Limitations of current neuroprotective therapies in dementia with Lewy bodies

INTRODUCTION: Dementia with Lewy bodies (DLB) is characterized by progressive cognitive, neuropsychiatric, motor, autonomic, and sleep impairment. Pharmacological interventions developed with disease-modifying intent have entered clinical testing, but their biological rationale and adequacy of evaluation remain uncertain. AREAS COVERED: This structured narrative review appraises pharmacological interventions developed with disease-modifying intent in DLB, focusing on biological rationale, central nervous system (CNS) exposure and target engagement, and whether trials adequately tested neuroprotection or altered clinical progression. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2023 through 29 July 2026, with trial and registry reconciliation continuing through 30 July 2026. Twelve DLB trials evaluated interventions targeting endosomal signaling, kinase-related proteostasis, autophagy-lysosomal function, cellular bioenergetics, oligomer-associated synaptic injury, or neurotrophic signaling. No completed trial established neuroprotection or disease modification. Interpretation was limited by biological heterogeneity, Alzheimer disease co-pathology, incomplete CNS target-engagement evidence, short treatment duration, small samples, and endpoints unable to distinguish symptomatic effects from altered progression. EXPERT OPINION: Future trials should prioritize biomarker-supported diagnosis, prospective co-pathology assessment, demonstrated CNS exposure and target engagement, and longer follow-up combining clinical and mechanism-linked outcomes.