Abstract Details

Title 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

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S1 - New Perspectives on Alzheimer's Therapeutics (2:24 PM-2:36 PM)

Poster/Presentation
Number 008

Objective

To investigate the effects of semaglutide on transcriptomics, proteomics and biomarkers in patients with early Alzheimer’s disease (AD).

Background

Semaglutide is a potential treatment for AD. The phase 3 studies (evoke:NCT04777396 and evoke+:NCT04777409) investigate the efficacy of semaglutide in patients with AD. Preclinical findings suggest semaglutide modulates AD-related biological processes. This clinical study (NCT05891496) aimed to expand the molecular understanding of semaglutide in AD, with its primary results presented here (cerebrospinal fluid [CSF] semaglutide concentrations presented separately [Alford et al.]).

Design/Methods

This interventional, randomized, parallel-group, double-blind, placebo-controlled, multicenter, multinational study evaluated effects of semaglutide in 23 participants with early AD (confirmed amyloid positivity). Participants were randomized (1:1) to semaglutide (up-titrated to 1.0mg) or placebo for 12 weeks. Co-primary endpoints comprised change from baseline in gene expression in CSF and blood samples. Exploratory endpoints included changes in AD-specific biomarkers and post hoc analyses of immune cell gene expression, proteomics and T-cell landscape.

Results

No significant intergroup differences were observed in the number of differentially expressed genes when aggregated across cell types in CSF or blood. Semaglutide significantly reduced biomarker CSF levels of phosphorylated tau181, total tau and neurogranin versus placebo. Post hoc analyses revealed that semaglutide reduced proteins associated with postsynaptic dysfunction and natural killer (NK) cell function, while increasing proteins related to innate immunity and lysosomal function. Semaglutide also modulated immune cell transcriptomes in CSF. NK cells exhibited the largest number of significantly differentially expressed genes, and genes associated with cytotoxic activity were significantly downregulated in NK cells and clonally expanded CD8⁺ T-cells from CSF samples of semaglutide-treated participants.

Conclusions

These data indicate that semaglutide modulates AD pathways and CSF immune cell function in patients with early AD through reduced cytotoxic activity in NK cells and CD8⁺ T-cells, and AD-related biomarker reduction.

Previously presented at CTAD25 and published in JPAD (Frederiksen et al. 2025;DOI:TBC).

Authors/Disclosures
Dylan M. Belmont-Rausch, PhD PRESENTER	Dr. Belmont-Rausch has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Belmont-Rausch has or had stock in Novo Nordisk.Dr. Belmont-Rausch has or had stock in Viking Therapeutics.Dr. Belmont-Rausch has or had stock in Madrigal Pharmaceuticals.
Kristian S. Frederiksen, MD, PhD	Dr. FREDERIKSEN has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer (Nature). Dr. FREDERIKSEN has received research support from AP Møller Fonden. Dr. FREDERIKSEN has received publishing royalties from a publication relating to health care.
Paul Mystkowski, MD (Novo Nordisk)	Dr. Mystkowski has received personal compensation for serving as an employee of Novo Nordisk. Dr. Mystkowski has stock in Novo Nordisk.
Marie Bentsen (Novo Nordisk)	Marie Bentsen has received personal compensation for serving as an employee of Novo Nordisk.
Lisbeth Carstensen, PhD	Ms. Carstensen has received personal compensation for serving as an employee of Novo Nordisk A/S. Ms. Carstensen has stock in Novo Nordisk A/S.
Brian Cutler	Mr. Cutler has nothing to disclose.
Redwan Farooq, MB, BChir, MRCP (Charing Cross Hospital)	Dr. Farooq has nothing to disclose.
Lea Y. Hildebrandt, PhD	Ms. Hildebrandt has received personal compensation for serving as an employee of Novo Nordisk A/S. Ms. Hildebrandt has stock in Novo Nordisk A/S.
Marti Jimenez Mausbach	Marti Jimenez Mausbach has received personal compensation for serving as an employee of Novo Nordisk. Marti Jimenez Mausbach has stock in Novo Nordisk.
Peter Johannsen, MD (Novo Nordisk)	Dr. Johannsen has received personal compensation for serving as an employee of Novo Nordisk. Dr. Johannsen has or had stock in Novo Nordisk.
Gabriel Martino, MD	Dr. Martino has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Martino has stock in Novo Nordisk. Dr. Martino has stock in Roche. Dr. Martino has stock in Eli Lilly.
Joseph Polex-Wolf, PhD	Dr. Polex-Wolf has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Polex-Wolf has stock in Novo Nordisk.
Amaya Zaratiegui, MD	Mrs. Zaratiegui has received personal compensation for serving as an employee of Novo Nordisk A/S. Mrs. Zaratiegui has stock in Novo Nordisk A/S.
Giovanni B. Frisoni	Dr. Frisoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk. Dr. Frisoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novo Nordisk. Dr. Frisoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novo Nordisk. The institution of Dr. Frisoni has received research support from Novo Nordisk.
Kate Attfield, MD, PhD	Dr. Attfield has nothing to disclose.
Lotte B. Knudsen, DMSc	Dr. Knudsen has stock in Novo Nordisk. Dr. Knudsen has received intellectual property interests from a discovery or technology relating to health care.

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