2026 American Academy of Neurology Abstract Website

Kristian Frederiksen¹, Paul Mystkowski², Marie Bentsen³, Dylan Belmont-Rausch³, Lisbeth Carstensen³, Brian Cutler⁴, Redwan Farooq⁴, Lea Hildebrandt³, Marti Jimenez Mausbach³, Peter Johannsen³, Gabriel Martino³, Joseph Polex-Wolf³, Amaya Zaratiegui³, Giovanni Frisoni⁵, Kate Attfield⁴, Lotte Knudsen³
¹Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, ²Novo Nordisk Inc., ³Novo Nordisk, ⁴Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, ⁵Geneva Memory Center, Geneva University Hospitals

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).