Combination Therapy with Semaglutide and Anti-Amyloid Antibodies for Alzheimers Disease - PROJECT SUMMARY/ABSTRACT: Recent FDA accelerated approvals of two anti-amyloid antibody treatments, aducanumab and lecanemab, for early-stage Alzheimer’s disease (AD) provide the first disease-modifying treatments to date, albeit with moderate slowing of cognitive decline, and vascular side effects known as Amyloid Related Imaging Abnormalities due to edema (ARIA-E) or microhemorrhages (ARIA-H) in ~12-35% of patients, especially ApoE4 carriers. While the cause of ARIA is unknown, it has been suggested that Ab clearance by anti-amyloid antibodies is mediated by perivascular drainage which may transiently lead to amyloid accumulating in the blood vessel wall and inducing inflammation, which in turn may increase BBB breakdown, leading to edema or microhemorrhages (Cogswell et al., 2022). Therefore, there is still a large unmet need to improve cognitive efficacy and safety of anti-amyloid immunotherapy. Semaglutide is a Glucagon-Like Peptide-1 Receptor (GLP-1R) agonist, that is FDA approved for the treatment of Type 2 Diabetes Mellitus and obesity, that has strong anti-inflammatory, neuroprotective and pro-vascular health effects. Previous studies have shown beneficial effects of semaglutide in stroke models, diabetes models, LPS models and other disease models. Novo Nordisk, the inventor of semaglutide, is conducting two large Phase 3a clinical trials to test the efficacy of semaglutide in early-stage AD (EVOKE, EVOKE+). While other GLP-1R agonists have shown benefits in AD mouse models, semaglutide, a longer lasting form, has not yet been tested in amyloid AD mouse models. The goal of this project is to determine whether the combination of semaglutide with anti-amyloid antibody therapy will enhance the efficacy beyond that of either treatment alone and attenuate the vascular side effects seen with anti-amyloid antibodies. We propose the following 3 Aims: 1. We hypothesize that semaglutide alone will reduce or reverse inflammation and neurodegeneration and spare cognition in 2 amyloid AD-like mouse models: 5XE4 mice which overexpress human mutant APP/PS1 on a human ApoE4/4 background and APPSAA knockin mice which express physiologic levels of human mutant APP. Mice will be dosed for 12 weeks at 2 ages – pre-plaque and after robust plaque and vascular amyloid accumulation. 2. We hypothesize that combination therapy with semaglutide and anti- amyloid antibodies (murine versions of lecanemab and donanemab) will enhance efficacy compared to either treatment alone in the 5XE4 model which develops abundant plaques, vascular amyloid, inflammation and cognitive decline with aging. 3. We hypothesize that acute semaglutide co-treatment with a murine precursor to bapineuzumab (3D6) shown to cause a high amount of ARIA, will mitigate microhemorrhagic side effects in aged 5XE4 mice. Outcomes include behavioral testing, pathological and biochemical measures, bulk RNAseq and in- depth analysis of transcriptomic changes within cell populations in cortex and hippocampus, and mapping of the mouse data to human data available on the NIH-sponsored AMP-AD portal. If successful, combination trials in humans could be initiated to improve the efficacy and safety of anti-amyloid antibody immunotherapy.
