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Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25
Butt OH, Long JM, Henson RL, Herries E, Sutphen CL, Fagan AM, Cruchaga C, Ladenson JH et al.. Neurobiology of aging, 2021-02-11
Topic: Brain proteins, microglia and lab models
Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.
Key findings
- CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001).
- Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels.
Why it matters
Among 274 cognitively normal people, those carrying the APOE ε4 risk variant had higher levels of the presynaptic marker CSF SNAP-25, but not the postsynaptic marker neurogranin, even after adjusting for amyloid status. This is a biomarker observation and does not show that measuring or changing SNAP-25 affects the development of Alzheimer disease.
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Study details
- Participants274
- Evidence strengthLow
How this study scored 46/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of aging) |
| Journal's citation record | 3 / 4 | Neurobiology of Aging: journal h-index 263 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 2 / 4 | 274 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 | 3 / 7 | Cited 20 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.9 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 2 / 6 | Cited 1.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 4 other studies in this library |
| Still being cited | 1 / 4 | Cited 13 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Suzanne Elizabeth Schindler: h-index 56 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33765432) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 46 / 100 | — |
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Read the original
- DOI: 10.1016/j.neurobiolaging.2021.02.008
- PubMed: 33765432
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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
Butt, O. H., Long, J. M., Henson, R. L., Herries, E., Sutphen, C. L., Fagan, A. M., et al. (2021). Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25. Neurobiology of aging. https://doi.org/10.1016/j.neurobiolaging.2021.02.008
Vancouver
Butt OH, Long JM, Henson RL, Herries E, Sutphen CL, Fagan AM, et al. Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25. Neurobiology of aging. 2021. doi:10.1016/j.neurobiolaging.2021.02.008. PMID: 33765432.
BibTeX
@article{butt2021-33765432,
author = {Butt, O. H. and Long, J. M. and Henson, R. L. and Herries, E. and Sutphen, C. L. and Fagan, A. M. and Cruchaga, C. and Ladenson, J. H. and others},
title = {{Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25}},
journal = {Neurobiology of aging},
year = {2021},
doi = {10.1016/j.neurobiolaging.2021.02.008},
pmid = {33765432},
url = {https://doi.org/10.1016/j.neurobiolaging.2021.02.008}
}
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