Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2019

Open Access 01-12-2019 | Alzheimer's Disease | Review

ApoE4: an emerging therapeutic target for Alzheimer’s disease

Authors: Mirna Safieh, Amos D. Korczyn, Daniel M. Michaelson

Published in: BMC Medicine | Issue 1/2019

Login to get access

Abstract

Background

The growing body of evidence indicating the heterogeneity of Alzheimer’s disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that the development of a single magic cure suitable for all cases may not be possible. This calls for a shift in paradigm where targeted treatment is developed for specific AD subpopulations that share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of AD, is expressed in more than half of AD patients and is thus an important possible AD therapeutic target.

Review

This review focuses initially on the pathological effects of apoE4 in AD, as well as on the corresponding cellular and animal models and the suggested cellular and molecular mechanisms which mediate them. The second part of the review focuses on recent apoE4-targeted (from the APOE gene to the apoE protein and its interactors) therapeutic approaches that have been developed in animal models and are ready to be translated to human. Further, the issue of whether the pathological effects of apoE4 are due to loss of protective function or due to gain of toxic function is discussed herein. It is possible that both mechanisms coexist, with certain constituents of the apoE4 molecule and/or its downstream signaling mediating a toxic effect, while others are associated with a loss of protective function.

Conclusion

ApoE4 is a promising AD therapeutic target that remains understudied. Recent studies are now paving the way for effective apoE4-directed AD treatment approaches.
Literature
1.
Giacobini E, Gold G. Alzheimer disease therapy--moving from amyloid-β to tau. Nat Rev Neurol. 2013;9(12):677–86.PubMedCrossRef
2.
Iqbal K, Liu F, Gong C-X. Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol. 2014;88(4):631–9.PubMedPubMedCentralCrossRef
3.
4.
Iturria-Medina Y, Hachinski V, Evans AC. The vascular facet of late-onset Alzheimer’s disease: an essential factor in a complex multifactorial disorder. Curr Opin Neurol. 2017;30(6):623–9.PubMedCrossRef
5.
Vijayan M, Kumar S, Bhatti JS, Reddy PH. Molecular links and biomarkers of stroke, vascular dementia, and Alzheimer’s disease. Prog Mol Biol Transl Sci. 2017;146:95–126.PubMedCrossRef
6.
Naj AC, Schellenberg GD. Alzheimer’s disease genetics consortium (ADGC). Genomic variants, genes, and pathways of Alzheimer’s disease: an overview. Am J Med Genet B Neuropsychiatr Genet. 2017;174(1):5–26.PubMedPubMedCentralCrossRef
7.
Apostolova LG, Risacher SL, Duran T, et al. Associations of the top 20 Alzheimer disease risk variants with brain amyloidosis. JAMA Neurol. 2018;75(3):328–41.PubMedPubMedCentralCrossRef
8.
9.
Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255–63.PubMedCrossRef
10.
Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci. 1996;19(1):53–77.PubMedCrossRef
11.
Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimers Dement. 2014;10(6):861–8.PubMedCrossRef
12.
Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(3):a006312.PubMedPubMedCentralCrossRef
13.
Di Battista AM, Heinsinger NM, Rebeck GW. Alzheimer’s disease genetic risk factor APOE-ε4 also affects normal brain function. Curr Alzheimer Res. 2016;13(11):1200–7.PubMedCrossRef
14.
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):633–43.PubMedCrossRef
15.
Feingold KR, Grunfeld C. Introduction to lipids and lipoproteins. South Dartmouth: MDText.com, Inc.; 2000.
16.
17.
18.
Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol. 2017;133(2):155–75.PubMedCrossRef
19.
20.
Chapman J, Korczyn AD, Karussis DM, Michaelson DM. The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurol. 2001;57(8):1482–5.CrossRef
21.
Rannikmae K, Kalaria RN, Greenberg SM, et al. APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis. J Neurol Neurosurg Psychiatry. 2014;85(3):300–5.PubMedCrossRef
22.
23.
Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7.PubMedPubMedCentralCrossRef
24.
Treves TA, Bornstein NM, Chapman J, et al. APOE-epsilon 4 in patients with Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord. 1996;10(4):189–91.PubMedCrossRef
25.
Shin S, Walz KA, Archambault AS, et al. Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis. J Neuroimmunol. 2014;271(1–2):8–17.PubMedPubMedCentralCrossRef
26.
Chapman J, Vinokurov S, Achiron A, et al. APOE genotype is a major predictor of long-term progression of disability in MS. Neurol. 2001;56(3):312–6.CrossRef
27.
