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Distinct Aβ40 and Aβ42 co-assembly pathways with free lipids: Experiment-driven MD study
Pandey R, Olabi T, Lee M, Urbanc B.. bioRxiv, 2026-10-02
Topic: Disease mechanisms in lab and animal studies
Amyloid β-protein (Aβ), which is known for its role in Alzheimer's disease (AD), is also involved in several physiological functions. Of the two predominant isoforms, Aβ40 and Aβ42, the latter is more aggregation-prone and more active in health and disease. In the brain, Aβ interacts with free lipids, which may affect its assembly pathways. Here, thioflavin T (ThT) fluorescence spectroscopy is combined with molecular dynamics (MD) to investigate Aβ40 and Aβ42 co-assembly with free dimyristoylphosphatidylcholine (DMPC) and DMPC/cholesterol (CHOL) lipids. ThT measurements at several protein-to-lipid (PL) ratios show isoform- and lipid composition-dependent kinetics of Aβ fibril formation with clear isoform-dependent lipid effects at a PL ratio of 1:5. Early co-assembly stages of six Aβ40/Aβ42 with DMPC and DMPC/CHOL lipids at this PL ratio are then examined by MD. MD results indicate that lipids alter the secondary structure more and interact more avidly with Aβ40 than with Aβ42. In turn, Aβ40 increases the planar order of lipid bicelles more than Aβ42. Unlike Aβ40, Aβ42 decreases the nematic order of CHOL. In DMPC/CHOL lipids, Aβ42 but not Aβ40 exhibits two Aβ-lipid interaction modes associated with mutually exclusive Aβ42-lipid and Aβ42-Aβ42 interactions. Our MD findings provide a plausible explanation for an experimentally observed increase in the lag time for Aβ40 fibril formation in DMPC lipids and even more so in DMPC/CHOL lipids that contrasts with much smaller effects of lipids on Aβ42 fibril formation and offer additional atomistic-level insights into Aβ co-assembly with lipids amenable to experimental testing.
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APA 7th
Pandey, R., Olabi, T., Lee, M., & Urbanc, B. (2026). Distinct Aβ40 and Aβ42 co-assembly pathways with free lipids: Experiment-driven MD study. bioRxiv. https://doi.org/10.64898/2026.09.28.755027
Vancouver
Pandey R, Olabi T, Lee M, Urbanc B. Distinct Aβ40 and Aβ42 co-assembly pathways with free lipids: Experiment-driven MD study. bioRxiv. 2026. doi:10.64898/2026.09.28.755027.
BibTeX
@article{pandey2026-72021b1f,
author = {Pandey, R. and Olabi, T. and Lee, M. and Urbanc, B.},
title = {{Distinct Aβ40 and Aβ42 co-assembly pathways with free lipids: Experiment-driven MD study}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.28.755027},
url = {https://doi.org/10.64898/2026.09.28.755027}
}
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Key findings
- MD results indicate that lipids alter the secondary structure more and interact more avidly with Aβ40 than with Aβ42.
- In DMPC/CHOL lipids, Aβ42 but not Aβ40 exhibits two Aβ-lipid interaction modes associated with mutually exclusive Aβ42-lipid and Aβ42-Aβ42 interactions.
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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, studied in people 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 | 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 | 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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