REWIND-Dementia
(2026)Objective
To examine associations between dulaglutide treatment, Alzheimer's disease and related dementia (ADRD) plasma biomarkers (NfL, p-tau217, GFAP), and substantive cognitive impairment (SCI) in adults with type 2 diabetes.
Study Summary
• Participants with baseline NfL ≥56 pg/mL had a dulaglutide-associated 2-year reduction in NfL (−27.4% vs −14.2%; p = 0.003)
• Participants with baseline p-tau217 ≥0.25 pg/mL had a 22% dulaglutide-associated SCI reduction (HR = 0.78; p = 0.0064)
• Limited 2-year effects on p-tau217 and GFAP overall
Intervention
Once-weekly subcutaneous dulaglutide 1.5 mg versus placebo, with plasma biomarker (NfL, p-tau217, GFAP) and cognitive assessments at baseline, 2 years, and 5 years.
Inclusion Criteria
Adults ≥50 years with type 2 diabetes, previous cardiovascular event or cardiovascular risk factors, HbA1c ≤9.5%, BMI ≥23 kg/m², on up to two oral glucose-lowering drugs ± basal insulin; with baseline + Year 2 biomarker data and ≥1 follow-up MoCA/DSST score.
Study Design
Arms: Dulaglutide 1.5 mg weekly (n=3741) vs Placebo (n=3627)
Patients per Arm: Dulaglutide n=3741; Placebo n=3627
Outcome
• NfL ≥56 pg/mL subgroup: dulaglutide significantly reduced NfL (LS mean 63.8 vs 75.4 pg/mL; p = 0.003)
• p-tau217 ≥0.25 pg/mL subgroup: 22% reduction in SCI with dulaglutide (HR = 0.78; p = 0.0064)
• Baseline NfL negatively associated with baseline standardized MoCA and DSST scores (both p < 0.001)
• No significant overall changes in p-tau217 or GFAP
Bottom Line
In a post hoc analysis of REWIND, dulaglutide did not significantly change ADRD biomarkers or SCI overall, but in participants with elevated baseline NfL (≥56 pg/mL) it produced a significant 2-year reduction in NfL, and in those with elevated baseline p-tau217 (≥0.25 pg/mL) it was associated with a 22% reduction in SCI — suggesting potential benefit in biomarker-defined high-risk subgroups.
Major Points
- Post hoc analysis of 7368 REWIND participants (dulaglutide n=3741; placebo n=3627) with baseline and 2-year plasma biomarkers
- Overall, dulaglutide did not significantly change NfL, p-tau217, GFAP, or SCI
- Significant treatment-by-baseline NfL interaction (p < 0.001): in those with NfL ≥56 pg/mL, dulaglutide reduced NfL at 2 years (−27.4% vs −14.2%; p = 0.003)
- In participants with baseline p-tau217 ≥0.25 pg/mL (29% of cohort), dulaglutide reduced SCI by 22% (HR = 0.78; p = 0.0064)
- Baseline NfL was negatively associated with baseline standardized MoCA and DSST scores after adjustment for age/sex (both p < 0.001)
- p-tau217 and GFAP showed limited 2-year treatment-related changes overall
- Findings support exploring incretin-related cognitive effects in biomarker-defined high-risk subgroups in future trials
Study Design
- Study Type
- Post hoc analysis of a multicenter, international, randomized, double-blind, placebo-controlled cardiovascular outcomes trial
- Randomization
- Yes
- Blinding
- Double-blind; biomarkers measured without knowledge of clinical data or treatment assignment
- Sample Size
- 9901
- Follow-up
- Median 5.4 years (biomarkers at baseline and 2 years; cognitive testing at baseline, 2 years, 5 years, and end of study)
- Centers
- 371
Primary Outcome
Definition: Change in plasma ADRD biomarkers (NfL, p-tau217, GFAP) from baseline to 2 years and treatment-by-baseline-biomarker interactions
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| NfL LS mean 30.1 ± 0.03 pg/mL (10.2% increase from baseline) | NfL LS mean 29.8 ± 0.03 pg/mL (9.1% increase from baseline) | - | 0.47 (overall NfL change) |
Limitations & Criticisms
- Post hoc, exploratory analysis with p-values not adjusted for multiplicity
- Biomarker measurements limited to baseline and 2-year timepoints
- Overall biomarker and SCI effects were nonsignificant; significance limited to subgroups
- Population restricted to T2D patients with cardiovascular risk; generalizability to non-diabetic AD populations unclear
- SCI defined by cognitive test performance thresholds rather than clinical dementia diagnosis
Citation
Wilson JM, et al. Dulaglutide and neurodegeneration biomarkers: REWIND post hoc analysis. Alzheimer's Dement. 2026;22:e71391.