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Progressive behavioral and cognitive decline in Drosophila harboring AD- associated APOE4 variants
Biglari S, Yeragi E, Bamisaye D, Gonzalez C, Garcia R, Losoya A, Arekere AD, Payne C et al.. bioRxiv, 2026-09-12
Topic: Genetics and APOE
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, and its incidence is rising rapidly with population aging. Pathologically, AD is characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau neurofibrillary tangles. Human genomic studies have identified numerous risk alleles, with the APOE4 variant representing the strongest and most common genetic risk factor, present in approximately 75% of AD patients. However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis. Emerging evidence highlights a central role for oxidized lipid metabolism in AD. Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility. To systematically investigate APOE function in vivo , we tested humanized Drosophila expressing the human APOE3, or APOE4 variants in place of the Drosophila ortholog Glial Lazarillo ( GLaz ). The lifespan of APOE3 and APOE4 flies do not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis. APOE4 flies exposed to rotenone exhibit several AD-associated phenotypes, including age-related memory loss and chemosensory deficits, supporting the use of this model to investigate AD pathogenesis. Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges. Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.
Key findings
- However, APOE4 is neither necessary nor sufficient to cause disease, suggesting that additional genetic and environmental factors contribute to AD pathogenesis.
- Disruption of lipid metabolism leads to lipid accumulation, reactive oxygen species (ROS) toxicity, and neurodegeneration, suggesting that oxidative stress may be a critical factor in enhancing AD susceptibility.
- The lifespan of APOE3 and APOE4 flies do not differ under standard housing conditions, but the lifespan of APOE4 flies is significantly reduced when exposed to the ROS-promoting drug rotenone, supporting a multi-hit model of disease pathogenesis.
- Furthermore, progressive AD-associated phenotypes are also observed in APOE4 flies maintained on an obesogenic diet, suggesting that enhanced disease susceptibility is not specific to rotenone-induced stress but reflects a broader vulnerability to metabolic challenges.
- Together, these findings establish a scalable model to dissect APOE-dependent mechanisms and identify therapeutic targets in AD.
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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 and randomised / 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 multi-centre 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 (bioRxiv) |
| 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 | Laboratory or animal study (title names “drosophila”) — scores zero |
| 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 | 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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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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.
APA 7th
Biglari, S., Yeragi, E., Bamisaye, D., Gonzalez, C., Garcia, R., Losoya, A., et al. (2026). Progressive behavioral and cognitive decline in Drosophila harboring AD- associated APOE4 variants. bioRxiv. https://doi.org/10.64898/2026.09.08.750261
Vancouver
Biglari S, Yeragi E, Bamisaye D, Gonzalez C, Garcia R, Losoya A, et al. Progressive behavioral and cognitive decline in Drosophila harboring AD- associated APOE4 variants. bioRxiv. 2026. doi:10.64898/2026.09.08.750261.
BibTeX
@article{biglari2026-bb67e0bb,
author = {Biglari, S. and Yeragi, E. and Bamisaye, D. and Gonzalez, C. and Garcia, R. and Losoya, A. and Arekere, A. D. and Payne, C. and others},
title = {{Progressive behavioral and cognitive decline in Drosophila harboring AD- associated APOE4 variants}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.08.750261},
url = {https://doi.org/10.64898/2026.09.08.750261}
}
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