Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Mini-Review Article

APOE4: A Culprit for the Vulnerability of COVID-19 in Alzheimer's Patients

Author(s): Ahsas Goyal, Prashant Singh Kushwah, Neetu Agrawal* and Shilpi Pathak

Volume 20, Issue 1, 2023

Published on: 22 February, 2023

Page: [162 - 169] Pages: 8

DOI: 10.2174/1567202620666230202140612

Price: $65

Abstract

Apolipoprotein E4 (APOE4) is one of the primary genetic risk factors for late-onset of Alzheimer's disease (AD). While its primary function is to transport cholesterol, it also regulates metabolism, aggregation, and deposition of amyloid-β (Aβ) in the brain. The disruption in the generation and removal of Aβ in the brain is the primary cause of memory and cognitive loss and thus plays a significant role in the development of AD. In several prior genetic investigations, the APOE4 allele has been linked to higher susceptibility to severe acute respiratory syndrome (SARSCoV- 2) infection and COVID-19 mortality. However, information on the involvement of APOE4 in the underlying pathology and clinical symptoms is limited. Due to the high infection and mortality rate of COVID-19 in AD individuals, challenges have been identified in the management of AD patients during the COVID-19 pandemic. In order to provide evidence-based, more effective healthcare, it is critical to identify underlying concerns and, preferably, biomarkers. The risk variant APOE4 imparts enhanced infectivity by the underlying coronavirus SARS-CoV-2 at a cellular level, genetic level, and route level. Here we review existing advances in clinical and basic research on the AD-related gene APOE, as well as the role of APOE in AD pathogenesis, using neurobiological evidence. Moreover, the role of APOE in severe COVID-19 in Alzheimer's patients has also been reviewed.

Keywords: APOE4, apolipoprotein, alzheimer, COVID-19, amyloid-β, SARS-CoV-2.

