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bioRxiv · 10.64898/2026.05.30.729004

Lipidated ApoE is found in nanoscale proximity to Aβ aggregates in human Alzheimer brains.

Owusu Kwarteng, D.·Jackson, R. J.·Nakajima, T.·Altig, K.·Melloni, A.·Oakley, D.·Serrano-Pozo, A.·Maesako, M.·Hyman, B.
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Abstract

Apolipoprotein E (APOE) associates with amyloid plaques (A{beta}) in Alzheimer disease (AD). The {varepsilon}4 allele of apolipoprotein E (APOE{varepsilon}4) is the strongest genetic risk factor for sporadic AD and exacerbates A{beta} plaque burden relative to APOE{varepsilon}3 and APOE{varepsilon}2. The majority of ApoE associates with multiple lipid classes to form lipoproteins both in the brain and the periphery. However, the lipidation status of A{beta} plaque-associated ApoE is not yet fully defined. Here, we use fluorescence lifetime imaging microscopy coupled with Forster resonance energy transfer (FLIM-FRET) to determine the lipidation status of ApoE in plaques, as well as the nanoscale spatial proximity of ApoE and A{beta} to anionic lipids and cholesterol within human AD brain tissue. We demonstrate that lipids are in close nanoscale proximity to ApoE and A{beta} within A{beta} plaques. Our results reveal that lipidated ApoE complexes enriched in anionic lipids and cholesterol are core constituents of AD plaques in-situ. We propose a pathological mechanism in which the surface presentation of anionic lipids on ApoE lipoproteins facilitates initial interaction with and subsequent aggregation of A{beta}.

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Owusu Kwarteng, D., Jackson, R. J., Nakajima, T., Altig, K., Melloni, A., Oakley, D., Serrano-Pozo, A., Maesako, M., Hyman, B.. 2026-06-03. Lipidated ApoE is found in nanoscale proximity to Aβ aggregates in human Alzheimer brains.. https://doi.org/10.64898/2026.05.30.729004

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