APOE-Targeted Therapeutics for Alzheimer's Disease
Hussein N Yassine, Cristelle Hugo, Bernadette O'Donovan, Isaiah O Stephens, Lance A Johnson, Gregory Cole, Julia Tcw, Jan Johansson et al.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2025-11-12
Topic: Inflammation, microglia and astrocytes
Apolipoprotein E (APOE) is the major lipid transport protein in the brain. Produced primarily by astrocytes and microglia, it delivers cholesterol and other lipids for membrane repair, synaptic maintenance, and immune regulation. Through interactions with specific lipid receptors, APOE maintains neuronal and vascular health. The APOE ε4 allele (APOE4), carried by approximately one-quarter of the population, has an altered protein conformation, which reduces lipid transport efficiency and modifies receptor binding. These changes disrupt lipid homeostasis, increase risk of chronic unresolved neuroinflammation and vascular inflammation, and cause breakdown of the blood-brain barrier (BBB), thus increasing neuronal vulnerability to disease pathology and elevating risk for Alzheimer's disease (AD). In this review, we organize the effects of APOE4 into three interconnected "hits" that modulate disease progression: disrupted lipid handling, neurovascular inflammation, and neuronal dysfunction. These interconnected hits help explain why amyloid- and tau-directed therapies alone have modest success in treating AD, particularly in APOE4 carriers. We review emerging APOE-related therapeutic strategies designed to address these mechanisms directly, including structure correctors to restore normal protein folding, agents that enhance lipidation and receptor-mediated lipid transport, approaches that modulate downstream inflammatory responses, and gene therapies aimed at isoform switching or allele silencing. By aligning therapeutic strategies with specific aspects of APOE4 biology, such approaches have the potential to provide broader and safer benefits, complement existing disease-modifying therapies, and improve outcomes for individuals at heightened genetic risk of AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Yassine, H. N., Hugo, C., O'Donovan, B., Stephens, I. O., Johnson, L. A., Cole, G., et al. (2025). APOE-Targeted Therapeutics for Alzheimer's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. https://doi.org/10.1523/jneurosci.1388-25.2025
Vancouver
Yassine HN, Hugo C, O'Donovan B, Stephens IO, Johnson LA, Cole G, et al. APOE-Targeted Therapeutics for Alzheimer's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2025. doi:10.1523/jneurosci.1388-25.2025. PMID: 41224653.
BibTeX
@article{yassine2025-41224653,
author = {Yassine, Hussein N and Hugo, Cristelle and O'Donovan, Bernadette and Stephens, Isaiah O and Johnson, Lance A and Cole, Gregory and Tcw, Julia and Johansson, Jan and others},
title = {{APOE-Targeted Therapeutics for Alzheimer's Disease}},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
year = {2025},
doi = {10.1523/jneurosci.1388-25.2025},
pmid = {41224653},
url = {https://doi.org/10.1523/jneurosci.1388-25.2025}
}
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- These changes disrupt lipid homeostasis, increase risk of chronic unresolved neuroinflammation and vascular inflammation, and cause breakdown of the blood-brain barrier (BBB), thus increasing neuronal vulnerability to disease pathology and elevating risk for Alzheimer's disease (AD).
- In this review, we organize the effects of APOE4 into three interconnected "hits" that modulate disease progression: disrupted lipid handling, neurovascular inflammation, and neuronal dysfunction.
- These interconnected hits help explain why amyloid- and tau-directed therapies alone have modest success in treating AD, particularly in APOE4 carriers.
- We review emerging APOE-related therapeutic strategies designed to address these mechanisms directly, including structure correctors to restore normal protein folding, agents that enhance lipidation and receptor-mediated lipid transport, approaches that modulate downstream inflammatory responses, and gene therapies aimed at isoform switching or allele silencing.
- By aligning therapeutic strategies with specific aspects of APOE4 biology, such approaches have the potential to provide broader and safer benefits, complement existing disease-modifying therapies, and improve outcomes for individuals at heightened genetic risk of AD.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 43/100
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, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of neuroscience : the official journal of the Society for Neuroscience) |
| 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 41224653) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
Related studies in Genetics
Also tagged “apoe2”
266 studies in the library carry the topic tag “apoe2”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 266 tagged studies.