[1]
Sharma H, Singh S, Pathak S. Pathogenesis of COVID-19, disease outbreak: A review. Curr Pharm Biotechnol 2021; 22(12): 1591-601.
[http://dx.doi.org/10.2174/1389201022666210127113441] [PMID: 33504302]
[2]
Arif A, Ansari S, Ahsan H, Mahmood R, Khan FH. An overview of COVID-19 pandemic: immunology and pharmacology. J Immunoassay Immunochem 2021; 42(5): 493-512.
[http://dx.doi.org/10.1080/15321819.2021.1904414] [PMID: 33788668]
[3]
To KKW, Sridhar S, Chiu KHY, et al. Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic. Emerg Microbes Infect 2021; 10(1): 507-35.
[http://dx.doi.org/10.1080/22221751.2021.1898291] [PMID: 33666147]
[4]
Schein CH, Levine CB, McLellan SLF, et al. Synthetic proteins for COVID-19 diagnostics. Peptides 2021; 143: 170583.
[http://dx.doi.org/10.1016/j.peptides.2021.170583] [PMID: 34087220]
[5]
Long MJC, Aye Y. Science’s Response to CoVID‐19. ChemMedChem 2021; 16(15): 2288-314.
[http://dx.doi.org/10.1002/cmdc.202100079] [PMID: 33811458]
[6]
Pradhan M, Shah K, Alexander A, et al. COVID-19: clinical presentation and detection methods. J Immunoassay Immunochem 2022; 43(1): 1951291.
[http://dx.doi.org/10.1080/15321819.2021.1951291] [PMID: 34355645]
[7]
Singh S, Kumar A, Sharma H. In-vitro and In-vivo experimental models for MERS-CoV, SARSCoV, and SARS-CoV-2 viral infection: A compendious review. Recent Pat Biotechnol 2022; 16(2): 82-101.
[http://dx.doi.org/10.2174/1872208316666220124101611] [PMID: 35068398]
[8]
Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol 2021; 19(8): 528-45.
[http://dx.doi.org/10.1038/s41579-021-00535-6] [PMID: 33753932]
[9]
Chakraborty C, Sharma AR, Bhattacharya M, Agoramoorthy G, Lee SS. Evolution, mode of transmission, and mutational landscape of newly emerging SARS-CoV-2 Variants. MBio 2021; 12(4): e01140-21.
[http://dx.doi.org/10.1128/mBio.01140-21] [PMID: 34465019]
[10]
Yang AC, Kern F, Losada PM, et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 2021; 595(7868): 565-71.
[http://dx.doi.org/10.1038/s41586-021-03710-0] [PMID: 34153974]
[11]
Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol 2021; 268(9): 3059-71.
[http://dx.doi.org/10.1007/s00415-021-10406-y] [PMID: 33486564]
[12]
Johansson A, Mohamed MS, Moulin TC, Schiöth HB. Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms. J Neuroimmunol 2021; 358: 577658.
[http://dx.doi.org/10.1016/j.jneuroim.2021.577658] [PMID: 34304141]
[13]
Reza-Zaldívar EE, Hernández-Sapiéns MA, Minjarez B, et al. Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System. Front Immunol 2021; 11: 621735.
[http://dx.doi.org/10.3389/fimmu.2020.621735] [PMID: 33584720]
[14]
Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019. JAMA Neurol 2020; 77(8): 1018-27.
[http://dx.doi.org/10.1001/jamaneurol.2020.2065] [PMID: 32469387]
[15]
Özkan Oktay E, Tuncay S, Kaman T, et al. An update comprehensive review on the status of COVID-19: vaccines, drugs, variants and neurological symptoms. Turk J Biol 2021; 45(SI-1): 342-57.
[http://dx.doi.org/10.3906/biy-2106-23] [PMID: 34803439]
[16]
Ahmed MU, Hanif M, Ali MJ, et al. Neurological manifestations of COVID-19 (SARS-CoV-2): A review. Front Neurol 2020; 11: 518.
[http://dx.doi.org/10.3389/fneur.2020.00518] [PMID: 32574248]
[17]
Jafari Khaljiri H, Jamalkhah M, Amini Harandi A, Pakdaman H, Moradi M, Mowla A. Comprehensive review on neuro-COVID-19 pathophysiology and clinical consequences. Neurotox Res 2021; 39(5): 1613-29.
[http://dx.doi.org/10.1007/s12640-021-00389-z] [PMID: 34169404]
[18]
Needham EJ, Chou SHY, Coles AJ, Menon DK. Neurological implications of COVID-19 infections. Neurocrit Care 2020; 32(3): 667-71.
[http://dx.doi.org/10.1007/s12028-020-00978-4] [PMID: 32346843]
[19]
Toniolo S, Scarioni M, Di Lorenzo F, et al. Dementia and COVID-19, A bidirectional liaison: risk factors, biomarkers, and optimal health care. J Alzheimers Dis 2021; 82(3): 883-98.
[http://dx.doi.org/10.3233/JAD-210335] [PMID: 34092646]
[20]
Keyhanian K, Umeton RP, Mohit B, Davoudi V, Hajighasemi F, Ghasemi M. SARS-CoV-2 and nervous system: From pathogenesis to clinical manifestation. J Neuroimmunol 2021; 350: 577436.
[http://dx.doi.org/10.1016/j.jneuroim.2020.577436] [PMID: 33212316]
[21]
