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. 2026 Aug 8;18(3):e70432.
doi: 10.1002/dad2.70432. eCollection 2026 Jul-Sep.

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

Martí Jiménez-Mausbach  1 , Betty M Tijms  2 , Clare Paterson  3 , Jan Christian Refsgaard  1
Affiliations

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

Martí Jiménez-Mausbach et al. Alzheimers Dement (Amst). .

Abstract

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.

Keywords: Alzheimer's disease; Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity; SomaScan; SomaSignal; blood biomarkers; cardiovascular disease; dementia risk; glucagon‐like peptide‐1 receptor agonists; obesity; proteomics; semaglutide.

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Conflict of interest statement

M. Jiménez‐Mausbach and J. C. Refsgaard are employees of and minor shareholders in Novo Nordisk A/S. C. Paterson is an employee and shareholder of Illumina. B. M. Tijms is coinventor on a patent of CSF proteomic subtypes (published under patent no. US2022196683A1, owner VUmc Foundation). She receives research funding from ZonMw (VIDI grant #09150171910068), the European Research Council (DecipherAD, #101171721), and the Amsterdam Cohort Hub; all payments were made to her institution. She has received consulting fees from Novo Nordisk and Roche, and payment for lectures/presentations from Sanofi and Novo Nordisk, all paid to her institution. . Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Study flow diagram for the SELECT dSST proteomics substudy. Of the 17,604 SELECT trial participants randomized 1:1 to once‐weekly subcutaneous semaglutide 2.4 mg or matched placebo, the present analysis included participants aged ≥  65 years with available paired non‐fasted serum samples at both baseline and week 104 (n  =  2970). Participants with discordant sample storage sites between timepoints (n  =  15) were excluded to ensure analytical consistency. CVD, cardiovascular disease; dSST, Dementia SomaSignal Test; OW, once weekly; s.c., subcutaneous; SELECT, Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity.
FIGURE 2
FIGURE 2
Predefined dSST dementia risk category thresholds for (A) 5‐year and (B) 20‐year predicted all‐cause dementia risk. Categories (low, medium–low, medium–high, high) were defined relative to the training dataset average risk (dSST score 6.5 for 5‐year; dSST score 15 for 20‐year) and correspond to increasing observed event rates in the ARIC study cohort, ranging from 1.5% to 20.3% for 5‐year risk and 3.8% to 35.6% for 20‐year risk. Thresholds were established in the original dSST validation study (Duggan et al. 7 ) and applied without modification to both baseline and week 104 measurements in the present analysis. ARIC, Atherosclerosis Risk in Communities; dSST, Dementia SomaSignal Test.
FIGURE 3
FIGURE 3
Semaglutide attenuated the longitudinal increase in proteomics‐based predicted dementia risk. Upper panels show the change from baseline to week 104 in 5‐year and 20‐year logit‐transformed predicted dementia risk (95% CI) for each treatment arm (SELECT participants aged ≥ 65 years; n  =  2970). Lower panels show the treatment effect of semaglutide 2.4 mg versus placebo as an OR with 95% CI, derived by exponentiating the treatment coefficient from linear regression of the change in logit‐transformed predicted risk at week 104; OR  <  1.0 favors semaglutide (dashed line, OR 1.0). Compared to placebo, semaglutide was associated with a 2.5‐fold lower increase in 5‐year predicted dementia risk (OR 0.74, 95% CI 0.65–0.85; P  <  0.001; 26% lower predicted event rate) and 1.67‐fold lower increase in 20‐year predicted dementia risk (OR 0.91, 95% CI 0.88–0.94; P  <  0.001; 8.8% lower predicted event rate). CI, confidence interval; dSST, Dementia SomaSignal Test; OR, odds ratio; SELECT, Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity.
FIGURE 4
FIGURE 4
Semaglutide shifted the distribution of dSST risk categories toward lower risk. Bar charts show the proportion of participants classified into each dSST risk category (low, medium–low, medium–high, high) at baseline (prior to treatment initiation) and after 104 weeks of treatment for the semaglutide 2.4 mg and placebo arms. A shift from higher to lower risk categories between baseline and week 104 is more pronounced in the semaglutide arm. Ordinal logistic regression estimated 36% lower odds of being classified into a higher risk category with semaglutide versus placebo at week 104 (OR 0.64, 95% CI 0.55–0.75; P < 0.001). CI, confidence interval; dSST, Dementia SomaSignal Test; OR, odds ratio.
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