Liu B, Shen Y, Cen L, Tang Y. Apolipoprotein E gene polymorphism in a Chinese population with vascular dementia: a meta-analysis. Dement Geriatr Cogn Disord. 2012;33(2–3):96–103.PubMedCrossRef
28.
Li L, Bao Y, He S, et al. The association between apolipoprotein E and functional outcome after traumatic brain injury. Medicine (Baltimore). 2015;94(46):e2028.CrossRef
29.
Kassam I, Gagnon F, Cusimano MD. Association of the APOE-ε4 allele with outcome of traumatic brain injury in children and youth: a meta-analysis and meta-regression. J Neurol Neurosurg Psychiatry. 2016;87(4):433–40.PubMedCrossRef
30.
Xiying M, Wenbo W, Wangyi F, Qinghuai L. Association of apolipoprotein E polymorphisms with age-related macular degeneration subtypes: an updated systematic review and meta-analysis. Arch Med Res. 2017;48(4):370–7.PubMedCrossRef
31.
Espina M, Arcinue CA, Ma F, et al. Outer retinal tubulations response to anti-VEGF treatment. Br J Ophthalmol. 2016;100(6):819–23.PubMedCrossRef
32.
Koch G, Di Lorenzo F, Loizzo S, et al. CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer’s disease. Sci Rep. 2017;7(1):13728.PubMedPubMedCentralCrossRef
33.
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A. 2010;107(26):12011–6.PubMedPubMedCentralCrossRef
34.
35.
Chung W-S, Verghese PB, Chakraborty C, et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci. 2016;113(36):10186–91.PubMedCrossRefPubMedCentral
36.
Masuda T, Shimazawa M, Hashimoto Y, et al. Apolipoprotein E2 and E3, but not E4, promote retinal pathologic neovascularization. Invest Ophthalmol Vis Sci. 2017;58(2):1208–17.PubMedCrossRef
37.
Mishra A, Ferrari R, Heutink P, et al. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain. 2017;140(5):1437–46.PubMedCrossRef
38.
Stevens M, van Duijn CM, de Knijff P, et al. Apolipoprotein E gene and sporadic frontal lobe dementia. Neurol. 1997;48(6):1526–9.CrossRef
39.
Hofman A, Ott A, Breteler MM, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet. 1997;349(9046):151–4.PubMedCrossRef
40.
McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurol. 1999;53(6):1308–11.CrossRef
41.
Newman MF, Laskowitz DT, White WD, et al. Apolipoprotein E polymorphisms and age at first coronary artery bypass graft. Anesth Analg. 2001;92(4):824–9.PubMedCrossRef
42.
Schneider JA, Bienias JL, Wilson RS, et al. The apolipoprotein E epsilon4 allele increases the odds of chronic cerebral infarction [corrected] detected at autopsy in older persons. Stroke. 2005;36(5):954–9.PubMedCrossRef
43.
Chapman J, Wang N, Treves TA, Korczyn AD, Bornstein NM. ACE, MTHFR, factor V Leiden, and APOE polymorphisms in patients with vascular and Alzheimer’s dementia. Stroke. 1998;29(7):1401–4.PubMedCrossRef
44.
Sudlow C, Martínez González NA, Kim J, Clark C. Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. Stroke. 2006;37(2):364–70.PubMedCrossRef
45.
Poels MMF, Vernooij MW, Ikram MA, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41(10 Suppl):S103–6.PubMedCrossRef
46.
Hanson AJ, Craft S, Banks WA. The APOE genotype: modification of therapeutic responses in Alzheimer’s disease. Curr Pharm Des. 2015;21(1):114–20.PubMedCrossRef
47.
Dorey E, Chang N, Liu QY, Yang Z, Zhang W. Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer’s disease. Neurosci Bull. 2014;30(2):317–30.PubMedPubMedCentralCrossRef
48.
49.
Kok E, Haikonen S, Luoto T, et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol. 2009;65(6):650–7.PubMedCrossRef
50.
Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995;333(19):1242–7.PubMedCrossRef
51.
Shinohara M, Petersen RC, Dickson DW, Bu G. Brain regional correlation of amyloid-β with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-β accumulation. Acta Neuropathol. 2013;125(4):535–47.PubMedPubMedCentralCrossRef
52.
Huynh T-PV, Davis AA, Ulrich JD, Holtzman DM. Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J Lipid Res. 2017;58(5):824–36.PubMedPubMedCentralCrossRef
53.
Tai LM, Bilousova T, Jungbauer L, et al. Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem. 2013;288(8):5914–26.PubMedPubMedCentralCrossRef
54.
Liu S, Park S, Allington G, et al. Targeting apolipoprotein E/amyloid β binding by peptoid CPO_Aβ17-21 P ameliorates Alzheimer’s disease related pathology and cognitive decline. Sci Rep. 2017;7(1):8009.PubMedPubMedCentralCrossRef
55.
56.
Du J, Chang J, Guo S, Zhang Q, Wang Z. ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neurosci Lett. 2009;464(2):140–5.PubMedCrossRef
57.
Nielsen HM, Mulder SD, Beliën JAM, et al. Astrocytic Aβ1-42 uptake is determined by Aβ-aggregation state and the presence of amyloid-associated proteins. Glia. 2010;58(10):1235–46.PubMedCrossRef
58.
59.
