PIN1-p53 bifurcation dictates opposite cell fate decisions in Alzheimer’s disease and glioblastoma via distinct energy landscape topologies
Lyu J.. Research Square, 2026-10-29
Topic: Genetics and APOE
Although Alzheimer’s disease (AD) and glioblastoma (GBM) share common aging-related risk factors, they lead to opposite cellular fates—neurodegeneration versus uncontrolled proliferation. The system-level mechanisms driving this striking divergence remain elusive. Here, we integrated single-cell and single-nucleus transcriptomic data from AD (84 donors) and GBM (18 samples) to comparatively map the energy landscape of cell fate decisions in these two diseases. By computing a PIN1-p53 Bifurcation Index and CellEnergy landscape, we reveal that AD and GBM diverge at a critical Bifurcation Point. AD cells descend from a Health Peak into a deep AD Valley, characterized by a senescent profile with PIN1 downregulation and p53 activation. In contrast, GBM cells settle on a flat, low-energy GBM Plateau, exhibiting a proliferative profile driven by PIN1 overexpression and p53 suppression. We further identified pioneer gene candidates at the Bifurcation Point, with MDM2 and PIN1 upregulated in AD, and BBC3 in GBM. Interpreted within the Hyper Solution Landscape (HSL) framework, these findings provide a biological explanation for the path-dependent nature of cell fate decisions and provide a mechanistic framework linking the PIN1-p53 axis to the inverse comorbidity between AD and cancer, suggesting that the PIN1-p53 axis acts as a critical decision node.
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APA 7th
Lyu, J. (2026). PIN1-p53 bifurcation dictates opposite cell fate decisions in Alzheimer’s disease and glioblastoma via distinct energy landscape topologies. Research Square. https://doi.org/10.21203/rs.3.rs-11415613/v1
Vancouver
Lyu J. PIN1-p53 bifurcation dictates opposite cell fate decisions in Alzheimer’s disease and glioblastoma via distinct energy landscape topologies. Research Square. 2026. doi:10.21203/rs.3.rs-11415613/v1.
BibTeX
@article{lyu2026-d9d173bc,
author = {Lyu, J.},
title = {{PIN1-p53 bifurcation dictates opposite cell fate decisions in Alzheimer’s disease and glioblastoma via distinct energy landscape topologies}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11415613/v1},
url = {https://doi.org/10.21203/rs.3.rs-11415613/v1}
}
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Key findings
- Although Alzheimer’s disease (AD) and glioblastoma (GBM) share common aging-related risk factors, they lead to opposite cellular fates—neurodegeneration versus uncontrolled proliferation.
- Interpreted within the Hyper Solution Landscape (HSL) framework, these findings provide a biological explanation for the path-dependent nature of cell fate decisions and provide a mechanistic framework linking the PIN1-p53 axis to the inverse comorbidity between AD and cancer, suggesting that the PIN1-p53 axis acts as a critical decision node.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people 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 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| 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 | 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) |
| 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 | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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