The aim of this exploratory phase 3 study is to investigate the effect of once-weekly subcutaneous semaglutide on central (cerebrospinal fluid [CSF]) and peripheral (blood) inflammation using single-cell transcriptomics (i.e. gene expression in individual cells) to expand the molecular understanding of semaglutide and Alzheimer’s disease (AD).

Evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have therapeutic potential in AD, potentially reducing cognitive decline in people with AD. Real-world evidence has shown decreased dementia risk in patients with type 2 diabetes. Non-clinical data reveal that GLP-1 RAs impact upon neuroinflammation and other biological processes believed to be involved in AD pathophysiology, including effects on central and peripheral immune cells. The safety and efficacy of the once-daily GLP-1 RA semaglutide in early AD (Clinical Dementia Rating global score 0.5–1) is being investigated in two phase 3 trials (evoke [NCT04777396] and evoke+ [NCT04777409]).

An interventional, randomized, parallel-group, double-blind, placebo-controlled, multinational study designed to evaluate the effects of semaglutide versus placebo on central and peripheral inflammation in participants with early AD (NCT05891496). The 24 participants (aged 55–75 years, with established amyloid positivity) were randomized to receive escalating doses of semaglutide or placebo for 12 weeks, followed by a 52-week open-label extension. Central and peripheral inflammation will be investigated using single-cell RNA sequencing, T-cell receptor sequencing and proteomics; AD-related biomarkers (including glial fibrillary acidic protein and phosphorylated tau 217) will link cellular changes to AD pathology proxies. All changes will be assessed after 12 weeks’ treatment.

Study read-out is expected in 2025.