Zekonyte J, Sakai K, Nicoll JAR, Weller RO, Carare RO. Quantification of molecular interactions between ApoE, amyloid-beta (Aβ) and laminin: relevance to accumulation of Aβ in Alzheimer’s disease. Biochim Biophys Acta. 2016;1862(5):1047–53.PubMedCrossRef
60.
Rodriguez GA, Tai LM, LaDu MJ, Rebeck GW. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation. 2014;11(1):111.PubMedPubMedCentralCrossRef
61.
Kim J, Yoon H, Basak J, Kim J. Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Mol Cell. 2014;37(11):767–76.CrossRef
62.
Liao F, Yoon H, Kim J. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Curr Opin Lipidol. 2017;28(1):60–7.PubMedPubMedCentral
63.
Poirier J, Miron J, Picard C, et al. Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease. Neurobiol Aging. 2014;35(Suppl 2):S3–10.PubMedPubMedCentralCrossRef
64.
Tai LM, Ghura S, Koster KP, et al. APOE-modulated Aβ-induced neuroinflammation in Alzheimer’s disease: current landscape, novel data, and future perspective. J Neurochem. 2015;133(4):465–88.PubMedPubMedCentralCrossRef
65.
Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012;335(6075):1503–6.PubMedPubMedCentralCrossRef
66.
Hampel H, Blennow K, Shaw LM, et al. Total and phosphorylated tau protein as biological markers of Alzheimer’s disease. Exp Gerontol. 2010;45(1):30–40.PubMedCrossRef
67.
Damoiseaux JS, Seeley WW, Zhou J, et al. Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J Neurosci. 2012;32(24):8254–62.PubMedPubMedCentralCrossRef
68.
Leoni V. The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer’s disease. Clin Chem Lab Med. 2011;49(3):375–83.PubMedCrossRef
69.
Salomon-Zimri S, Glat MJ, Barhum Y, et al. Reversal of ApoE4-driven brain pathology by vascular endothelial growth factor treatment. J Alzheimers Dis. 2016;53(4):1443–58.PubMedCrossRef
70.
Liraz O, Boehm-Cagan A, Michaelson DM. ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol Neurodegener. 2013;8(1):16.PubMedPubMedCentralCrossRef
71.
Genis I, Gordon I, Sehayek E, Michaelson DM. Phosphorylation of tau in apolipoprotein E-deficient mice. Neurosci Lett. 1995;199(1):5–8.PubMedCrossRef
72.
Tesseur I, Van Dorpe J, Spittaels K, et al. Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol. 2000;156(3):951–64.PubMedPubMedCentralCrossRef
73.
Mannix R, Meehan WP, Mandeville J, et al. Clinical correlates in an experimental model of repetitive mild brain injury. Ann Neurol. 2013;74(1):65–75.PubMedPubMedCentralCrossRef
74.
75.
Dubnikov T, Cohen E. The emerging roles of early protein folding events in the secretory pathway in the development of neurodegenerative maladies. Front Neurosci. 2017;11:48.PubMedPubMedCentralCrossRef
76.
Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase. J Biol Chem. 2004;279(43):44795–801.PubMedCrossRef
77.
Brecht WJ, Harris FM, Chang S, et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24(10):2527–34.PubMedCrossRefPubMedCentral
78.
Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J Biol Chem. 2004;279(43):44795–801.PubMedCrossRef
79.
Wennberg AM, Tosakulwong N, Lesnick TG, et al. Association of apolipoprotein E ε4 with transactive response DNA-binding protein 43. JAMA Neurol. 2018;75(11):1347–54.PubMedCrossRefPubMedCentral
80.
Yang H-S, Yu L, White CC, et al. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol. 2018;17(9):773–81.PubMedCrossRefPubMedCentral
81.
Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141(7):2181–93.PubMedCrossRefPubMedCentral
82.
Lemke S, Vicini J, Su H. Dietary intake of stearidonic acid – enriched soybean oil increases the omega-3 index : randomized, double-blind clinical study of efficacy and safety. Am J Clin Nutr. 2010;92(4):766–75.PubMedCrossRef
83.
Belkouch M, Hachem M, Elgot A, et al. The pleiotropic effects of omega-3 docosahexaenoic acid on the hallmarks of Alzheimer’s disease. J Nutr Biochem. 2016;38:1–11.PubMedCrossRef
84.
Nock TG, Chouinard-Watkins R, Plourde M. Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862(10 Pt A):1068–78.PubMedCrossRef
85.
86.
Salem N, Vandal M, Calon F. The benefit of docosahexaenoic acid for the adult brain in aging and dementia. Prostaglandins Leukot Essent Fat Acids. 2015;92:15–22.CrossRef
87.
Kariv-Inbal Z, Yacobson S, Berkecz R, et al. The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. J Alzheimers Dis. 2012;28(3):667–83.PubMedCrossRef
88.
Yassine HN, Braskie MN, Mack WJ, et al. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E ε4 carriers. JAMA Neurol. 2017;74(3):339.PubMedPubMedCentralCrossRef
89.
Harris JR, Milton NGN. Cholesterol in Alzheimer’s disease and other amyloidogenic disorders. Subcell Biochem. 2010;51:47–75.PubMedCrossRef
90.
