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Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration
Adrián G Palacios, Sarah X Zhang, Mónica L Acosta. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-08
Topic: Inflammation, microglia and astrocytes
Diabetic retinopathy (DR) and Alzheimer's disease (AD) are progressive neurodegenerative disorders affecting the eye and the brain, respectively. Despite targeting different organs, they share common molecular mechanisms. A central process connecting these conditions is the unfolded protein response (UPR), which maintains protein homeostasis in the endoplasmic reticulum (ER). Dysregulation of UPR pathways, particularly the IRE1-XBP1 and PERK-eIF2α pathways, can lead to inflammation, oxidative stress, and neurodegeneration. While the IRE1-XBP1 pathway regulates protein folding and inflammatory signaling, the PERK-eIF2α pathway reduces protein synthesis but may trigger apoptosis if persistently activated. Emerging therapies targeting UPR pathways and ER chaperones show promise in mitigating neurodegenerative damage in DR and AD. This review highlights shared pathophysiological mechanisms, explore retinal biomarkers for early AD detection, and emphasizes UPR modulation as a therapeutic strategy for neurodegeneration in aging-related diseases. HIGHLIGHTS: Diabetic retinopathy (DR, ocular disorder) and Alzheimer's disease (AD, cerebral disorder) share common molecular mechanisms, including oxidative stress, inflammation, and proteostasis dysfunction. UPR is a critical pathway linking both diseases through endoplasmic reticulum (ER) stress and neurodegeneration and targeting unfolded protein response (UPR) pathways, ER chaperones (e.g., P58IPK), and anti-inflammatory treatments show promise. The IRE1-XBP1 pathway regulates protein homeostasis and inflammation; XBP1s protects against ER stress in both retinal and brain neurons. The PERK-eIF2α pathway suppresses protein synthesis under stress but may induce apoptosis via ATF4 and CHOP if chronically activated. Age-related decline in metabolism, proteostasis, and neurovascular function intensifies disease progression and exacerbates molecular and cellular damage in both DR and AD.
Key findings
- HIGHLIGHTS: Diabetic retinopathy (DR, ocular disorder) and Alzheimer's disease (AD, cerebral disorder) share common molecular mechanisms, including oxidative stress, inflammation, and proteostasis dysfunction.
- UPR is a critical pathway linking both diseases through endoplasmic reticulum (ER) stress and neurodegeneration and targeting unfolded protein response (UPR) pathways, ER chaperones (e.g., P58IPK), and anti-inflammatory treatments show promise.
- The IRE1-XBP1 pathway regulates protein homeostasis and inflammation; XBP1s protects against ER stress in both retinal and brain neurons.
- The PERK-eIF2α pathway suppresses protein synthesis under stress but may induce apoptosis via ATF4 and CHOP if chronically activated.
- Age-related decline in metabolism, proteostasis, and neurovascular function intensifies disease progression and exacerbates molecular and cellular damage in both DR and AD.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty 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, multi-centre collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| 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 | 4 / 5 | 2025 — within 3 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 40760071) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Palacios, A. G., Zhang, S. X., & Acosta, M. L. (2025). Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.70497
Vancouver
Palacios AG, Zhang SX, Acosta ML. Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.70497. PMID: 40760071.
BibTeX
@article{palacios2025-40760071,
author = {Palacios, Adrián G and Zhang, Sarah X and Acosta, Mónica L},
title = {{Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.70497},
pmid = {40760071},
url = {https://doi.org/10.1002/alz.70497}
}
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