Jha NK, Ojha S, Jha SK, et al. Evidence of Coronavirus (CoV) pathogenesis and emerging pathogen SARS-CoV-2 in the nervous system: A review on neurological impairments and manifestations. J Mol Neurosci 2021; 71(11): 2192-209.
[http://dx.doi.org/10.1007/s12031-020-01767-6] [PMID: 33464535]
[22]
Gavriatopoulou M, Korompoki E, Fotiou D, et al. Organ-specific manifestations of COVID-19 infection. Clin Exp Med 2020; 20(4): 493-506.
[http://dx.doi.org/10.1007/s10238-020-00648-x] [PMID: 32720223]
[23]
Moradi HR, Hajali V, Khaksar Z, Vafaee F, Forouzanfar F, Negah SS. The next step of neurogenesis in the context of Alzheimer’s disease. Mol Biol Rep 2021; 48(7): 5647-60.
[http://dx.doi.org/10.1007/s11033-021-06520-9] [PMID: 34232464]
[24]
Blackman J, Swirski M, Clynes J, Harding S, Leng Y, Coulthard E. Pharmacological and non‐pharmacological interventions to enhance sleep in mild cognitive impairment and mild Alzheimer’s disease: A systematic review. J Sleep Res 2021; 30(4): e13229.
[http://dx.doi.org/10.1111/jsr.13229] [PMID: 33289311]
[25]
Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med 2010; 12(1): 1-12.
[http://dx.doi.org/10.1007/s12017-009-8104-z] [PMID: 20232515]
[26]
Agrawal N, Pathak S, Goyal A. Potential papain-like protease inhibitors against COVID-19: A comprehensive In Silico based review. Comb Chem High Throughput Screen 2022; 25(11): 1838-58.
[http://dx.doi.org/10.2174/1386207325666211122123602] [PMID: 34809541]
[27]
Chen G, Xu T, Yan Y, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 2017; 38(9): 1205-35.
[http://dx.doi.org/10.1038/aps.2017.28] [PMID: 28713158]
[28]
Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 2015; 11(8): 457-70.
[http://dx.doi.org/10.1038/nrneurol.2015.119] [PMID: 26195256]
[29]
Manchikalapudi AL, Chilakala RR, Kalia K, Sunkaria A. Evaluating the role of microglial cells in clearance of Aβ from Alzheimer’s Brain. ACS Chem Neurosci 2019; 10(3): 1149-56.
[http://dx.doi.org/10.1021/acschemneuro.8b00627] [PMID: 30609357]
[30]
Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci 2016; 8: 160.
[http://dx.doi.org/10.3389/fnagi.2016.00160] [PMID: 27458370]
[31]
Khalil YA, Rabès JP, Boileau C, Varret M. APOE gene variants in primary dyslipidemia. Atherosclerosis 2021; 328: 11-22.
[http://dx.doi.org/10.1016/j.atherosclerosis.2021.05.007] [PMID: 34058468]
[32]
Lozano S, Padilla V, Avila ML, et al. APOE gene associated with cholesterol-related traits in the hispanic population. Genes 2021; 12(11): 1768.
[http://dx.doi.org/10.3390/genes12111768] [PMID: 34828374]
[33]
Fitz NF, Nam KN, Wolfe CM, et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat Commun 2021; 12(1): 3416.
[http://dx.doi.org/10.1038/s41467-021-23762-0] [PMID: 34099706]
[34]
Lanfranco MF, Sepulveda J, Kopetsky G, Rebeck GW. Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation. Glia 2021; 69(6): 1478-93.
[http://dx.doi.org/10.1002/glia.23974] [PMID: 33556209]
[35]
Zhou X, Fu AKY, Ip NY. APOE signaling in neurodegenerative diseases: an integrative approach targeting APOE coding and noncoding variants for disease intervention. Curr Opin Neurobiol 2021; 69: 58-67.
[http://dx.doi.org/10.1016/j.conb.2021.02.001] [PMID: 33647674]
[36]
Gao P, Ji M, Liu X, et al. Apolipoprotein E mediates cell resistance to influenza virus infection. Sci Adv 2022; 8(38): eabm6668.
[http://dx.doi.org/10.1126/sciadv.abm6668] [PMID: 36129973]
[37]
Kurki SN, Kantonen J, Kaivola K, et al. APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study. Acta Neuropathol Commun 2021; 9(1): 199.
[http://dx.doi.org/10.1186/s40478-021-01302-7] [PMID: 34949230]
[38]
Ostendorf BN, Patel MA, Bilanovic J, et al. Common human genetic variants of APOE impact murine COVID-19 mortality. Nature 2022; 611(7935): 346-51.
[http://dx.doi.org/10.1038/s41586-022-05344-2] [PMID: 36130725]
[39]
Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 2022; 23(1): 3-20.
[http://dx.doi.org/10.1038/s41580-021-00418-x] [PMID: 34611326]
[40]
Finch CE, Kulminski AM. The ApoE Locus and COVID-19: Are we going where we have been? J Gerontol A Biol Sci Med Sci 2021; 76(2): e1-3.
[http://dx.doi.org/10.1093/gerona/glaa200] [PMID: 32777042]
[41]