Zhu L, Zhong M, Elder GA, et al. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis. Proc Natl Acad Sci U S A. 2015;112(38):11965–70.PubMedPubMedCentralCrossRef
91.
Grimm MOW, Zimmer VC, Lehmann J, Grimm HS, Hartmann T. The impact of cholesterol, DHA, and sphingolipids on Alzheimer’s disease. Biomed Res Int. 2013;2013:814390.PubMedCrossRef
92.
Zinser EG, Hartmann T, Grimm MOW. Amyloid beta-protein and lipid metabolism. Biochim Biophys Acta Biomembr. 2007;1768(8):1991–2001.CrossRef
93.
Vestergaard M, Hamada T, Morita M, Takagi M. Cholesterol, lipids, amyloid beta, and Alzheimers. Curr Alzheimer Res. 2010;7(3):262–70.PubMedCrossRef
94.
Bangen KJ, Beiser A, Delano-Wood L, et al. APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline. J Stroke Cerebrovasc Dis. 2013;22(8):1361–9.PubMedCrossRef
95.
Anstey KJ, Lipnicki DM, Low L-F. Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry. 2008;16(5):343–54.PubMedCrossRef
96.
97.
Hu J, Liu C-C, Chen X-F, et al. Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice. Mol Neurodegener. 2015;10(1):6.PubMedPubMedCentralCrossRef
98.
Yassine HN, Rawat V, Mack WJ, et al. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther. 2016;8(1):25.PubMedPubMedCentralCrossRef
99.
Heinsinger NM, Gachechiladze MA, Rebeck GW. Apolipoprotein E genotype affects size of ApoE complexes in cerebrospinal fluid. J Neuropathol Exp Neurol. 2016;75(10):918–24.PubMedCrossRefPubMedCentral
100.
Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem. 2008;104(5):1145–66.PubMedCrossRef
101.
Wahrle SE, Jiang H, Parsadanian M, et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004;279(39):40987–93.PubMedCrossRef
102.
Fitz NF, Cronican AA, Saleem M, et al. Abca1 deficiency affects Alzheimer’s disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci. 2012;32(38):13125–36.PubMedPubMedCentralCrossRef
103.
Boehm-Cagan A, Bar R, Liraz O, et al. ABCA1 agonist reverses the ApoE4-driven cognitive and brain pathologies. J Alzheimers Dis. 2016;54(3):1219–33.PubMedCrossRef
104.
Boehm-Cagan A, Bar R, Harats D, et al. Differential effects of apoE4 and activation of ABCA1 on brain and plasma lipoproteins. PLoS One. 2016;11(11):e0166195.PubMedPubMedCentralCrossRef
105.
Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol. 2013;108:21–43.PubMedCrossRef
106.
Chen HK, Ji ZS, Dodson SE, et al. Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for alzheimer disease. J Biol Chem. 2011;286(7):5215–21.PubMedCrossRef
107.
Chang S, ran Ma T, Miranda RD, et al. Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci U S A. 2005;102(51):18694–9.PubMedPubMedCentralCrossRef
108.
Wolf AB, Caselli RJ, Reiman EM, Valla J. APOE and neuroenergetics: an emerging paradigm in Alzheimer’s disease. Neurobiol Aging. 2013;34(4):1007–17.PubMedCrossRef
109.
Zhou M, Huang T, Collins N, et al. APOE4 induces site-specific tau phosphorylation through calpain-CDK5 signaling pathway in EFAD-Tg mice. Curr Alzheimer Res. 2016;13(9):1048–55.PubMedCrossRef
110.
Friedland-Leuner K, Stockburger C, Denzer I, Eckert GP, Müller WE. Mitochondrial dysfunction: cause and consequence of Alzheimer’s disease. Prog Mol Biol Transl Sci. 2014;127:183–210.PubMedCrossRef
111.
Tesseur I, Van Dorpe J, Bruynseels K, et al. Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol. 2000;157(5):1495–510.PubMedPubMedCentralCrossRef
112.
113.
Kolev MV, Ruseva MM, Harris CL, Morgan BP, Donev RM. Implication of complement system and its regulators in Alzheimer’s disease. Curr Neuropharmacol. 2009;7(1):1–8.PubMedPubMedCentralCrossRef
114.
McGeer PL, Rogers J, McGeer EG. Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years. J Alzheimers Dis. 2016;54(3):853–7.PubMedCrossRef
115.
Zhang S, Li X, Ma G, et al. CLU rs9331888 polymorphism contributes to Alzheimer’s disease susceptibility in Caucasian but not east Asian populations. Mol Neurobiol. 2016;53(3):1446–51.PubMedCrossRef
116.
Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci. 2016;17(4):201–7.PubMedCrossRef
117.
118.
Reale M, Kamal MA, Velluto L, et al. Relationship between inflammatory mediators, Abeta levels and ApoE genotype in Alzheimer disease. Curr Alzheimer Res. 2012;9(4):447–57.PubMedPubMedCentralCrossRef
119.
Gorelick PB. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann N Y Acad Sci. 2010;1207(1):155–62.PubMedCrossRef
120.
Härtig W, Brückner G, Schmidt C, et al. Co-localization of beta-amyloid peptides, apolipoprotein E and glial markers in senile plaques in the prefrontal cortex of old rhesus monkeys. Brain Res. 1997;751(2):315–22.PubMedCrossRef
121.
Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci U S A. 2010;107(48):20816–21.PubMedPubMedCentralCrossRef
122.
