Oral Semaglutide in Patients With Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and a major global healthcare burden. Currently, the disease is only treated symptomatically and an effective disease-modifying therapy (DMT) that may slow the disease progression, and prevent cognitive and functional deterioration, is yet to emerge. Glucagon-like peptide-1 (GLP-1) analogues are being studied to treat neurodegenerative diseases, due to evidence of their neuroprotective effects in mouse models of AD. This study investigates Semaglutide, a modified human GLP-1RA in Alzheimer's disease to understand the mechanism of the disease. The primary objective of this study is to evaluate the safety and tolerability of oral semaglutide in individuals with mild AD. Moreover, the secondary objective of the study is to evaluate the change in synaptic density using PET before and after treatment with semaglutide.

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Key information

Conditions

Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies

Age range

50 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Capable of giving and capacity to give informed consent.
An individual who can act as a reliable study partner with regular contact
Diagnosis of Alzheimer's disease according to the revised NIA-AA criteria
Age from 50 years
Mini-Mental State Examination (MMSE) score of ≥18; likely complete all the assessments
Rosen Modified Hachinski Ischemic score ≤4
On stable medication for 2 months before the screening visit; on or off cholinesterase inhibitors
Fluency in English and evidence of adequate premorbid intellectual functioning
Likely to be able to participate in all scheduled evaluations and complete all required tests

Exclusion criteria

Any contraindications to the use of oral semaglutide
Significant neurological disease other than AD that may affect cognition
MRI/CT showing unambiguous aetiological evidence of cerebrovascular disease with regard to their dementia or vascular dementia fulfilling NINCDSAIREN criteria
Current presence of a clinically significant major psychiatric disorder
Current clinically significant systemic illness that is likely to result in deterioration of the subject's condition or affect the subject's safety during the study
Myocardial infarction within the last 1 year
Other clinically significant abnormality on physical, neurological or laboratory examination that could compromise the study or be detrimental to the subject
History of alcohol or drug dependence within the last 2 years
Current use of narcotic medications which could affect cognition. Subjects on anticoagulants will be allowed, but will not have an arterial line inserted
Women of childbearing potential. Women who could become pregnant will be required to use adequate contraception throughout the trial. Please see appendix A for more information. All women of childbearing potential will take a pregnancy test before the PET scan.
Any contraindications to MRI scanning
Any historical evidence of pancreatitis or gallstones as proven by ultrasound or medical admission.
History of medullary thyroid cancer
Patients diagnosed with T2DM who are unwilling to change their treatment to semaglutide.

Treatment and study plan

Semaglutide (Rybelsus®)

Drug

All subjects will receive oral semaglutide once daily (4-weekly dose escalation from 3 mg to 7 mg and finally 14 mg). This dose escalation schedule is specified in the IMP (Rybelsus) SmPC.

Placebo

Drug

Matched oral Placebo to be taken once daily.

Primary outcomes

To evaluate the safety and tolerability of oral semaglutide in an AD population.

Time frame: Adverse events monitoring: Baseline; Weeks 4, 8, 26, 39, 52

To assess the safety and tolerability of (1-year) Semaglutide treatment in patients with AD using composite outcome measure of the adverse events evaluated from the safety assessments. This will be assessed by the number of participants using a composite measure generated from abnormal vital signs, abnormal 12-lead ECG readings, abnormal laboratory (blood) tests, abnormalities found in MRI scans, abnormal physical exam findings, and abnormal neurological/psychiatric evaluation.

Secondary outcomes

To evaluate the change in synaptic density using [18F] SynVesT-1 before and after treatment.

Time frame: [18F] SynVesT-1 PET will be conducted at baseline and Week 52 (end of treatment).

Synaptic density will be assessed, using [18F] SynVesT-1, at baseline and after 1-year of treatment with Semaglutide.

Study contacts

Contact information is provided by the study sponsor or research team.

Paul Edison, MD, PhD, FRCP, FRCPI

CONTACT

[email protected]

+44 2075941083

Sponsors and collaborators

Lead sponsor

Imperial College London

Other

Registry information

Official study title

Evaluating the Effects of GLP-1 Analogue, Oral Semaglutide, in Patients With Alzheimer's Disease

Important dates

Study start: 2025
Primary completion: 2027
Study completion: 2028
First posted: Oct 1, 2025
Registry last updated: Oct 1, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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