To measure the concentration of semaglutide in the cerebrospinal fluid (CSF) of patients with early Alzheimer’s disease (AD) after 12 weeks’ treatment.

Semaglutide, a glucagon-like peptide-1 analogue, is a potential treatment for AD. Two randomized, placebo-controlled, phase 3 studies aiming to determine the efficacy and safety of semaglutide in patients with AD are ongoing (evoke [NCT04777396] and evoke⁺ [NCT04777409]). Yet, the mode of action of semaglutide in the nervous system of patients with AD remains unclear. To investigate this, a mechanistic clinical study was conducted (NCT05891496), with semaglutide concentrations in the CSF reported here. Primary results are presented separately (Frederiksen et al.).

This interventional, randomized, parallel-group, double-blind, placebo-controlled, multicenter, multinational study evaluated the effects of semaglutide 1.0 mg versus placebo in patients with early AD (established amyloid positivity). A total of 23 participants (aged 55–75 years) were randomized 1:1 to semaglutide, titrated up to a 1.0 mg dose, or placebo, both administered subcutaneously once weekly for 12 weeks. Concentration of semaglutide in CSF at week 12 was determined using liquid chromatography with tandem mass spectrometry, with a lower limit of quantification (LLOQ) of 67.5 pmol/L. Values below LLOQ were imputed to LLOQ/2.

At week 12, semaglutide concentration levels exceeding the LLOQ were detected in the CSF of 80% (8/10) of participants treated with semaglutide who had CSF samples at this week (mean±standard deviation: 138.6±117.5 pmol/L). Among the two participants with semaglutide concentrations below the LLOQ, one had not been titrated to the full 1.0 mg dose of semaglutide, remaining on a 0.5 mg dose until week 12.

Following 12 weeks of once-weekly subcutaneous semaglutide treatment, the molecule was detectable in the CSF of patients with early AD, providing the first clinical evidence of semaglutide entering the CSF.

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