Du Z, Jia H, Liu J, Zhao X, Xu W. Effects of three hydrogen-rich liquids on hemorrhagic shock in rats. J Surg Res. 2015;193(1):377–82.PubMedCrossRef
123.
Ophir G, Amariglio N, Jacob-Hirsch J, et al. Apolipoprotein E4 enhances brain inflammation by modulation of the NF-kappaB signaling cascade. Neurobiol Dis. 2005;20(3):709–18.PubMedCrossRef
124.
Cash JG, Kuhel DG, Basford JE, et al. Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. J Biol Chem. 2012;287(33):27876–84.PubMedPubMedCentralCrossRef
125.
Li X, Montine KS, Keene CD, Montine TJ. Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. FASEB J. 2015;29(5):1754–62.PubMedPubMedCentralCrossRef
126.
Fan Y-Y, Cai Q-L, Gao Z-Y, et al. APOE ε4 allele elevates the expressions of inflammatory factors and promotes Alzheimer’s disease progression: a comparative study based on Han and she populations in the Wenzhou area. Brain Res Bull. 2017;132:39–43.PubMedCrossRef
127.
Teter B, LaDu MJ, Sullivan PM, Frautschy SA, Cole GM. Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain. Neuroreport. 2016;23(7):829–38.
128.
Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283(46):31315–22.PubMedPubMedCentralCrossRef
129.
Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, et al. Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging. 2015;32(2):139–47.PubMedCrossRef
130.
131.
Raffai RL, Weisgraber KH. Cholesterol: from heart attacks to Alzheimer’s disease. J Lipid Res. 2003;44(8):1423–30.PubMedCrossRef
132.
133.
Mielke MM, Leoutsakos J-M, Tschanz JT, et al. Interaction between vascular factors and the APOE ε4 allele in predicting rate of progression in Alzheimer’s disease. J Alzheimers Dis. 2011;26(1):127–34.PubMedPubMedCentralCrossRef
134.
Bell RD. The imbalance of vascular molecules in Alzheimer’s disease. J Alzheimers Dis. 2012;32(3):699–709.PubMedCrossRef
135.
136.
Saito S, Yamamoto Y, Ihara M. Mild cognitive impairment: at the crossroad of neurodegeneration and vascular dysfunction. Curr Alzheimer Res. 2015;12(6):507–12.PubMedCrossRef
137.
Schöberl F, Eren OE, Wollenweber FA, Kraus T, Kellert L. Sporadic cerebral amyloid angiopathy: an overview with clinical cases. Fortschr Neurol Psychiatr. 2016;84(9):534–41.PubMedCrossRef
138.
Cortes-Canteli M, Zamolodchikov D, Ahn HJ, Strickland S, Norris EH. Fibrinogen and altered hemostasis in Alzheimer’s disease. J Alzheimers Dis. 2012;32(3):599–608.PubMedPubMedCentralCrossRef
139.
Ahn HJ, Chen Z-L, Zamolodchikov D, Norris EH, Strickland S. Interactions of β-amyloid peptide with fibrinogen and coagulation factor XII may contribute to Alzheimer’s disease. Curr Opin Hematol. 2017;24(5):427–31.PubMedPubMedCentralCrossRef
140.
Hultman K, Strickland S, Norris EH. The APOE ɛ4/ɛ4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer’s disease patients. J Cereb Blood Flow Metab. 2013;33(8):1251–8.PubMedPubMedCentralCrossRef
141.
Deane R, Sagare A, Hamm K, et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118(12):4002–13.PubMedPubMedCentralCrossRef
142.
Stanley M, Macauley SL, Holtzman DM. Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J Exp Med. 2016;213(8):1375–85.PubMedPubMedCentralCrossRef
143.
Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63–80.PubMedCrossRef
144.
Yarchoan M, Toledo JB, Lee EB, et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol. 2014;128(5):679–89.PubMedPubMedCentralCrossRef
145.
Moloney AM, Griffin RJ, Timmons S, et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31(2):224–43.PubMedCrossRef
146.
Keeney JT-R, Ibrahimi S, Zhao L. Human ApoE isoforms differentially modulate glucose and amyloid metabolic pathways in female brain: evidence of the mechanism of neuroprotection by ApoE2 and implications for Alzheimer’s disease prevention and early intervention. J Alzheimers Dis. 2015;48(2):411–24.PubMedPubMedCentralCrossRef
147.
Zhao N, Liu C-C, Van Ingelgom AJ, et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron. 2017;96(1):115–29.e5.PubMedPubMedCentralCrossRef
148.
Traversy M-T, Vandal M, Tremblay C, et al. Altered cerebral insulin response in transgenic mice expressing the epsilon-4 allele of the human apolipoprotein E gene. Psychoneuroendocrinol. 2017;77:203–10.CrossRef
149.
Chan ES, Chen C, Cole GM, Wong B-S. Differential interaction of apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice. Sci Rep. 2015;5(1):13842.PubMedPubMedCentralCrossRef
150.
Ong Q-R, Chan ES, Lim M-L, Cole GM, Wong B-S. Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice. Sci Rep. 2014;4(1):3754.PubMedPubMedCentralCrossRef
151.
Freiherr J, Hallschmid M, Frey WH, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27(7):505–14.PubMedPubMedCentralCrossRef
152.
