The small HDL particle hypothesis of Alzheimer's disease

Ashley E Martinez; Gali Weissberger; Zsuzsanna Kuklenyik; Xulei He; Cristiana Meuret; Trusha Parekh; Jon C Rees; Bryan A Parks; Michael S Gardner; Sarah M King; Timothy S Collier; Michael G Harrington; Melanie D Sweeney; Xinhui Wang; Berislav V Zlokovic; Elizabeth Joe; Daniel A Nation; Lon S Schneider; Helena C Chui; John R Barr; S Duke Han; Ronald M Krauss; Hussein N Yassine

doi:10.1002/alz.12649

The small HDL particle hypothesis of Alzheimer's disease

Alzheimers Dement. 2023 Feb;19(2):391-404. doi: 10.1002/alz.12649. Epub 2022 Apr 13.

Authors

Ashley E Martinez¹, Gali Weissberger², Zsuzsanna Kuklenyik³, Xulei He¹, Cristiana Meuret¹, Trusha Parekh¹, Jon C Rees³, Bryan A Parks³, Michael S Gardner³, Sarah M King⁴, Timothy S Collier⁵, Michael G Harrington⁶, Melanie D Sweeney⁷, Xinhui Wang⁶, Berislav V Zlokovic⁷, Elizabeth Joe⁶, Daniel A Nation⁸, Lon S Schneider^{6

9}, Helena C Chui⁶, John R Barr³, S Duke Han¹⁰, Ronald M Krauss⁴, Hussein N Yassine^{1

6}

Affiliations

¹ Department of Medicine, University of Southern California, Los Angeles, California, USA.
² The Interdisciplinary Department of Social Sciences, Bar Ilan University, Israel.
³ Clinical Chemistry Branch, Division of Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁴ Departments of Pediatrics and Medicine, University of California, San Francisco, California, USA.
⁵ Quest Diagnostics, Cleveland HeartLab, Cleveland, Ohio, USA.
⁶ Department of Neurology, University of Southern California, Los Angeles, California, USA.
⁷ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA.
⁸ Irvine, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
⁹ Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, California, USA.
¹⁰ Department of Family Medicine, University of Southern California, Los Angeles, California, USA.

Abstract

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

Keywords: APOE; HDL; cerebrospinal fluid; cognition; lipidomics; proteomics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / cerebrospinal fluid
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoprotein E4
Apolipoproteins E
Brain
Cognition
Humans

Substances

Apolipoproteins E
Apolipoprotein E4
Amyloid beta-Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding