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. BarrS. Duke Han, Ronald M. Krauss, Hussein N. Yassine

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Pages (from-to)391-404
Number of pages14
JournalAlzheimer's and Dementia
Issue number2
Early online date13 Apr 2022
StatePublished - Feb 2023

Bibliographical note

Funding Information:
HNY is supported by R21AG056518, R01AG055770, R01AG054434, R01AG067063 from the National Institute on Aging (NIA), and from the Batey Foundation (Ion Mobility Instrumentation). SDH was supported by R01AG055430 and RF1AG068166. XW was supported by R01AG033078, RF1AG054068, R01ES025888, P50AG005142, and P30AG066530. MGH was supported by the L.K. Whittier Foundation and HMRI Aging Research Program: RO1AG054434, and R01AG055770, and P01AG052350. RMK was supported by P50GM115318, the Dairy Research Institute, Quest Diagnostics, and Saliogen. GW received support from T32 AG000037. ZK received support from the Centers for Disease Control and Prevention allocated for Cardiovascular Biomarker Research. LSS is supported by P30 AG066530, grants/contracts from Eisai, Eli Lilly, Roche/Genentech, Biogen, Biohaven, Novartis, and Washington University/NIA DIAN‐TU paid to the institution, and is also supported by the Della Martin Foundation. BVZ receives support from P01AG052350, P50AG005142, R01NS034467, R01AG039452, R01AG023084, Alzheimer's Association strategic 509279 grant, Cure Alzheimer's Fund, the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference no.16 CVD 05, and Open Philanthropy. HCC receives support from P30AG066530, P01G052350, AG058162, R01AG055770, R01AG054434, ES025888, RF1AG054068, R56AG069130, and R01AG072490. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Publisher Copyright:
© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.


  • APOE
  • HDL
  • cerebrospinal fluid
  • cognition
  • lipidomics
  • proteomics


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