The neuroprotective promise of semaglutide for Alzheimer’s disease

To the Editor,

The potential role of semaglutide (Ozempic/Wegovy) in preventing Alzheimer’s disease (AD) is an area of growing interest and significant clinical importance. Recent research provides compelling evidence suggesting that this glucagon-like peptide-1 receptor agonist (GLP-1RA), primarily known for its efficacy in type 2 diabetes mellitus (T2DM) and weight management, may offer neuroprotective benefits against AD.

A large-scale study utilizing nationwide real-world data in the US demonstrated a significant association between semaglutide use and a reduced risk of first-time AD diagnosis in T2DM patients. Specifically, semaglutide was linked to a 40% to 70% lower risk of AD diagnosis compared to other antidiabetic medications, with consistent findings across various subgroups including those with and without obesity, different genders, and age groups^[1]. These findings are further supported by observations of significantly lower AD-related medication prescriptions among semaglutide users^[1].

Preclinical evidence has long hinted at semaglutide’s neuroprotective capabilities, suggesting its role in mitigating neurodegeneration and neuroinflammation^[1]. Animal model studies have shown that semaglutide administration is associated with reductions in amyloid-beta plaque deposition and a decrease in neuroinflammation, key pathological hallmarks of AD^[2]. The multimodal mechanisms through which semaglutide may exert its neuroprotective effects include addressing neuroinflammatory, vascular, and other AD-related processes^[3].

Currently, two large-scale, double-blind, placebo-controlled Phase 3 clinical trials, EVOKE and EVOKE +, are underway to further investigate the efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease^[3,4]. These trials are crucial for establishing definitive clinical evidence regarding semaglutide’s potential in delaying or preventing AD onset. The ongoing EVOKE Plus study, for instance, involves a rigorous design with participants receiving either semaglutide or placebo over an extended period, including a cerebrospinal fluid (CSF) sub-study to explore underlying mechanisms^[4].

While these findings are promising and provide real-world evidence for semaglutide’s impact on AD, it is important to acknowledge that observational studies, such as the one conducted by Wang et al^[1], cannot establish definitive causal conclusions^[5].

Nevertheless, the consistent association observed across different studies and the plausible biological mechanisms underscore the urgent need for further randomized clinical trials to fully assess semaglutide’s potential as a therapeutic agent for AD prevention or delay.

Given the growing prevalence and profound societal impact of Alzheimer’s disease, and the absence of a cure, exploring existing medications with potential disease-modifying effects is paramount. Semaglutide, with its established safety profile and emerging evidence of neuroprotective properties, represents a compelling candidate for continued investigation in the fight against AD^[6].

Ethical approval

Not applicable.

Consent

Not all.

Sources of funding

None.

Author contributions

H.H. conceptualization, writing, reviewing and editing.

Conflicts of interest disclosure

The author declares no conflict of interest.

Guarantor

Dr. Hiba Hamdar.

Research registration unique identifying number (UIN)

Not applicable.

Peer and provenance statement

This letter to editor was written according to TITTAN guidelines.

Data availability statement

Not applicable.