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Evaluating Diabetes Drug Targets for Vascular Dementia Prevention Using Drug Target Mendelian Randomisation
Packer A, Austin L, Williams DM, Taylor-Bateman V, Anderson EL.. medRxiv, 2026-09-29
Topic: Genetics and APOE
Vascular dementia (VaD) is a leading cause of cognitive decline with no disease-modifying therapies. It remains unclear whether diabetes drug targets causally influence VaD risk. We applied two-sample, drug target Mendelian randomisation (MR) to test whether modulation of eight antidiabetic drug targets may alter VaD risk. MR models used variants within genes encoding antidiabetic drug targets, selected according to their effects on circulating glycated haemoglobin (HbA1c, N = 437,749) in primary analyses, and cortex-specific cis -eQTLs (N = 2,683) in secondary analyses. Outcomes were clinically diagnosed VaD (N = 7,009 cases/899,672 controls) and neuroimaging markers of cerebrovascular disease: white matter hyperintensity volume (WMH; N = 50,970), inverse fractional anisotropy (iFA; N = 31,125), and mean diffusivity (MD; N = 31,147). Type-2 diabetes mellitus (T2DM; N= 62,892 cases/596,424 controls) served as a positive control outcome. Genetic instruments were available for seven of the relevant targets using both HbA1c and cortex cis -eQTL data. In primary HbA1c-scaled analyses, no antidiabetic drug target showed evidence of association with VaD risk or cerebrovascular neuroimaging markers, although DPP4 inhibition demonstrated a suggestive protective association for VaD (OR = 0.68, 95% CI = 0.46 - 1.02, p = 0.063), though the confidence interval (CI) included the null. Secondary cortex cis -eQTL analyses were similarly null, except for PPARG modulation, which was predicted to reduce iFA (β = −0.50, 95% CI −0.99 to −0.02, p = 0.04). Overall, these findings provide little genetic evidence supporting currently licensed antidiabetic drugs as candidates for vascular dementia prevention, although DPP4 inhibition warrants further investigation in larger datasets.
Key findings
- In primary HbA1c-scaled analyses, no antidiabetic drug target showed evidence of association with VaD risk or cerebrovascular neuroimaging markers, although DPP4 inhibition demonstrated a suggestive protective association for VaD (OR = 0.68, 95% CI = 0.46 - 1.02, p = 0.063), though the confidence interval (CI) included the null.
- Overall, these findings provide little genetic evidence supporting currently licensed antidiabetic drugs as candidates for vascular dementia prevention, although DPP4 inhibition warrants further investigation in larger datasets.
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Study details
- Participants437,749
- Effect sizeOR = 0.68
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 37 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 62 points we could judge it on, which is 37 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| 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 | 4 / 4 | 437,749 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| 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 | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 23 of the 62 points we could judge it on is 37 out of 100. |
| Total | 37 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Packer, A., Austin, L., Williams, D. M., Taylor-Bateman, V., & Anderson, E. L. (2026). Evaluating Diabetes Drug Targets for Vascular Dementia Prevention Using Drug Target Mendelian Randomisation. medRxiv. https://doi.org/10.64898/2026.09.22.26363326
Vancouver
Packer A, Austin L, Williams DM, Taylor-Bateman V, Anderson EL. Evaluating Diabetes Drug Targets for Vascular Dementia Prevention Using Drug Target Mendelian Randomisation. medRxiv. 2026. doi:10.64898/2026.09.22.26363326.
BibTeX
@article{packer2026-928028a6,
author = {Packer, A. and Austin, L. and Williams, D. M. and Taylor-Bateman, V. and Anderson, E. L.},
title = {{Evaluating Diabetes Drug Targets for Vascular Dementia Prevention Using Drug Target Mendelian Randomisation}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.09.22.26363326},
url = {https://doi.org/10.64898/2026.09.22.26363326}
}
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