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

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.