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Stage-specific proteomic signatures of synaptopathy in Alzheimer’s disease
Georgiades T, Griffiths J, Gibbs F, Chandra E, Papageorgopoulou M, Liang D, Whitwell HJ, Matthews PM et al.. bioRxiv, 2026-10-03
Topic: Genetics and APOE
Synapse loss is the strongest pathological correlate of cognitive decline in Alzheimer’s disease, yet the molecular basis of synaptic vulnerability across disease progression remains poorly understood. We performed proteomic profiling of isolated synaptoneurosomes from post-mortem middle temporal gyrus tissue from 67 individuals, comprising 40 individuals spanning all Alzheimer’s disease Braak stages and 27 non-diseased controls. Differential abundance and weighted gene co-expression network analyses were combined with pathway, cell-type and gene set variation analyses to characterise stage-associated changes in the synaptic proteome. Brain-derived candidate proteins were subsequently evaluated using receiver operating characteristic and regression analyses against cognitive examination scores in two independent plasma proteomics datasets. We identified six distinct stage-associated synaptic proteomic signatures. Mitochondrial function and synaptic signalling declined by mid-stage Alzheimer’s disease, while clathrin-mediated endocytosis increased at mid-stage without further change at later stages. By contrast, proteostasis and perisynaptic astrocytic processes increased progressively throughout the disease course. Global excitatory and inhibitory protein signals also showed a progressive shift in their relative balance ( P = 7.80 × 10⁻ 3 ; adjusted R² = 0.072). These findings guided targeted investigation of candidate plasma markers linked to distinct synaptic processes in two independent proteomic datasets. We nominated 42 plasma proteins mapping to synaptic signatures of progression, which showed associations with disease stage and cognitive measures including Mini-Mental State Examination, Montreal Cognitive Assessment and Clinical Dementia Rating. PHGDH was prioritised across analyses through associations with cognitive impairment from early disease stages (Clinical Dementia Rating transition 0 to 0.5, false discovery rate = 8.87 × 10⁻ 18 ), neuropathological progression ( P = 6.85 × 10⁻ 7 ) and excitatory-inhibitory protein imbalance ( P = 5.56 × 10⁻ 3 ). Together, our findings define the stage-associated molecular changes at the AD synapse and connect distinct brain pathways to accessible plasma candidates, establishing a mechanistically anchored framework for future patient stratification and evaluation of synapse-directed therapies.
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APA 7th
Georgiades, T., Griffiths, J., Gibbs, F., Chandra, E., Papageorgopoulou, M., Liang, D., et al. (2026). Stage-specific proteomic signatures of synaptopathy in Alzheimer’s disease. bioRxiv. https://doi.org/10.64898/2026.10.02.755976
Vancouver
Georgiades T, Griffiths J, Gibbs F, Chandra E, Papageorgopoulou M, Liang D, et al. Stage-specific proteomic signatures of synaptopathy in Alzheimer’s disease. bioRxiv. 2026. doi:10.64898/2026.10.02.755976.
BibTeX
@article{georgiades2026-22f78c0d,
author = {Georgiades, T. and Griffiths, J. and Gibbs, F. and Chandra, E. and Papageorgopoulou, M. and Liang, D. and Whitwell, H. J. and Matthews, P. M. and others},
title = {{Stage-specific proteomic signatures of synaptopathy in Alzheimer’s disease}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.02.755976},
url = {https://doi.org/10.64898/2026.10.02.755976}
}
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Key findings
- These findings guided targeted investigation of candidate plasma markers linked to distinct synaptic processes in two independent proteomic datasets.
- Together, our findings define the stage-associated molecular changes at the AD synapse and connect distinct brain pathways to accessible plasma candidates, establishing a mechanistically anchored framework for future patient stratification and evaluation of synapse-directed therapies.
Study details
- Participants67
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 27 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 17 of the 62 points we could judge it on, which is 27 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 | 67 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) |
| 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 | 17 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 17 of the 62 points we could judge it on is 27 out of 100. |
| Total | 27 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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