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The Role of Cortisol in CNS Disease –11β-HSD1 Inhibition as a Potential New Therapeutic Strategy for Alzheimer’s Disease and Major Depressive Disorder
Fox SA, Taylor JD, Rolan PE, Ritchie CW, Seckl J, Hilt DC.. Preprints.org, 2026-10-16
Topic: Drug trials: efficacy and safety
Cortisol is primarily synthesized by the adrenal glands, but also within specific tissues via a distinct enzymatic pathway. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the synthesis of cortisol within cells to create local higher cortisol environments in those organs where it is highly expressed such as the liver and brain. An extensive preclinical and clinical literature suggests that chronically, excess cortisol is detrimental. Since 11β-HSD1 expression rises with ageing, contributes to cognitive and affective disorders, and is strongly associated with Alzheimer’s disease, 11β-HSD1 inhibitors may plausibly treat cognitive and functional decline in Alzheimer’s disease and improve depression. Two inhibitors (ABT-384 and emestedastat) were studied in 12-week trials in patients with clinically diagnosed, unconfirmed Alzheimer’s disease (AD) and showed no overall benefits as a cognitive enhancer. When a subgroup with elevated blood pTau181 was later evaluated in the emestedastat trial, a slowing in progression was observed. A trial of emestedastat treatment has also reported anti-depressant activity. Thus, 11β-HSD1 inhibition appears to be a viable therapeutic mechanism. A pivotal, confirmatory trial of emestedastat treatment in 247 patients with mild-moderate AD is due to report topline results in November this year.
Key findings
- An extensive preclinical and clinical literature suggests that chronically, excess cortisol is detrimental.
- Since 11β-HSD1 expression rises with ageing, contributes to cognitive and affective disorders, and is strongly associated with Alzheimer’s disease, 11β-HSD1 inhibitors may plausibly treat cognitive and functional decline in Alzheimer’s disease and improve depression.
- Two inhibitors (ABT-384 and emestedastat) were studied in 12-week trials in patients with clinically diagnosed, unconfirmed Alzheimer’s disease (AD) and showed no overall benefits as a cognitive enhancer.
- A pivotal, confirmatory trial of emestedastat treatment in 247 patients with mild-moderate AD is due to report topline results in November this year.
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Study details
- Participants247
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 29 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 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 18 of the 62 points we could judge it on, which is 29 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Preprints.org) |
| 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 | 2 / 4 | 247 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 | — / 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 | 18 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 18 of the 62 points we could judge it on is 29 out of 100. |
| Total | 29 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Fox, S. A., Taylor, J. D., Rolan, P. E., Ritchie, C. W., Seckl, J., & Hilt, D. C. (2026). The Role of Cortisol in CNS Disease –11β-HSD1 Inhibition as a Potential New Therapeutic Strategy for Alzheimer’s Disease and Major Depressive Disorder. Preprints.org. https://doi.org/10.20944/preprints202610.1646.v1
Vancouver
Fox SA, Taylor JD, Rolan PE, Ritchie CW, Seckl J, Hilt DC. The Role of Cortisol in CNS Disease –11β-HSD1 Inhibition as a Potential New Therapeutic Strategy for Alzheimer’s Disease and Major Depressive Disorder. Preprints.org. 2026. doi:10.20944/preprints202610.1646.v1.
BibTeX
@article{fox2026-7db41b34,
author = {Fox, S. A. and Taylor, J. D. and Rolan, P. E. and Ritchie, C. W. and Seckl, J. and Hilt, D. C.},
title = {{The Role of Cortisol in CNS Disease –11β-HSD1 Inhibition as a Potential New Therapeutic Strategy for Alzheimer’s Disease and Major Depressive Disorder}},
journal = {Preprints.org},
year = {2026},
doi = {10.20944/preprints202610.1646.v1},
url = {https://doi.org/10.20944/preprints202610.1646.v1}
}
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