Amyloid clearing therapy in dementia with lewy bodies plus alzheimers disease (act DLB+)

The National Institute of Neurological Disorders and Stroke awarded The Leland Stanford Junior University a cooperative agreement of $4,161,896 on August 1, 2026, to conduct a Phase 2 double-blind placebo-controlled clinical trial evaluating the safety and efficacy of donanemab in 400 participants with dementia with Lewy bodies plus Alzheimer's disease (DLB+AD). The award funds the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The trial will assess whether anti-amyloid immunotherapy slows alpha-synuclein seeding and pathology in patients with concurrent DLB and AD, addressing a gap in clinical knowledge since monoclonal antibody treatments approved for mild AD lack safety and efficacy data in this comorbid population. Following the randomized controlled phase, the award supports a 12-month long-term extension observational period to gather additional clinical, biomarker, and imaging data for public use. Stanford will establish a community engagement research and inclusivity committee and involve people with lived experience of DLB+AD to enhance participant recruitment and result generalizability. The performance period extends through June 30, 2033, with work performed in Palo Alto, California.

Abstract

Dementia with lewy bodies (DLB) is the second most common dementia after alzheimer's disease (ad). Ad pathology CO-occurs in over 50% of people with DLB. There are no FDA approved medications for DLB. Recently, monoclonal antibody treatments have been approved for the treatment of mild ad, but there are no data on their safety and efficacy in people with concomitant DLB. Though these drugs are available to providers, any additional benefit or harm to patients with DLB+ad is unknown. Pathology studies have shown that ad and DLB pathology CO-occurrence correlates with higher TAU pathology burden and α-synuclein pathology, raising the possibility that ad and α-synuclein pathology in DLB+ad may interact rather than CO- occur as independent pathologies. If true, then anti-amyloid therapy in people with DLB+ad may slow α- synuclein seeding and pathology. Conversely, amyloid deposition may be incidental and associated with age. Thus, there is equipoise about the potential benefits and an urgent need to systematically study amyloid clearing immunotherapy in DLB+ad. Our proposal in this U01 application will evaluate the safety and efficacy of donanemab in a phase 2 double blind placebo controlled clinical trial of 400 participants with DLB+ad (aims 1-3) with a long-term extension observational period of 12 months to gather additional clinical, biomarker, and imaging data to share with the greater scientific community (aim 4). Because longitudinal data are minimal in this population of biomarker confirmed DLB+ad, we plan to provide this data for public use and establish a community engagement research and inclusivity committee and involve people with lived experience of this disease in shaping this project to enhance participation. By including people representative of the community, the data will enhance the generalizability of results. Discovering new treatments for DLB, specifically whether donenamab and possibly other mabs targeting amyloid therapies are helpful in patients with DLB+ad, will only be possible because of this unique partnership with our team of experts and pharma partner. This therapeutic approach, if successful, will enable a critical step in discovering a new treatment for patients with DLB +ad, where there currently are none.