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Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer’s disease
Zeng X, Abrahamson EE, Balogun WG, Kofler J, Paljug WR, Pivtoraiko VN, Ikonomovic MD, Karikari TK.. medRxiv, 2026-10-07
Topic: Disease mechanisms in lab and animal studies
Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau proteins are a hallmark neuropathology of Alzheimer’s disease. However, the molecular basis underlying their spatial heterogeneity and biochemical complexity remain unclear. To address this, we performed mass spectrometry–based proteomic profiling of two neocortical regions with different susceptibilities to NFT pathology—the inferior temporal (IT) and middle frontal (MF) cortices—from 27 autopsy cases stratified by Braak NFT stage (Low 0–II, n=8; Mid III–IV, n=11; High V–VI, n=8). Brain homogenates were sequentially fractionated using buffers of increasing solubility (TBS, Na₂CO₃, and Urea), followed by trypsin digestion and analysis by nanoLC–MS/MS with data-independent acquisition. Proteins were identified using PEAKS Studio 12 and linear mixed-effects models were applied to assess Braak stage–associated and region-specific changes in protein abundance and solubility. A total of 5,573 protein groups were identified, including 452 differentially expressed proteins (DEPs), 183 bidirectional expression proteins (BEPs), and 693 differentially soluble proteins (DSPs) associated with NFT pathology. These proteins were enriched in pathways related to cytoskeletal organization, synaptic transmission, metabolism, vesicular trafficking, and proteostasis. Marked regional differences were observed, with limited overlap between IT and MF across DEPs, BEPs, and DSPs. Protein change in MF was dynamic with a higher number of BEPs and suggested active cytoskeletal remodeling, whereas IT showed fewer BEPs and evidence of structural disruption, including alterations in intermediate filament components, consistent with vulnerability of IT and possible compensatory/plasticity changes in MF cortex. MF cortex had the greatest downregulation of DEPs between Low and Mid Braak stages, while the transition from Mid to High Braak stage showed upregulation of most of DEPs in both regions. In addition, widespread changes in protein solubility were observed, particularly decreased solubility at later Braak stages, implicating disruption of proteostasis. Together, these findings highlight region- and stage-dependent proteomic alterations associated with tau pathology and underscore their relevance for understanding disease mechanisms and informing biomarker development.
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APA 7th
Zeng, X., Abrahamson, E. E., Balogun, W. G., Kofler, J., Paljug, W. R., Pivtoraiko, V. N., et al. (2026). Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer’s disease. medRxiv. https://doi.org/10.64898/2026.10.04.26361149
Vancouver
Zeng X, Abrahamson EE, Balogun WG, Kofler J, Paljug WR, Pivtoraiko VN, et al. Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer’s disease. medRxiv. 2026. doi:10.64898/2026.10.04.26361149.
BibTeX
@article{zeng2026-3cf01276,
author = {Zeng, X. and Abrahamson, E. E. and Balogun, W. G. and Kofler, J. and Paljug, W. R. and Pivtoraiko, V. N. and Ikonomovic, M. D. and Karikari, T. K.},
title = {{Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer’s disease}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.10.04.26361149},
url = {https://doi.org/10.64898/2026.10.04.26361149}
}
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 8 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
- A total of 5,573 protein groups were identified, including 452 differentially expressed proteins (DEPs), 183 bidirectional expression proteins (BEPs), and 693 differentially soluble proteins (DSPs) associated with NFT pathology.
- Together, these findings highlight region- and stage-dependent proteomic alterations associated with tau pathology and underscore their relevance for understanding disease mechanisms and informing biomarker development.
Study details
- Participants5,573
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 31 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 19 of the 62 points we could judge it on, which is 31 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 | 3 / 4 | 5,573 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 | 19 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 19 of the 62 points we could judge it on is 31 out of 100. |
| Total | 31 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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