Avgerinos KI, Kalaitzidis G, Malli A, et al. Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: a systematic review. J Neurol. 2018;265(7):1497–510.PubMedCrossRefPubMedCentral
153.
Claxton A, Baker LD, Hanson A, et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis. 2015;44(3):897–906.PubMedCrossRef
154.
Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323–31.PubMedPubMedCentralCrossRef
155.
Licht T, Keshet E. Delineating multiple functions of VEGF-A in the adult brain. Cell Mol Life Sci. 2013;70(10):1727–37.PubMedCrossRef
156.
Mateo I, Llorca J, Infante J, et al. Low serum VEGF levels are associated with Alzheimer’s disease. Acta Neurol Scand. 2007;116(1):56–8.PubMedCrossRef
157.
Tang H, Mao X, Xie L, Greenberg DA, Jin K. Expression level of vascular endothelial growth factor in hippocampus is associated with cognitive impairment in patients with Alzheimer’s disease. Neurobiol Aging. 2013;34(5):1412–5.PubMedCrossRef
158.
Chiappelli M, Borroni B, Archetti S, et al. VEGF gene and phenotype relation with Alzheimer’s disease and mild cognitive impairment. Rejuvenation Res. 2006;9(4):485–93.PubMedCrossRef
159.
Boros BD, Greathouse KM, Gentry EG, et al. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 2017;82(4):602–14.PubMedPubMedCentralCrossRef
160.
Androuin A, Potier B, Nägerl UV, et al. Evidence for altered dendritic spine compartmentalization in Alzheimer’s disease and functional effects in a mouse model. Acta Neuropathol. 2018;135(6):839–54.PubMedCrossRef
161.
Rodriguez GA, Burns MP, Weeber EJ, Rebeck GW. Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex. Learn Mem. 2013;20(5):256–66.PubMedPubMedCentralCrossRef
162.
Dumanis SB, Tesoriero JA, Babus LW, et al. ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo. J Neurosci. 2009;29(48):15317–22.PubMedPubMedCentralCrossRef
163.
Wang Y, Manis PB. Synaptic transmission at the cochlear nucleus endbulb synapse during age-related hearing loss in mice. J Neurophysiol. 2005;94(3):1814–24.PubMedCrossRef
164.
Ashford JW. APOE genotype effects on Alzheimer’s disease onset and epidemiology. J Mol Neurosci. 2004;23(3):157–66.PubMedCrossRef
165.
Shinohara M, Tachibana M, Kanekiyo T, Bu G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res. 2017;58(7):1267–81.PubMedPubMedCentralCrossRef
166.
Hayashi H, Campenot RB, Vance DE, Vance JE. Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1. J Neurosci. 2007;27(8):1933–41.PubMedCrossRefPubMedCentral
167.
Sen A, Alkon DL, Nelson TJ. Apolipoprotein E3 (ApoE3) but not ApoE4 protects against synaptic loss through increased expression of protein kinase C epsilon. J Biol Chem. 2012;287(19):15947–58.PubMedPubMedCentralCrossRef
168.
Ulrich V, Konaniah ES, Herz J, et al. Genetic variants of ApoE and ApoER2 differentially modulate endothelial function. Proc Natl Acad Sci U S A. 2014;111(37):13493–8.PubMedPubMedCentralCrossRef
169.
Martinelli N, Olivieri O, Shen G-Q, et al. Additive effect of LRP8/APOER2 R952Q variant to APOE epsilon2/epsilon3/epsilon4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study. BMC Med Genet. 2009;10(1):41.PubMedPubMedCentralCrossRef
170.
171.
Li J, Kanekiyo T, Shinohara M, et al. Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem. 2012;287(53):44593–601.PubMedPubMedCentralCrossRef
172.
Belinson H, Lev D, Masliah E, Michaelson DM. Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. J Neurosci. 2008;28(18):4690–701.PubMedPubMedCentralCrossRef
173.
Gilat-Frenkel M, Boehm-Cagan A, Liraz O, et al. Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo. Curr Alzheimer Res. 2014;11(6):549–57.PubMedPubMedCentralCrossRef
174.
Maezawa I, Nivison M, Montine KS, Maeda N, Montine TJ. Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J. 2006;20(6):797–9.PubMedCrossRef
175.
176.
Bonham LW, Desikan RS, Yokoyama JS, Initiative A’s DN. The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer’s disease. Acta Neuropathol Commun. 2016;4(1):65.PubMedPubMedCentralCrossRef
177.
Ungar L, Altmann A, Greicius MD. Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. Brain Imaging Behav. 2014;8(2):262–73.PubMedPubMedCentralCrossRef
178.
Kolovou G, Damaskos D, Anagnostopoulou K, Cokkinos DV. Apolipoprotein E gene polymorphism and gender. Ann Clin Lab Sci. 2009;39(2):120–33.PubMed
179.
Zepa L, Frenkel M, Belinson H, et al. ApoE4-driven accumulation of intraneuronal oligomerized Aβ42 following activation of the amyloid cascade in vivo is mediated by a gain of function. Int J Alzheimers Dis. 2011;2011:792070.PubMedPubMedCentral
180.
Koster KP, Smith C, Valencia-Olvera AC, et al. Rexinoids as therapeutics for Alzheimer’s disease: role of APOE. Curr Top Med Chem. 2017;17(6):708–20.PubMedCrossRef
