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Glucagon-like peptide-1 receptor agonist initiation and risk of clinically recorded Alzheimer's disease-type dementia in older adults with type 2 diabetes: a target trial emulation using causal machine learning
Schroeder, J.; Ciora, O.-A.; Heesen, P.; Bendszus, M.; Levin, J.; Perneczky, R.; Bally, L.; Feuerriegel et al.. medRxiv (preprint), 2026-08-24
Topic: Amyloid, tau and blood-test diagnosis
AbstractO_ST_ABSBackgroundC_ST_ABSGlucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors are increasingly used for type 2 diabetes. Despite established metabolic, cardiovascular, and renal benefits, it remains uncertain whether GLP-1 receptor agonists are associated with longer clinically recorded Alzheimers disease (AD)-type dementia-free survival than sulfonylureas (SU) or SGLT2 inhibitors. MethodsUsing All of Us electronic health records, we emulated target trials among adults aged[≥] 55 years with type 2 diabetes, a 12-month washout, and no prior dementia. We compared GLP1 receptor agonists with SU and SGLT2 inhibitors. Propensity score weighting and doubly robust estimation addressed confounding. Causal survival forests estimated individualized treatment effects on 48-month RMST free from clinically recorded AD-type dementia. FindingsIn the GLP-1 receptor agonist versus SU comparison (6,328 individuals; 48-month NNT{approx} 202), initiation was associated with a small but statistically significant increase in AD-type dementia-free survival (ATE 0{middle dot}21 months; 95% CI: 0{middle dot}07-0{middle dot}35). The highest-benefit stratum gained 0{middle dot}45 months (95% CI: 0{middle dot}28-0{middle dot}62). In the SGLT2 inhibitor comparison (3,070 individuals; 48-month NNT{approx} 245), the average effect was not statistically significant (ATE 0{middle dot}06 months; 95% CI: -0{middle dot}18-0{middle dot}31), but treatment effects were heterogeneous. The highest-benefit stratum gained 0{middle dot}83 months (95% CI: 0{middle dot}49- 1{middle dot}17). Predicted benefit was associated with older age, insulin use, lower HbA1c, and lower BMI. InterpretationGLP-1 receptor agonists may delay clinically recorded AD-type dementia compared with SU. Comparative effectiveness versus SGLT2 inhibitors may vary, supporting study. Given hypothesis-generating findings, diabetes treatment selection should remain guided by glycemic, cardiovascular, renal, and patient-centered considerations. FundingGerman Federal Ministry of Research, Technology and Space (03LWH0181B).
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APA 7th
Schroeder, J., Ciora, O.-A., Heesen, P., Bendszus, M., Levin, J., Perneczky, R., et al. (2026). Glucagon-like peptide-1 receptor agonist initiation and risk of clinically recorded Alzheimer's disease-type dementia in older adults with type 2 diabetes: a target trial emulation using causal machine learning. medRxiv (preprint). https://doi.org/10.64898/2026.08.21.26361012
Vancouver
Schroeder J, Ciora O.-A, Heesen P, Bendszus M, Levin J, Perneczky R, et al. Glucagon-like peptide-1 receptor agonist initiation and risk of clinically recorded Alzheimer's disease-type dementia in older adults with type 2 diabetes: a target trial emulation using causal machine learning. medRxiv (preprint). 2026. doi:10.64898/2026.08.21.26361012.
BibTeX
@article{schroeder2026-3ea6500a,
author = {Schroeder, J. and Ciora, O.-A. and Heesen, P. and Bendszus, M. and Levin, J. and Perneczky, R. and Bally, L. and Feuerriegel and others},
title = {{Glucagon-like peptide-1 receptor agonist initiation and risk of clinically recorded Alzheimer's disease-type dementia in older adults with type 2 diabetes: a target trial emulation using causal machine learning}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.08.21.26361012},
url = {https://doi.org/10.64898/2026.08.21.26361012}
}
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Key findings
- Despite established metabolic, cardiovascular, and renal benefits, it remains uncertain whether GLP-1 receptor agonists are associated with longer clinically recorded Alzheimers disease (AD)-type dementia-free survival than sulfonylureas (SU) or SGLT2 inhibitors.
- FindingsIn the GLP-1 receptor agonist versus SU comparison (6,328 individuals; 48-month NNT{approx} 202), initiation was associated with a small but statistically significant increase in AD-type dementia-free survival (ATE 0{middle dot}21 months; 95% CI: 0{middle dot}07-0{middle dot}35).
- In the SGLT2 inhibitor comparison (3,070 individuals; 48-month NNT{approx} 245), the average effect was not statistically significant (ATE 0{middle dot}06 months; 95% CI: -0{middle dot}18-0{middle dot}31), but treatment effects were heterogeneous.
- Predicted benefit was associated with older age, insulin use, lower HbA1c, and lower BMI.
- InterpretationGLP-1 receptor agonists may delay clinically recorded AD-type dementia compared with SU.
Why it matters
In this target trial emulation, starting a GLP-1 receptor agonist was associated with a small but statistically significant increase in dementia-free survival compared with sulfonylureas, while the average effect in the SGLT2 inhibitor comparison was not statistically significant. These are observational associations from electronic health records, not proof that the drug prevents Alzheimer's disease.
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Study details
- Participants6,328
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 30 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 28 of the 94 points we could judge it on, which is 30 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 6,328 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Stefan Feuerriegel: h-index 44 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Imperial College London: institution h-index 1,744 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 10 institution(s) in 3 countries |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 28 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 28 of the 94 points we could judge it on is 30 out of 100. |
| Total | 30 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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