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The Egyptian Journal of Neurology, Psychiatry and Neurosurgery

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Open Access 01-12-2021 | Alzheimer's Disease | Review

An insight into Alzheimer’s disease and its on-setting novel genes

Authors: Jaanaky Vigneswaran, Sivaloganathan Anogh Muthukumar, Mohamed Shafras, Geetika Pant

Published in: The Egyptian Journal of Neurology, Psychiatry and Neurosurgery | Issue 1/2021

Abstract

According to the World Health Organisation, as of 2019, globally around 50 million people suffer from dementia, with approximately another 10 million getting added to the list every year, wherein Alzheimer’s disease (AD) stands responsible for almost a whopping 60–70% for the existing number of cases. Alzheimer’s disease is one of the progressive, cognitive-declining, age-dependent, neurodegenerative diseases which is distinguished by histopathological symptoms, such as formation of amyloid plaque, senile plaque, neurofibrillary tangles, etc. Majorly four vital transcripts are identified in the AD complications which include Amyloid precursor protein (APP), Apolipoprotein E (ApoE), and two multi-pass transmembrane domain proteins—Presenilin 1 and 2. In addition, the formation of the abnormal filaments such as amyloid beta (Aβ) and tau and their tangling with some necessary factors contributing to the formation of plaques, neuroinflammation, and apoptosis which in turn leads to the emergence of AD. Although multiple molecular mechanisms have been elucidated so far, they are still counted as hypotheses ending with neuronal death on the basal forebrain and hippocampal area which results in AD. This review article is aimed at addressing the overview of the molecular mechanisms surrounding AD and the functional forms of the genes associated with it.

World Health Organization. Dementia. 2021. https://www.who.int/news-room/fact-sheets/detail/dementia#:~:text=Alzheimer's%20disease%20is%20the%20most,dependency%20among%20older%20people%20globally. Accessed 07 Oct 2021.

Chávez-Gutiérrez L, Szaruga M. Mechanisms of neurodegeneration—insights from familial Alzheimer’s disease. Semin Cell Dev Biol. 2020;105:75–85. https://doi.org/10.1016/j.semcdb.2020.03.005.CrossRefPubMed

Weidner WS, Barbarino P. P4-443: the state of the art of dementia research new frontiers. Alzheimers Dement. 2019;15(7):P1473.CrossRef

Bielschowsky M. Die Silberimpragnation der Axencylinder. New Centralbl. 1902;21:579–84.

Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, Wehnert A, et al. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science. 1990;248(4959):1120–2. https://doi.org/10.1126/science.1971458.CrossRefPubMed

Vermunt L, Sikkes SAM, van den Hout A, Handels R, Bos I, van der Flier WM, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019;15(7):888–98. https://doi.org/10.1016/j.jalz.2019.04.001.CrossRefPubMedPubMedCentral

Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71(4):505–8. https://doi.org/10.1001/jamaneurol.2013.5847.CrossRefPubMed

Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312–39. https://doi.org/10.1016/j.cell.2019.09.001.CrossRefPubMedPubMedCentral

Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673–734.CrossRef

10.

Mullane K, Williams M. Alzheimer’s disease beyond amyloid: Can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery? Biochem Pharmacol. 2020;177(113945): 113945.CrossRef

11.

Bertram L, Tanzi RE. Alzheimer disease risk genes: 29 and counting. Nat Rev Neurol. 2019;15(4):191–2. https://doi.org/10.1038/s41582-019-0158-4.CrossRefPubMed

12.

De Jonghe C, Zehr C, Yager D, Prada CM, Younkin S, Hendriks L, et al. Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion. Neurobiol Dis. 1998;5(4):281–6. https://doi.org/10.1006/nbdi.1998.0202.CrossRefPubMed

13.

Uddin MS, Kabir MT, Mamun AA, Barreto GE, Rashid M, Perveen A, et al. Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease. Int Immunopharmacol. 2020;84(106479): 106479. https://doi.org/10.1016/j.intimp.2020.106479.CrossRefPubMed

14.

Uddin MS, Mamun AA, Labu ZK, Hidalgo-Lanussa O, Barreto GE, Ashraf GM, et al. Autophagic dysfunction in Alzheimer’s disease: cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis. J Cell Physiol. 2019;234(6):8094–112. https://doi.org/10.1002/jcp.27588.CrossRefPubMed

15.

Kabir MT, Sufian MA, Uddin MS, Begum MM, Akhter S, Islam A, et al. NMDA receptor antagonists: repositioning of memantine as a multitargeting agent for Alzheimer’s therapy. Curr Pharm Des. 2019;25(33):3506–18. https://doi.org/10.2174/1381612825666191011102444.CrossRefPubMed

16.

Haapasalo A, Kovacs DM. The many substrates of presenilin/γ-secretase. J Alzheimers Dis. 2011;25(1):3–28. https://doi.org/10.3233/JAD-2011-101065.CrossRefPubMedPubMedCentral

17.

