Zheng JJ, Hong BV, Agus JK, Tang X, Guo F, Lebrilla CB, Maezawa I, Jin LW, Vreeland WN, Ripple DC, Zivkovic AM. Analysis of TEM micrographs with deep learning reveals APOE genotype-specific associations between HDL particle diameter and Alzheimer's dementia. Cell Rep Methods. 2025 Jan 27;5(1):100962. PubMed.
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University of Southern California
Zheng et al. report a novel method, analyzing TEM micrographs of plasma HDL particles with a deep learning model, to measure diameters of individual HDL particles derived from a cohort of 183 participants stratified by cognitive status. This report provides a detailed analysis of HDL subclass distribution and finds a higher abundance of small HDLs in participants with dementia compared to controls in those with an APOE3/4 genotype, whereas people with the APOE3/3 genotype had higher variability in the abundance of different HDL subclasses.
This work underscores the importance of cholesterol metabolism in Alzheimer’s disease. A greater variability of different HDL species in people without Alzheimer’s suggests better HDL cholesterol transport and anti-inflammatory properties. While smaller HDL particles are efficient in cholesterol efflux ex vivo, failure of small HDL particles in vivo to mature into larger particles can result in poor exchange of cholesterol and a greater risk of inflammation.
Our recent work implicates oxidized cholesterol in the brains of patients with Alzheimer’s with a paradoxical increase in ABCA1 expression, but not function (Wang et al., 2025). Whether the smaller HDL particles described in this report can travel into the brain and efficiently participate in cholesterol exchange remain to be determined.
References:
Wang S, Li B, Li J, Cai Z, Hugo C, Sun Y, Qian L, Tcw J, Chui HC, Dikeman D, Asante I, Louie SG, Bennett DA, Arvanitakis Z, Remaley AT, Kerman BE, Yassine HN. Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD. Mol Neurodegener. 2025 Feb 4;20(1):15. PubMed.
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