2026
Dr. Oblak proposes to develop a combination therapy that enhances the effectiveness and safety of anti-amyloid antibody treatment by optimizing how microglia respond to amyloid plaques. The project focuses on SHIP1, a key regulator of microglial signaling encoded by the Alzheimer’s disease risk gene INPP5D. While anti-amyloid antibodies such as lecanemab successfully recruit microglia to clear amyloid, they can also trigger excessive inflammation and vascular side effects, including amyloid-related imaging abnormalities (ARIA). Building on strong preliminary data demonstrating that the novel SHIP1 modulator TAD-32 enhances microglial phagocytosis while reducing inflammatory activation, the team will determine whether the sequence in which TAD-32 and lecanemab are administered influences treatment efficacy and safety. The goal is to identify an optimized therapeutic strategy that improves amyloid clearance while minimizing harmful immune responses.
The project combines humanized amyloid mouse models with single-cell and spatial multi-omics to define how treatment order shapes microglial function. In Aim 1, the investigators will compare whether administering lecanemab before TAD-32 or priming microglia with TAD-32 before antibody treatment produces distinct microglial activation states and molecular pathways. Aim 2 will determine which treatment sequence provides the greatest reduction in amyloid pathology while preserving synapses, reducing neurodegeneration, and minimizing vascular inflammation and ARIA-related changes. Aim 3 will integrate transcriptomic, proteomic, and plasma biomarker data to identify the molecular mechanisms underlying successful treatment responses and develop biomarkers that could guide future clinical use. Together, these studies aim to establish a rational combination therapy strategy that could improve the clinical benefits of currently approved anti-amyloid therapies while reducing their associated risks.
Adrian Oblak, Ph.D.
