Why Lewy Pathology Must Be a Critical Consideration in the Design of Clinical Trials for Neurodegenerative Diseases: Dr. Jon B. Toledo Explains

Lewy body disease includes Parkinson’s disease and dementia with Lewy bodies, characterized by Lewy pathology (LP) in the brain and nerves. LP, made up of α-synuclein-containing inclusions such as Lewy bodies and Lewy neurites, plays a key role in cognitive, motor and neuropsychiatric issues in aging populations. LP often occurs alongside other neurodegenerative pathologies, especially Alzheimer’s disease neuropathologic changes (ADNC), resulting in a complex interaction of overlapping biological processes.

Dr. Jon B. Toledo is an assistant professor of neurology who researches Lewy body disease, Alzheimer’s disease, and the intersection of neurodegenerative and non-neurodegenerative conditions. We sat down with him to shed light on why Lewy pathology must be a crucial consideration when designing clinical trials for neurodegenerative diseases.

Q: Why must Lewy pathology be a critical consideration when designing clinical trials for neurodegenerative diseases?

Dr. Toledo: Clinical trials for neurodegenerative diseases can be improved by specifically accounting for the presence and extent of LP. The high prevalence of LP as a co-pathology in several neurodegenerative diseases, including Alzheimer’s disease, has a significant impact on the clinical presentation, disease progression and treatment responses. Accounting for LP is therefore critical when designing clinical trials because the presence, distribution and severity of this pathology can profoundly influence both the natural history of disease and the response to therapeutic interventions.

Q: Is it challenging to recruit a homogenous patient population for clinical trials for neurodegenerative diseases?

Dr. Toledo: It is challenging to recruit a homogeneous patient population as the presence of co-pathologies leads to marked clinical and pathological heterogeneity. One enormous challenge in clinical trials for neurodegenerative diseases is disease heterogeneity, which complicates the development of early diagnostic tools and the understanding of disease prognosis. Another consideration is that excluding participants with common comorbidities might raise questions about the generalizability of treatments.

Q. What can be done to enhance clinical trial efficiency?

Dr. Toledo: To enhance trial efficiency, clinical trials can utilize enrichment strategies based on genetic, molecular or imaging biomarkers to categorize patients based on their pathology. The incorporation of imaging tests into routine examinations of patients with neurodegeneration can help build a more comprehensive database for retrospective studies. For targeted therapies, identifying the presence or absence of Alzheimer’s and Lewy pathology is vital for accurately assessing target engagement and treatment outcomes. Additional biomarkers are needed for other tauopathies and TDP-43 proteinopathies. Accounting for all neurodegenerative diagnoses can identify which patients are most likely to benefit from a specific targeted therapy and help with patient selection, stratification, and outcome interpretation.

Q: What role do biomarkers play in clinical trials for neurodegenerative diseases?

Dr. Toledo: Current clinical trials evaluating disease-modifying treatments confirm the presence of the targeted pathology using biomarkers. However, these trials usually do not account for the presence of co-pathologies using biomarkers to detect co-pathologies. People with cognitive deficits often present multiple neurodegenerative conditions, which can affect progression and treatment response. Evaluating co-pathologies in future clinical trials will be crucial because of their impact on clinical presentation, cognitive performance, disease progression and biomarkers.

For further information on neurodegenerative diseases and Dr. Toledo’s work on this topic, please see the following papers:

Jon B. Toledo, David P Salmon, Melissa J Armstrong, Douglas Galasko. Cognitive decline profiles associated with Lewy pathology in the context of Alzheimer’s disease neuropathologic change. Alzheimer’s Res Ther. 2024 Dec 20;16(1):270. doi: 10.1186/s13195-024-01628-z.

Di Wang, Nicolas Honnorat, Jon B Toledo, Karl Li, Sokratis Charisis, Tanweer Rashid, Anoop Benet Nirmala, Sachintha Ransara Brandigampala, Mariam Mojtabai, Sudha Seshadri, Mohamad Habes. Deep learning reveals pathology-confirmed neuroimaging signatures in Alzheimer’s, vascular and Lewy body dementias. Brain. 2025 Jun 3;148(6):1963-1977. doi: 10.1093/brain/awae388.

Jon B Toledo, Carla Abdelnour, Rimona S Weil, Daniel Ferreira, Federico Rodriguez-Porcel, Andrea Pilotto, Kathryn A Wyman-Chick, Michel J Grothe, Joseph P M Kane, Angela Taylor, Arvid Rongve, Sonja Scholz, James B Leverenz, Bradley F Boeve, Dag Aarsland, Ian G McKeith, Simon Lewis, Iracema Leroi, John P Taylor; ISTAART Lewy body dementias Trial Methods Working Group. Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design. Alzheimer's Dement. 2023 Jan;19(1):318-332. doi: 10.1002/alz.12814.