181.
Ophir G, Meilin S, Efrati M, et al. Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice. Neurobiol Dis. 2003;12(1):56–64.PubMedCrossRef
182.
Ulrich JD, Burchett JM, Restivo JL, et al. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener. 2013;8(1):13.PubMedPubMedCentralCrossRef
183.
Sullivan PM, Han B, Liu F, et al. Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol Aging. 2011;32(5):791–801.PubMedCrossRef
184.
Zhao N, Liu C-C, Qiao W, Bu G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol Psychiatry. 2018;83(4):347–57.PubMedCrossRef
185.
Doudna JA, Charpentier E. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096.CrossRefPubMed
186.
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420–4.PubMedPubMedCentralCrossRef
187.
Offen D, Rabinowitz R, Michaelson D, Ben-Zur T. Towards gene-editing treatment for alzheimer’s disease: ApoE4 allele-specific knockout using CRISPR cas9 variant. Sci Direct. 2018;20(5):S18.
188.
Tachibana M, Shinohara M, Yamazaki Y, et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol. 2016;277:1–9.PubMedCrossRef
189.
Talwar P, Silla Y, Grover S, et al. Genomic convergence and network analysis approach to identify candidate genes in Alzheimer’s disease. BMC Genomics. 2014;15(1):199.PubMedPubMedCentralCrossRef
190.
Chen Q, Liang B, Wang Z, et al. Influence of four polymorphisms in ABCA1 and PTGS2 genes on risk of Alzheimer’s disease: a meta-analysis. Neurol Sci. 2016;37(8):1209–20.PubMedCrossRef
191.
Van den Bossche T, Sleegers K, Cuyvers E, et al. Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation. Neurol. 2016;86(23):2126–33.CrossRef
192.
Kim J, Eltorai AEM, Jiang H, et al. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis. J Exp Med. 2012;209(12):2149–56.PubMedPubMedCentralCrossRef
193.
Liao F, Hori Y, Hudry E, et al. Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis. J Neurosci. 2014;34(21):7281–92.PubMedPubMedCentralCrossRef
194.
Luz I, Liraz O, Michaelson DM. An anti-apoE4 specific monoclonal antibody counteracts the pathological effects of apoE4 in vivo. Curr Alzheimer Res. 2016;13(8):918–29.PubMedCrossRef
195.
Chen H-K, Liu Z, Meyer-Franke A, et al. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J Biol Chem. 2012;287(8):5253–66.PubMedCrossRef
196.
Huang Y, Liu XQ, Wyss-Coray T, et al. Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci U S A. 2001;98(15):8838–43.PubMedPubMedCentralCrossRef
197.
Harris FM, Brecht WJ, Xu Q, et al. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A. 2003;100(19):10966–71.PubMedPubMedCentralCrossRef
198.
Gonneaud J, Arenaza-Urquijo EM, Fouquet M, et al. Relative effect of APOE ε4 on neuroimaging biomarker changes across the lifespan. Neurol. 2016;87(16):1696–703.CrossRef
199.
Kantarci K, Lowe V, Przybelski SA, et al. APOE modifies the association between Aβ load and cognition in cognitively normal older adults. Neurol. 2012;78(4):232–40.CrossRef
200.
Murphy KR, Landau SM, Choudhury KR, et al. Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. Neuroimage. 2013;78:474–80.PubMedCrossRef
201.
Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT. APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann Neurol. 2015;77(6):917–29.PubMedPubMedCentralCrossRef
202.
203.
Fleisher AS, Chen K, Liu X, et al. Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging. 2013;34(1):1–12.PubMedCrossRef
204.
Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12.PubMedCrossRef
205.
Sadowski M, Pankiewicz J, Scholtzova H, et al. Links between the pathology of Alzheimer’s disease and vascular dementia. Neurochem Res. 2004;29(6):1257–66.PubMedCrossRef
206.
Liao F, Li A, Xiong M, et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 2018;128(5):2144–55.PubMedPubMedCentralCrossRef
207.
Verghese PB, Castellano JM, Garai K, et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013;110(19):E1807–16.PubMedPubMedCentralCrossRef
208.
Ruiz J, Kouiavskaia D, Migliorini M, et al. The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res. 2005;46(8):1721–31.PubMedCrossRef
209.
Bachmeier C, Shackleton B, Ojo J, et al. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. NeuroMolecular Med. 2014;16(4):686–96.PubMedPubMedCentralCrossRef
210.
He X, Cooley K, Chung CHY, Dashti N, Tang J. Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. J Neurosci. 2007;27(15):4052–60.PubMedCrossRefPubMedCentral
211.
Ghosal K, Stathopoulos A, Thomas D, et al. The apolipoprotein-E-mimetic COG112 protects amyloid precursor protein intracellular domain-overexpressing animals from Alzheimer’s disease-like pathological features. Neurodegener Dis. 2013;12(1):51–8.PubMedCrossRef
212.
