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Plasma Proteomic Analysis of APOE ε4 Homozygotes Identifies Preclinical Alzheimer’s Disease Alterations Potentially Modulated by Semaglutide
Dammer EB, Afshar S, Bian S, Seyfried NT, The Global Neurodegeneration Proteomics Consortium (GNPC), Levey AI, Fortea J, Johnson EC.. medRxiv, 2026-02-17
Topic: Genetics and APOE
Individuals who carry two copies of the apolipoprotein E ε4 ( APOE ε4) allele are at high risk of developing Alzheimer’s disease (AD), yet the effects of APOE ε4 homozygosity on biological pathways related to AD over the lifespan are unknown. Here we analyzed the plasma proteomes of APOE ε4/ε4 individuals with and without AD-related cognitive impairment ( n =413) and compared them to the proteomes of cognitively unimpaired individuals with APOE ε3/ε3 genotype ( n =2764) from ages 20 to 90. Multiple biological pathways were altered in young adulthood in ε4 homozygotes including metabolism and glucagon-like peptide 1/insulin growth factor (GLP-1/IGF), mitochondrial, microtubule, proteostasis, and synaptic pathways. Semaglutide—a GLP-1 receptor agonist—demonstrated reversal effects on metabolic and synaptic pathway alterations in ε4 homozygotes at preclinical and clinical AD stages. Targeting metabolic and other pathways for therapeutic intervention in ε4/ε4 individuals by at least age 50 will likely be the most effective approach to decrease risk for AD in this special population. One Sentence Summary Dammer et al . characterize proteomic changes in APO E ε4 homozygotes from ages 20 to 90 and identify disease pathways potentially treatable with GLP-1 receptor agonists.
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APA 7th
Dammer, E. B., Afshar, S., Bian, S., Seyfried, N. T., Levey, A. I., Fortea, J., et al. (2026). Plasma Proteomic Analysis of APOE ε4 Homozygotes Identifies Preclinical Alzheimer’s Disease Alterations Potentially Modulated by Semaglutide. medRxiv. https://doi.org/10.64898/2026.02.14.26346321
Vancouver
Dammer EB, Afshar S, Bian S, Seyfried NT, Levey AI, Fortea J, et al. Plasma Proteomic Analysis of APOE ε4 Homozygotes Identifies Preclinical Alzheimer’s Disease Alterations Potentially Modulated by Semaglutide. medRxiv. 2026. doi:10.64898/2026.02.14.26346321.
BibTeX
@article{dammer2026-827b8960,
author = {Dammer, E. B. and Afshar, S. and Bian, S. and Seyfried, N. T. and Levey, A. I. and Fortea, J. and Johnson, E. C.},
title = {{Plasma Proteomic Analysis of APOE ε4 Homozygotes Identifies Preclinical Alzheimer’s Disease Alterations Potentially Modulated by Semaglutide}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.02.14.26346321},
url = {https://doi.org/10.64898/2026.02.14.26346321}
}
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 7 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
- Semaglutide—a GLP-1 receptor agonist—demonstrated reversal effects on metabolic and synaptic pathway alterations in ε4 homozygotes at preclinical and clinical AD stages.
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Study details
- Participants413
- 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 (medRxiv) |
| 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 | 413 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. |
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