progression. Such revision will be crucial for the appropriate selection of participants and correct timing of targeted interventions in clinical research.