Hubacek JA, Dlouha L, Dusek L, Majek O, Adamkova V. Apolipoprotein E4 Allele in Subjects with COVID-19. Gerontology 2021; 67(3): 320-2.
[http://dx.doi.org/10.1159/000516200] [PMID: 33965962]
[42]
Inal J. Biological factors linking ApoE ε4 variant and severe COVID-19. Curr Atheroscler Rep 2020; 22(11): 70.
[http://dx.doi.org/10.1007/s11883-020-00896-y] [PMID: 33006059]
[43]
Kuo CL, Pilling LC, Atkins JL, et al. APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. J Gerontol A Biol Sci Med Sci 2020; 75(11): 2231-2.
[http://dx.doi.org/10.1093/gerona/glaa131] [PMID: 32451547]
[44]
Wang C, Zhang M, Garcia G Jr, et al. ApoE-isoform-dependent SARS-CoV-2 neurotropism and cellular response. Cell Stem Cell 2021; 28(2): 331-342.e5.
[http://dx.doi.org/10.1016/j.stem.2020.12.018] [PMID: 33450186]
[45]
Xiong N, Schiller MR, Li J, Chen X, Lin Z. Severe COVID-19 in Alzheimer’s disease: APOE4’s fault again? Alzheimers Res Ther 2021; 13(1): 111.
[http://dx.doi.org/10.1186/s13195-021-00858-9] [PMID: 34118974]
[46]
Miners S, Kehoe PG, Love S. Cognitive impact of COVID-19: looking beyond the short term. Alzheimers Res Ther 2020; 12(1): 170.
[http://dx.doi.org/10.1186/s13195-020-00744-w] [PMID: 33380345]
[47]
Getz GS, Reardon CA. Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall. J Lipid Res 2009; 50: S156-61.
[http://dx.doi.org/10.1194/jlr.R800058-JLR200] [PMID: 19018038]
[48]
Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 2021; 20(1): 68-80.
[http://dx.doi.org/10.1016/S1474-4422(20)30412-9] [PMID: 33340485]
[49]
Kasparian K, Graykowski D, Cudaback E. Commentary: APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort. Front Immunol 2020; 11: 1939.
[http://dx.doi.org/10.3389/fimmu.2020.01939] [PMID: 33042114]
[50]
Gkouskou K, Vasilogiannakopoulou T, Andreakos E, et al. COVID-19 enters the expanding network of apolipoprotein E4-related pathologies. Redox Biol 2021; 41: 101938.
[http://dx.doi.org/10.1016/j.redox.2021.101938] [PMID: 33730676]
[51]
Kandimalla RJL, Wani WY, Anand R, et al. Apolipoprotein E levels in the cerebrospinal fluid of north Indian patients with Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2013; 28(3): 258-62.
[http://dx.doi.org/10.1177/1533317513481097] [PMID: 23612909]
[52]
Fernandez CG, Hamby ME, McReynolds ML, Ray WJ. The role of APOE4 in disrupting the homeostatic functions of astrocytes and microglia in aging and alzheimer’s disease. front aging neurosci 2019; 11: 14.
[http://dx.doi.org/10.3389/fnagi.2019.00014] [PMID: 30804776]
[53]
Kloske CM, Wilcock DM. The important interface between apolipoprotein E and neuroinflammation in Alzheimer’s Disease. Front Immunol 2020; 11: 754.
[http://dx.doi.org/10.3389/fimmu.2020.00754] [PMID: 32425941]
[54]
Yin MY, Du J, Wang Z. Aβ metabolism and the role of APOE in Alzheimer’s disease. J Alzheimers Dis Parkinsonism 2016; 06: 285.
[55]
Williams T, Borchelt DR, Chakrabarty P. Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease. Mol Neurodegener 2020; 15(1): 8.
[http://dx.doi.org/10.1186/s13024-020-0358-9] [PMID: 32005122]
[56]
Konttinen H, Cabral-da-Silva MC, Ohtonen S, et al. PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia. Stem Cell Reports 2019; 13(4): 669-83.
[http://dx.doi.org/10.1016/j.stemcr.2019.08.004] [PMID: 31522977]
[57]
Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: Accidental encounters or partners? Neuron 2014; 81(4): 740-54.
[http://dx.doi.org/10.1016/j.neuron.2014.01.045] [PMID: 24559670]
[58]
Ezzat K, Pernemalm M, Pålsson S, et al. The viral protein corona directs viral pathogenesis and amyloid aggregation. Nat Commun 2019; 10(1): 2331.
[http://dx.doi.org/10.1038/s41467-019-10192-2] [PMID: 31133680]
[59]
Uddin MS, Kabir MT, Al Mamun A, Abdel-Daim MM, Barreto GE, Ashraf GM. APOE and Alzheimer’s Disease: Evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol Neurobiol 2019; 56(4): 2450-65.
[http://dx.doi.org/10.1007/s12035-018-1237-z] [PMID: 30032423]
[60]
Norwitz NG, Saif N, Ariza IE, Isaacson RS. Precision nutrition for Alzheimer’s prevention in ApoE4 carriers. Nutrients 2021; 13(4): 1362.
[http://dx.doi.org/10.3390/nu13041362] [PMID: 33921683]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy