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Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer's Disease Therapeutics
Velázquez de Castro-Bono A, Castro-Luna G, Guil-Guerrero JL.. International journal of molecular sciences, 2026-06-02
Topic: Amyloid, tau and blood-test diagnosis
Alzheimer's disease (AD) is undergoing a profound paradigm shift, transitioning from a localized, monolithic proteinopathy into a complex, multisystem disorder. This critical review synthesizes recent mechanistic, translational, and clinical insights to dismantle the traditional linear amyloid cascade hypothesis. We explore the synergistic interplay between amyloid-β (Aβ) and tau propagation, positioning chronic neuroinflammation, endolysosomal failure, and metabolic starvation-often framed as "Type 3 Diabetes"-as fundamental disease drivers. Crucially, we highlight the emerging biological bridge of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota-gut-brain axis dysbiosis. The recent validation of disease-modifying therapies (DMTs) confirms Aβ clearance as a viable pharmacological target; however, the marginal clinical gains and severe radiological risks, such as Amyloid-Related Imaging Abnormalities (ARIA), expose the profound limitations of monotherapy. Ultimately, we argue that isolated amyloid clearance is merely an induction phase. The future of AD therapeutics mandates a sequential combination approach-pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance. Supported by scalable fluid biomarkers (e.g., plasma p-tau217) and the expanded ATN(I) framework, the field must embrace proactive precision medicine and inclusive clinical trial designs to successfully transform AD into a manageable chronic condition.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Velázquez de Castro-Bono, A., Castro-Luna, G., & Guil-Guerrero, J. L. (2026). Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer's Disease Therapeutics. International journal of molecular sciences. https://doi.org/10.3390/ijms27115042
Vancouver
Velázquez de Castro-Bono A, Castro-Luna G, Guil-Guerrero JL. Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer's Disease Therapeutics. International journal of molecular sciences. 2026. doi:10.3390/ijms27115042. PMID: 42278566.
BibTeX
@article{velazquezdecastrobono2026-42278566,
author = {Velázquez de Castro-Bono, A. and Castro-Luna, G. and Guil-Guerrero, J. L.},
title = {{Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer's Disease Therapeutics}},
journal = {International journal of molecular sciences},
year = {2026},
doi = {10.3390/ijms27115042},
pmid = {42278566},
url = {https://doi.org/10.3390/ijms27115042}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
Key findings
- Crucially, we highlight the emerging biological bridge of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota-gut-brain axis dysbiosis.
- The recent validation of disease-modifying therapies (DMTs) confirms Aβ clearance as a viable pharmacological target; however, the marginal clinical gains and severe radiological risks, such as Amyloid-Related Imaging Abnormalities (ARIA), expose the profound limitations of monotherapy.
- Ultimately, we argue that isolated amyloid clearance is merely an induction phase.
- The future of AD therapeutics mandates a sequential combination approach-pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance.
- Supported by scalable fluid biomarkers (e.g., plasma p-tau217) and the expanded ATN(I) framework, the field must embrace proactive precision medicine and inclusive clinical trial designs to successfully transform AD into a manageable chronic condition.
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Study details
- Evidence strengthLow
How this study scored 47/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, 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 27 of the 58 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (International journal of molecular sciences) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 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) |
| 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 | 2 / 2 | Indexed in PubMed (PMID 42278566) |
| Free to read | 2 / 2 | Free to read |
| Points | 27 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 27 of the 58 points we could judge it on is 47 out of 100. |
| Total | 47 / 100 | — |
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