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Sex-divergent trajectories of hippocampal and cortical NMDA receptor density across the Alzheimer’s disease continuum
Acosta-Martínez M, Carter V, Nessim A, Murphy S, Dhawan J, Beach TG, Serrano GE, Sundermann EE et al.. bioRxiv, 2026-08-07
Topic: Brain imaging, connectivity and assessment
While loss of NMDA receptors (NMDARs) is associated with Alzheimer’s disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Exam (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the CA1 field. However, there was a significant diagnosis by sex interaction driven by sex-specific changes in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that changes in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.
Key findings
- While loss of NMDA receptors (NMDARs) is associated with Alzheimer’s disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined.
- However, there was a significant diagnosis by sex interaction driven by sex-specific changes in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls.
- Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people 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 13 of the 62 points we could judge it on, which is 21 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 | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| 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 | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Acosta-Martínez, M., Carter, V., Nessim, A., Murphy, S., Dhawan, J., Beach, T. G., et al. (2026). Sex-divergent trajectories of hippocampal and cortical NMDA receptor density across the Alzheimer’s disease continuum. bioRxiv. https://doi.org/10.64898/2026.08.05.743051
Vancouver
Acosta-Martínez M, Carter V, Nessim A, Murphy S, Dhawan J, Beach TG, et al. Sex-divergent trajectories of hippocampal and cortical NMDA receptor density across the Alzheimer’s disease continuum. bioRxiv. 2026. doi:10.64898/2026.08.05.743051.
BibTeX
@article{acostamartinez2026-014f6f4c,
author = {Acosta-Martínez, M. and Carter, V. and Nessim, A. and Murphy, S. and Dhawan, J. and Beach, T. G. and Serrano, G. E. and Sundermann, E. E. and others},
title = {{Sex-divergent trajectories of hippocampal and cortical NMDA receptor density across the Alzheimer’s disease continuum}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.08.05.743051},
url = {https://doi.org/10.64898/2026.08.05.743051}
}
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