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Invited Commentary
July 10, 2020

Plasma Apolipoprotein E Levels and Risk of Dementia—You Are the Company You Keep

Author Affiliations
  • 1Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore
JAMA Netw Open. 2020;3(7):e209501. doi:10.1001/jamanetworkopen.2020.9501

Koch and colleagues1 report on the relationship between apolipoprotein E (apoE) levels within distinct high-density lipoproteins (HDL) fractions in plasma samples and risk of dementia in participants in the Ginkgo Evaluation of Memory Study (GEMS). Using a case-cohort design to assay archived plasma samples from 1351 GEMS participants, the investigators found that higher plasma apoE levels within the HDL fraction lacking apolipoprotein C-III (apoC3) were associated with both better cognition at baseline as well as reduced risk of incident all-cause dementia and Alzheimer disease (AD). This novel finding is provocative and raises additional questions about the potential role of apoE in the pathogenesis of dementia.

Although discovery of the ε4 allele of APOE gene as the strongest known genetic risk factor for sporadic AD was made more than 25 years ago,2 the precise mechanisms underlying this association remain unclear and the promise of APOE-guided AD therapies remains unrealized. APOE genotype also determines total plasma concentration of apoE protein, with lower levels observed in APOE ε4 carriers relative to noncarriers.3 Although plasma apoE concentrations are partially determined by APOE genotype and are inversely related to risk of AD and dementia, the biological mechanisms underlying this relationship are also not well understood. In healthy individuals with a normal circulating lipid profile, about 50% of circulating apoE protein is present in HDL.4 While the relationship between lower plasma HDL levels and increased risk of cardiovascular disease is well established, it has become increasingly clear that the molecular mechanisms underlying this association extend far beyond HDL concentrations and include the biological actions of other HDL-associated lipoproteins. The protective role of HDL in cardiovascular disease is believed to be mediated by its actions in enhancing cholesterol efflux from macrophage foam cells in the arterial wall as well as by anti-inflammatory and antithrombotic effects. However, these physiological roles of HDL can be disrupted by its associations with proinflammatory proteins such as apoC3, lipoprotein-associated phospholipase A2 (Lp-PLA2), and serum amyloid A1.5 Previous studies have established that higher apoC3 levels in HDL are associated with greater risk of coronary heart disease and diabetes—both established risk factors for dementia.6 The findings by Koch et al1 therefore raise the possibility that composition of the HDL-associated proteome may be a key determinant of apoE-associated risk of AD and all-cause dementia. Identifying HDL-associated protein cargo and apoE-interacting proteins in HDL fractions may hence provide further insights into the role of APOE in AD pathogenesis. Understanding the HDL-proteome has already provided intriguing clues about its complex roles in cardiovascular disease. HDL-associated proteins include complement factors and acute phase proteins suggesting that HDL plays an important role in the innate immune response.7 Furthermore, these studies reveal markers of dysfunctional HDL in patients with coronary artery disease including those related to oxidative damage. Extending these studies to elucidate the roles of HDL-associated apoE and other lipoproteins such as apoC3 and apoJ may provide a better understanding of their potential biological roles in mediating risk of dementia.

There may also be important clinical translational implications for the findings by Koch and colleagues. As multiple clinical trials have demonstrated the limitations of increasing plasma HDL levels as a therapeutic strategy against coronary artery disease, the potential clinical utility of targeting HDL-associated lipoproteins such as apoC3 has received increasing attention.8 These approaches may also be relevant to developing novel disease-modifying treatments for AD including apoE-based therapeutics targeting the complex interactions of these pleiotropic lipid mediators.

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Article Information

Published: July 10, 2020. doi:10.1001/jamanetworkopen.2020.9501

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Thambisetty M. JAMA Network Open.

Corresponding Author: Madhav Thambisetty, MD, PhD, Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, BRC Building, Room 4B-317, Baltimore, MD 21224 (thambisettym@mail.nih.gov).

Conflict of Interest Disclosures: None reported.

Koch  M, DeKosky  ST, Goodman  M,  et al.  Association of apolipoprotein E in lipoprotein subspecies with risk of dementia.   JAMA Netw Open. 2020;3(7):e209250. doi:10.1001/jamanetworkopen.2020.9250Google Scholar
Corder  EH, Saunders  AM, Strittmatter  WJ,  et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.   Science. 1993;261(5123):921-923. doi:10.1126/science.8346443PubMedGoogle ScholarCrossref
Martínez-Morillo  E, Hansson  O, Atagi  Y,  et al.  Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls.   Acta Neuropathol. 2014;127(5):633-643. doi:10.1007/s00401-014-1266-2PubMedGoogle ScholarCrossref
Castro  GR, Fielding  CJ.  Evidence for the distribution of apolipoprotein E between lipoprotein classes in human normocholesterolemic plasma and for the origin of unassociated apolipoprotein E (Lp-E).   J Lipid Res. 1984;25(1):58-67.PubMedGoogle Scholar
Zheng  C, Aikawa  M.  High-density lipoproteins: from function to therapy.   J Am Coll Cardiol. 2012;60(23):2380-2383. doi:10.1016/j.jacc.2012.08.999PubMedGoogle ScholarCrossref
Aroner  SA, Yang  M, Li  J,  et al.  Apolipoprotein C-III and high-density lipoprotein subspecies defined by apolipoprotein C-III in relation to diabetes risk.   Am J Epidemiol. 2017;186(6):736-744. doi:10.1093/aje/kwx143PubMedGoogle ScholarCrossref
Heinecke  JW.  The HDL proteome: a marker—and perhaps mediator—of coronary artery disease.   J Lipid Res. 2009;50(suppl):S167-S171. doi:10.1194/jlr.R800097-JLR200PubMedGoogle ScholarCrossref
Khetarpal  SA, Qamar  A, Millar  JS, Rader  DJ.  Targeting ApoC-III to reduce coronary disease risk.   Curr Atheroscler Rep. 2016;18(9):54. doi:10.1007/s11883-016-0609-yPubMedGoogle ScholarCrossref
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