Semaglutide Modulates CSF Immune Cell Activity and Reduces AD Tau Biomarkers in Phase 3 Substudy

A mechanistic substudy embedded within the phase 3 EVOKE program found that 12 weeks of treatment with semaglutide (Ozempic; Novo Nordisk), a glucagon-like peptide-1 (GLP-1) receptor agonist, significantly reduced cerebrospinal fluid (CSF) levels of phosphorylated tau181, total tau, and neurogranin compared to placebo in patients with early Alzheimer disease (AD), while also modulating immune cell transcriptomes in the CSF—findings that offer a window into the drug's mechanistic footprint in the central nervous system.¹ The data were presented at the 2026 American Academy of Neurology (AAN) Annual Meeting, held April 18 to 22 in Chicago, Illinois.

The study enrolled 23 participants with amyloid-confirmed early AD, who were randomly assigned in a 1:1 ratio to receive semaglutide or placebo for 12 weeks.¹ The study’s coprimary end points—changes from baseline in gene expression across cell types in CSF and blood—were not met, with no statistically significant intergroup differences observed. Although, semaglutide did significantly reduce CSF levels of phosphorylated tau181, total tau, and neurogranin versus placebo. Post hoc proteomic analyses also showed reductions in proteins associated with postsynaptic dysfunction and natural killer (NK) cell function, alongside increases in proteins related to innate immunity and lysosomal function. Immunophenotyping of CSF revealed that NK cells exhibited the greatest number of differentially expressed genes, with cytotoxic gene expression significantly downregulated in both NK cells and clonally expanded CD8+ T cells in the semaglutide group.

These findings add onto previously reported data from the EVOKE (NCT04777396) and EVOKE+ (NCT04777409) clinical trials. Last year, data from these studies were presented at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) conference, held December 1-4 in San Diego, California.² All told, treatment with the weight loss medication did not result in significantly slowed disease progression, despite patients showing improvements in plasma high sensitivity C-reactive protein (hs-CRP) and AD-relevant biomarkers. Encouragingly, safety and tolerability for oral semaglutide in participants with early AD was consistent with studies in other indications.

“While the data presented at CTAD was disappointing, pursuing this type of high-risk, high-reward research into Alzheimer’s pathobiology is essential to deepening our understanding of the disease and continuing to advance the science,” Howard Fillit, MD, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), said in a December 2025 statement.³ “Even negative trials move the field forward as they still teach us something. If we look to the early antiamyloid studies, which were also negative, they offered critical lessons that informed later trials and ultimately helped bring drugs like Leqembi and Kisunla to market. As we dig further into the data, there is much we can learn, including exploring the potential of GLP-1 drugs as a preventive therapy, which may still hold promise.”

In the trials, there were some signs of success, as semaglutide-treated patients demonstrated lowered AD-relevant biomarkers in cerebrospinal fluid. These included AD markers like pTau181 (treatment ratio, 0.92), pTau217 (0.91), npT181 (0.90), and npTau205 (0.91), as well as other markers of neuroinflammation (YKL-40; 0.93) and neurodegeneration (total tau: 0.93; neurogranin: 0.92).

At CTAD, NeurologyLive^® also sat down with Aaron Burstein, PharmD, head of search and evaluation at the Alzheimer's Drug Discovery Foundation, to discuss clinical AD data presented at the meeting. In the conversation, Burstein discussed recent advances in diagnostics and therapies in the field of AD that were highlighted during the meeting, as well as discussed a shift from traditional amyloid PET imaging and cerebrospinal fluid analysis to blood-based biomarkers capable of detecting amyloid and tau proteins.

"I’ll acknowledge that I am not a clinician, and so I don’t manage patient care,” Burstein told NeurologyLive. “But in my discussions within our organization, and even some of the data that I’ve seen [at CTAD 2025], I think it’s showing the importance of understanding the patient’s biomarker."

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REFERENCES
1. Frederiksen K, Mystkowski P, Bentsen M, et al. Effects of semaglutide on Alzheimer’s disease-related biological processes: results from a biofluid biomarker and multiomics immunophenotyping phase 3 study in patients with early Alzheimer’s disease after 12 weeks of treatment. Presented at: 2026 American Academy of Neurology Annual Meeting; April 18–22, 2026; Chicago, IL.
2. Cummings J, Johannsen P, Atri A, et al. evoke and evoke+: Two phase 3 randomised placebo-controlled trials of semaglutide in participants with early-stage Alzheimer’s disease (NCT04777396 and NCT04777409). Presented at: 2025 CTAD Conference; December 1-4; San Diego, CA.
3. New Data from Semaglutide Trials Provides Critical Insights to Guide Next Generation of Therapies Targeting Alzheimer’s Pathobiology. News release. Alzheimer’s Drug Discovery Foundation. December 4, 2025. Accessed December 4, 2025. https://www.alzdiscovery.org/news-room/announcements/new-data-from-semaglutide-trials-provides-critical-insights-to-guide-next-generation-of-therapies-targeting-alzheimers-pathobiology