The longevity gene APOE2 enhances pericyte function and reduces lipid droplets
Rais Reskiawan A Kadir, Joanna Bons, Genesis Vega Hormazabal, Prasanna Vadhana Ashok Kumaar, Cristian Gerónimo-Olvera, Kizito-Tshitoko Tshilenge, Philippe Pihán, Carlos Galicia Aguirre et al.. Brain : a journal of neurology, 2026-09-16
Topic: Genetics and APOE
Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity. To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation. Using unbiased proteomic profiling to understand these cellular phenotypes, we found significant alterations in lipid metabolism-related proteins. Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet (LD) accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated LD accumulation in APOE3 and APOE4 pericytes. Collectively, these findings demonstrate that APOE2 expression supports pericyte functionality through increased lipid processing, providing mechanistic insight into the cerebrovascular protective effects of APOE2 in pericytes. These findings could be translated into novel therapies aimed at enhancing pericyte function and lipid metabolism, particularly in individuals at risk for neurodegenerative diseases.
Key findings
- Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear.
- We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity.
- Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity.
- Using unbiased proteomic profiling to understand these cellular phenotypes, we found significant alterations in lipid metabolism-related proteins.
- Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing.
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Study details
- Evidence strengthLow
How this study scored 48/100
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 27 of the 56 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| 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 42744302) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 27 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 27 of the 56 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
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APA 7th
Kadir, R. R. A., Bons, J., Hormazabal, G. V., Kumaar, P. V. A., Gerónimo-Olvera, C., Tshilenge, K.-T., et al. (2026). The longevity gene APOE2 enhances pericyte function and reduces lipid droplets. Brain : a journal of neurology. https://doi.org/10.1093/brain/awag311
Vancouver
Kadir RRA, Bons J, Hormazabal GV, Kumaar PVA, Gerónimo-Olvera C, Tshilenge K.-T, et al. The longevity gene APOE2 enhances pericyte function and reduces lipid droplets. Brain : a journal of neurology. 2026. doi:10.1093/brain/awag311. PMID: 42744302.
BibTeX
@article{kadir2026-42744302,
author = {Kadir, Rais Reskiawan A and Bons, Joanna and Hormazabal, Genesis Vega and Kumaar, Prasanna Vadhana Ashok and Gerónimo-Olvera, Cristian and Tshilenge, Kizito-Tshitoko and Pihán, Philippe and Aguirre, Carlos Galicia and others},
title = {{The longevity gene APOE2 enhances pericyte function and reduces lipid droplets}},
journal = {Brain : a journal of neurology},
year = {2026},
doi = {10.1093/brain/awag311},
pmid = {42744302},
url = {https://doi.org/10.1093/brain/awag311}
}