Alzheimer's & dementia (Amsterdam, Netherlands) · 2026
Semaglutide attenuates a proteomics-based dementia risk signature in older adults with overweight or obesity and cardiovascular disease without diabetes: A post hoc analysis of the SELECT phase 3 trial.
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Jiménez-Mausbach Martí, Tijms Betty M, Paterson Clare, Refsgaard Jan Christian
Аннотация
INTRODUCTION: Plasma proteomics detect multi-pathway biological changes preceding dementia onset. The Dementia SomaSignal Test (dSST) is a validated 25-protein score predicting 5- and 20-year all-cause dementia risk. Preclinical and clinical data suggest glucagon-like peptide-1 receptor agonists may have neuroprotective effects.
METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes (n = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST.
RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44; P < 0.001).
DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.
METHODS: In a post hoc analysis of the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial, adults ≥ 65 years with overweight/obesity and cardiovascular disease without diabetes (n = 2970) were randomized to semaglutide 2.4 mg or placebo. Non-fasted serum samples at baseline and week 104 were analyzed using the dSST.
RESULTS: Semaglutide reduced increases in predicted dementia risk versus placebo: 2.5-fold less increase in 5-year risk (26.0% lower predicted event rate; odds ratio [OR] 0.74, 95% confidence interval [CI] 0.65-0.85) and 1.67-fold less increase in 20-year risk (8.8% lower; OR 0.91, 95% CI 0.88-0.94). It also reduced odds of higher dementia risk classification by 36% (β -0.44; P < 0.001).
DISCUSSION: Semaglutide slowed progression of a validated proteomics-based dementia risk signature.