Vitek MP, Christensen DJ, Wilcock D, et al. APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer’s disease transgenics. Neurodegener Dis. 2012;10(1–4):122–6.PubMedPubMedCentralCrossRef
213.
Wang W, Zhu X. HDL mimetic peptides affect apolipoprotein E metabolism: equal supplement or functional enhancer?: an editorial for ‘High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia’ on page 647. J Neurochem. 2018;147(5):580–3.PubMedCrossRefPubMedCentral
214.
Laskowitz DT, Song P, Wang H, et al. Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic. J Neurotrauma. 2010;27(11):1983–95.PubMedCrossRef
215.
216.
Wang H, Anderson LG, Lascola CD, et al. Apolipoprotein E mimetic peptides improve outcome after focal ischemia. Exp Neurol. 2013;241:67–74.PubMedCrossRef
217.
White CR, Garber DW, Anantharamaiah GM. Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review. J Lipid Res. 2014;55(10):2007–21.PubMedPubMedCentralCrossRef
218.
Rebeck GW, Kindy M, LaDu MJ. Apolipoprotein E and Alzheimer’s disease: the protective effects of ApoE2 and E3. J Alzheimers Dis. 2002;4(3):145–54.PubMedCrossRef
219.
Drenos F, Kirkwood TBL. Selection on alleles affecting human longevity and late-life disease: the example of apolipoprotein E. PLoS One. 2010;5(4):e10022.PubMedPubMedCentralCrossRef
220.
Suri S, Heise V, Trachtenberg AJ, Mackay CE. The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE ɛ2. Neurosci Biobehav Rev. 2013;37(10 Pt 2):2878–86.PubMedCrossRef
221.
Dodart J-C, Marr RA, Koistinaho M, et al. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2005;102(4):1211–6.PubMedPubMedCentralCrossRef
222.
Rosenberg JB, Kaplitt MG, De BP, et al. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer’s disease. Hum Gene Ther Clin Dev. 2018;29(1):24–47.PubMedPubMedCentralCrossRef
223.
Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169(7):1276–90.e17.PubMedCrossRef
224.
Brown GC, St George-Hyslop PH. Deciphering microglial diversity in Alzheimer’s disease. Science. 2017;356(6343):1123–4.PubMedCrossRef
225.
Wattananit S, Tornero D, Graubardt N, et al. Monocyte-derived macrophages contribute to spontaneous long-term functional recovery after stroke in mice. J Neurosci. 2016;36(15):4182–95.PubMedCrossRefPubMedCentral
226.
Altman R, Rutledge JC. The vascular contribution to Alzheimer’s disease. Clin Sci. 2010;119(10):407–21.CrossRef
227.
Rohn TT. Is apolipoprotein E4 an important risk factor for vascular dementia? Int J Clin Exp Pathol. 2014;7(7):3504–11.PubMedPubMedCentral
228.
Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res. 2009;50(Supplement):S183–8.PubMedPubMedCentralCrossRef
229.
Sengillo JD, Winkler EA, Walker CT, et al. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013;23(3):303–10.PubMedCrossRef
230.
Davey DA. Alzheimer’s disease and vascular dementia: one potentially preventable and modifiable disease? Part II: management, prevention and future perspective. Neurodegener Dis Manag. 2014;4(3):261–70.PubMedCrossRef
231.
232.
Parcon PA, Balasubramaniam M, Ayyadevara S, et al. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 2018;14(2):230–42.PubMedCrossRef
233.
Urfer-Buchwalder A, Urfer R. Identification of a nuclear respiratory factor 1 recognition motif in the apolipoprotein E variant APOE4 linked to Alzheimer’s disease. Sci Rep. 2017;7(1):40668.PubMedPubMedCentralCrossRef
234.
235.
Theendakara V, Peters-Libeu CA, Bredesen DE, Rao RV. Transcriptional effects of ApoE4: relevance to Alzheimer’s disease. Mol Neurobiol. 2018;55(6):5243–54.PubMedCrossRef
236.
Singhrao SK, Harding A, Chukkapalli S, et al. Apolipoprotein E related co-morbidities and Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):935–48.PubMedCrossRef
Metadata
Title
ApoE4: an emerging therapeutic target for Alzheimer’s disease
Authors
Mirna Safieh
Amos D. Korczyn
Daniel M. Michaelson
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2019
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-019-1299-4

Other articles of this Issue 1/2019

BMC Medicine 1/2019 Go to the issue

Opinion

Participatory praxis as an imperative for health-related stigma research

Research article

The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma: development and evaluation using the ASSURE prospective clinical trial cohort

Opinion

Knowledge translation in health: how implementation science could contribute more

Review

Body composition of children with moderate and severe undernutrition and after treatment: a narrative review

Research article

Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

Correspondence

Antenatal iron supplementation and birth weight in conditions of high exposure to infectious diseases