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Synaptic markers are associated with cognitive decline after accounting for amyloid burden among an at-risk Alzheimer’s disease cohort
Elizabeth M. Planalp, Rebecca E. Langhough, Erin McMullen Jonaitis, Carol Ann Van Hulle, Rachael E. Wilson, Gwendlyn Kollmorgen, Clara Quijano‐Rubio, Ozioma C. Okonkwo et al.. Scientific Reports, 2025-06-03
Topic: Amyloid, tau and blood-test diagnosis
Amyloid burden impacts cognitive decline in the pre-dementia stages of Alzheimer's disease (AD), but there remains significant variability in cognitive trajectories that may be explainable by markers of synaptic function and neurodegeneration. Leveraging longitudinal data from two harmonized, at-risk but predominantly unimpaired cohorts, we examined how several proteins measured from cerebrospinal fluid (CSF) differ by amyloid status, cognitive status, and impact cognitive decline measured using a Preclinical Alzheimer's Cognitive Composite. Four hundred and thirty-four individuals provided CSF biomarkers of amyloid-beta42 (ab42), phosphorylated tau (181), from which we identified Aβ + individuals using a cutoff based on a p-tau181/Aβ42 ratio. Other markers of neurodegeneration (N) included neurofilament light, neurogranin, SNAP-25, and NPTX2. Most biomarkers of N were higher in the Aβ + group and lower in cognitively unimpaired individuals, though NPTX2 exhibited the opposite pattern. Even in the face of Aβ+, NPTX2 was higher in individuals who showed slower rates of cognitive decline, suggesting NPTX2 may be associated with cognitive resilience. Moreover, a SNAP-25/NPTX2 ratio of synaptic dysfunction explained more variance in cognitive decline than other biomarkers alone. This work provides support for potentially useful biomarkers of synaptic function implicated in the clinical syndrome of AD, aiding in future diagnosis and staging efforts.
Key findings
- Amyloid burden impacts cognitive decline in the pre-dementia stages of Alzheimer's disease (AD), but there remains significant variability in cognitive trajectories that may be explainable by markers of synaptic function and neurodegeneration.
- Even in the face of Aβ+, NPTX2 was higher in individuals who showed slower rates of cognitive decline, suggesting NPTX2 may be associated with cognitive resilience.
Why it matters
In a longitudinal study of 434 at-risk but mostly unimpaired people, higher levels of the synaptic protein NPTX2 were linked to slower cognitive decline even in those with amyloid buildup. This identifies NPTX2 and a SNAP-25/NPTX2 ratio as possible markers of synaptic function, not as a treatment or cure.
Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 54/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Scientific Reports) |
| Journal's citation record | 3 / 4 | Scientific Reports: journal h-index 463 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 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 | 2 / 7 | Cited 9 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 5.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Sterling C. Johnson: h-index 112 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40461705) |
| Free to read | 2 / 2 | Free to read |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41598-025-04319-3
- PubMed: 40461705
- Original source →
- Free full text: Scientific Reports →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Planalp, E. M., Langhough, R. E., Jonaitis, E. M., Van Hulle, C. A., Wilson, R. E., Kollmorgen, G., et al. (2025). Synaptic markers are associated with cognitive decline after accounting for amyloid burden among an at-risk Alzheimer’s disease cohort. Scientific Reports. https://doi.org/10.1038/s41598-025-04319-3
Vancouver
Planalp EM, Langhough RE, Jonaitis EM, Van Hulle CA, Wilson RE, Kollmorgen G, et al. Synaptic markers are associated with cognitive decline after accounting for amyloid burden among an at-risk Alzheimer’s disease cohort. Scientific Reports. 2025. doi:10.1038/s41598-025-04319-3. PMID: 40461705.
BibTeX
@article{planalp2025-40461705,
author = {Planalp, Elizabeth M. and Langhough, Rebecca E. and Jonaitis, Erin McMullen and Van Hulle, Carol Ann and Wilson, Rachael E. and Kollmorgen, Gwendlyn and Quijano‐Rubio, Clara and Okonkwo, Ozioma C. and others},
title = {{Synaptic markers are associated with cognitive decline after accounting for amyloid burden among an at-risk Alzheimer’s disease cohort}},
journal = {Scientific Reports},
year = {2025},
doi = {10.1038/s41598-025-04319-3},
pmid = {40461705},
url = {https://doi.org/10.1038/s41598-025-04319-3}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.