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Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer’s Disease Model and Wild-Type Mice
Copeland MH, Youngstrom DE, Konrad KS, Diering GH, Letsinger AC, Aksu LR, Yakel JL, Cushman JD.. bioRxiv, 2026-07-27
Topic: Drug trials: efficacy and safety
Sleep disruption is common in Alzheimer’s disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.
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APA 7th
Copeland, M. H., Youngstrom, D. E., Konrad, K. S., Diering, G. H., Letsinger, A. C., Aksu, L. R., et al. (2026). Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer’s Disease Model and Wild-Type Mice. bioRxiv. https://doi.org/10.64898/2026.07.22.739929
Vancouver
Copeland MH, Youngstrom DE, Konrad KS, Diering GH, Letsinger AC, Aksu LR, et al. Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer’s Disease Model and Wild-Type Mice. bioRxiv. 2026. doi:10.64898/2026.07.22.739929.
BibTeX
@article{copeland2026-408c21ca,
author = {Copeland, M. H. and Youngstrom, D. E. and Konrad, K. S. and Diering, G. H. and Letsinger, A. C. and Aksu, L. R. and Yakel, J. L. and Cushman, J. D.},
title = {{Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer’s Disease Model and Wild-Type Mice}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.07.22.739929},
url = {https://doi.org/10.64898/2026.07.22.739929}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.
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Study details
- Participants16
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 23 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 randomized / 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 multicenter collaboration, so those were left out: it earned 14 of the 62 points we could judge it on, which is 23 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| 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 | 1 / 4 | 16 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “5xfad”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter 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 | 14 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 14 of the 62 points we could judge it on is 23 out of 100. |
| Total | 23 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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