Background

Semaglutide is a synthetic, long-acting analog of glucagon-like peptide-1, used to treat diabetes. Ozempic^TM is a once-per-week injection formulation, while Rybelsus^TM is is a daily pill. Rybelsus^TM was approved by the U.S. FDA in September 2019 as the first GLP-1 analog that does not need to be injected. It is also approved for use in Japan and the European Union.

GLP-1 is a hormone produced in the gut that activates receptors in the gut, liver, and pancreas to stimulate insulin release, and restore insulin sensitivity (for review, see Knudsen and Lau, 2019). In some people with Alzheimer’s disease, there is evidence for insulin resistance in the brain, providing a rationale for testing semaglutide as a potential therapeutic for AD. In addition, GLP-1 receptors expressed in the brain are involved in learning and neuroprotection (During et al., 2003). Other GLP-1 analogs, for example exendin-4, liraglutide, and lixisenatide, are currently in clinical trials for Parkinson’s or Alzheimer’s diseases.

There are several published preclinical studies for semaglutide in Alzheimer’s. A cell-based study implicated the drug in enhanced autophagy and reduced apoptosis (Chang et al., 2020). In a 3xTg mouse model of AD, semaglutide improved brain glucose uptake, improved learning and memory, and decreased Aβ plaques and tau tangles (Wang et al., 2023). An independent study using the APP/PS1 model reported similar positive results (Zhang et al., 2024). In contrast, other researchers found that although semaglutide caused weight loss and improved glucose tolerance in 5XFAD and APP/PS1 mice, it did not change amyloid plaque density, inflammation markers, or cognitive function (Germano et al., 2024).The drug is reported to be active in rodent models of Parkinson’s (Zhang et al., 2019; Zhang et al., 2018) and stroke (Yang et al., 2019). In rats or mice, semaglutide did not readily cross the blood brain barrier, although it did appear in the hypothalamus (Salameh et al., 2020; Lee et al., 2023). It is thought to act by lowering peripheral blood sugar, and reducing peripheral and central inflammation. It is suggested to act by lowering peripheral blood sugar, and reducing peripheral and central inflammation (e.g. De Paiva et al., 2024). In APP/PS1 mice, intranasal application did not result in brain entry (Abdulhameed et al., 2024).

Findings

In September 2018, researchers at the University of Oslo registered a Phase 2 trial of semaglutide for Parkinson’s disease. The study aims to enroll 120 newly diagnosed PD patients who will receive 1 mg drug or placebo by weekly injection for two years, followed by an additional two years of open-label administration. Per the registration entry, the trial has not begun recruiting.

In 2020, a Phase 2a trial of semaglutide tablets in 60 people with mild Alzheimer's disease received funding from the Alzheimer's Association's Part the Cloud program; no such trial is registered.

On December 16, 2020, Novo Nordisk announced it would begin development of semaglutide in people with early Alzheimer’s disease (see press release). Beginning in the first half of 2021, the Phase 3a program planned to enroll 3,700 people for a planned two-year course of a once-daily 14 mg semaglutide pill or placebo. The company said the decision was based on evaluation of GLP-1 data from preclinical models, real-world studies involving patient registry and insurance claims databases, and post hoc analysis of data from three large cardiovascular outcome trials of semaglutide and liraglutide. That analysis reportedly found a 53 percent reduction in the risk of developing dementia in people with Type 2 diabetes who took either GLP-1 agonist compared to placebo (see Nørgaard et al., 2022). An independent study using electronic health records found that, in people with Type 2 diabetes, those using semaglutide reduced their risk of an AD diagnosis by 40 to 70 percent, compared those using insulin or other diabetes drugs (Wang et al., 2024).

In May 2021, the company began two Phase 3 trials, each enrolling 1,840 people with mild cognitive impairment or mild dementia due to Alzheimer’s disease, confirmed by amyloid PET or CSF Aβ42. The trials are identical, except that one allows participants with subcortical vascular disease, and one does not. The sole primary outcome is change in CDR-SB. Secondary outcomes include other standard cognitive and functional scales, as well as cardiovascular events and stroke. The trials include a one-year extension. By mid-2023, both studies were fully enrolled and running at more than 400 centers worldwide, to be completed in October 2026.

In August 2022 enrollment began on a study evaluating the effect of semaglutide on tau accumulation in the brains of people who are amyloid-positive, with or without diabetes, and with no or mild cognitive impairment (Koychev et al., 2024). The study at the University of Oxford in the U.K. will treat 88 participants with a dose of 14 mg once daily oral semaglutide or placebo for one year, against a primary outcome of change in tau-PET. Secondary outcomes address potential mechanism of semaglutide action, including brain inflammation measured by TSPO-PET and GFAP protein levels, and blood biomarkers of Aβ, phosphorylated tau and neurofilament light. Other outcomes are hippocampal volume by MRI, cognition, quality of life, physical activity, and circadian rhythms. Supported by Novo Nordisk, the trial is expected to finish in March 2026.

In June 2023, Novo Nordisk began a small study on how semaglutide affects the immune system in people with Alzheimer’s. Twenty-four participants will receive 12 weekly subcutaneous injections with a pen injector, titrating to a final dose of 1 mg per week. After a 12-week placebo-controlled period, all participants will receive 1 mg/week for one year open-label. The primary endpoint is changes in gene expression in immune cells in blood and CSF, assessed by single-cell RNA sequencing. Secondaries are safety, and semaglutide concentration in blood. Study completion is anticipated in September 2025.

In January 2024, investigators at Sheba Medical Center in Israel began a study of the combination of semaglutide pills and intranasal insulin in people with mild cognitive impairment and metabolic syndrome. The trial will enroll 80 participants in four groups, who will receive each treatment with appropriate placebo, both treatments, or placebo only for one year. Primary outcomes are cognitive function, cerebral blood flow, and brain glucose uptake. Completion is expected in December 2027. The trial protocol is published (Davidy et al., 2024).

For details on these semaglutide trials, see clinicaltrials.gov and the WHO registry.