Wolfe MS. Unraveling the complexity of γ-secretase. Semin Cell Dev Biol. 2020;105:3–11. https://doi.org/10.1016/j.semcdb.2020.01.005.CrossRefPubMedPubMedCentral

18.

Kopan R, Ilagan MXG. Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol. 2004;5(6):499–504. https://doi.org/10.1038/nrm1406.CrossRefPubMed

19.

Hitzenberger M, Götz A, Menig S, Brunschweiger B, Zacharias M, Scharnagl C. The dynamics of γ-secretase and its substrates. Semin Cell Dev Biol. 2020;105:86–101. https://doi.org/10.1016/j.semcdb.2020.04.008.CrossRefPubMed

20.

Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120(3):885–90. https://doi.org/10.1016/s0006-291x(84)80190-4.CrossRefPubMed

21.

Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H. Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature. 1988;331(6156):530–2. https://doi.org/10.1038/331530a0.CrossRefPubMed

22.

Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y. Genomic organization of the human amyloid beta-protein precursor gene. Gene. 1990;87(2):257–63. https://doi.org/10.1016/0378-1119(90)90310-n.CrossRefPubMed

23.

Wolfe MS. Dysfunctional γ-secretase in familial Alzheimer’s disease. Neurochem Res. 2019;44(1):5–11. https://doi.org/10.1007/s11064-018-2511-1.CrossRefPubMed

24.

Weidemann A, König G, Bunke D, Fischer P, Salbaum JM, Masters CL, et al. Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell. 1989;57(1):115–26. https://doi.org/10.1016/0092-8674(89)90177-3.CrossRefPubMed

25.

Breen KC, Bruce M, Anderton BH. Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. J Neurosci Res. 1991;28(1):90–100. https://doi.org/10.1002/jnr.490280109.CrossRefPubMed

26.

Kumar-Singh S. Nonfibrillar diffuse amyloid deposition due to a gamma42-secretase site mutation points to an essential role for N-truncated Abeta42 in Alzheimer’s disease. Hum Mol Genet. 2000;9(18):2589–98. https://doi.org/10.1093/hmg/9.18.2589.CrossRefPubMed

27.

Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, et al. 3D structure of Alzheimer’s amyloid-beta(1–42) fibrils. Proc Natl Acad Sci U S A. 2005;102(48):17342–7. https://doi.org/10.1073/pnas.0506723102.CrossRefPubMedPubMedCentral

28.

Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJS, Hopkins R, Smith DW, et al. Β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995;81(4):525–31. https://doi.org/10.1016/0092-8674(95)90073-x.CrossRefPubMed

29.

Müller W, Eckert A, Hartmann H, Förstl H. Free intracellular calcium in aging and Alzheimer’s disease. In: Alzheimer Disease. Boston, MA: Birkhäuser Boston; 1994. p. 299–303. https://doi.org/10.1007/978-1-4615-8149-9_50

30.

Luo L, Tully T, White K. Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron. 1992;9(4):595–605. https://doi.org/10.1016/0896-6273(92)90024-8.CrossRefPubMed

31.

Daigle I, Li C. apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor. Proc Natl Acad Sci U S A. 1993;90(24):12045–9. https://doi.org/10.1073/pnas.90.24.12045.CrossRefPubMedPubMedCentral

32.

Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38(1):24–6. https://doi.org/10.1038/ng1718.CrossRefPubMed

33.

Howlett DR, Jennings KH, Lee DC, Clark MS, Brown F, Wetzel R, et al. Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. Neurodegeneration. 1995;4(1):23–32. https://doi.org/10.1006/neur.1995.0003.CrossRefPubMed

34.

Jarrett JT, Berger EP, Lansbury PT Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry. 1993;32(18):4693–7. https://doi.org/10.1021/bi00069a001.CrossRefPubMed

35.

Mantyh PW, Ghilardi JR, Rogers S, DeMaster E, Allen CJ, Stimson ER, et al. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J Neurochem. 1993;61(3):1171–4. https://doi.org/10.1111/j.1471-4159.1993.tb03639.x.CrossRefPubMed

36.

Bush AI, Pettingell WH, Multhaup G, Paradis Md, Vonsattel JP, Gusella JF, et al. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994;265(5177):1464–7. https://doi.org/10.1126/science.8073293.CrossRefPubMed

37.

Dyrks T, Dyrks E, Hartmann T, Masters C, Beyreuther K. Amyloidogenicity of beta A4 and beta A4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem. 1992;267(25):18210–7.CrossRef

38.

Koh J-Y, Yang LL, Cotman CW. β-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res. 1990;533(2):315–20. https://doi.org/10.1016/0006-8993(90)91355-k.CrossRefPubMed

39.

Copani A, Koh J-Y, Cotman CW. B-Amyloid increases neuronal susceptibility to injufy by glucose deprivation. NeuroReport. 1991;2(12):763–5. https://doi.org/10.1097/00001756-199112000-00008.CrossRefPubMed

40.

Price JL, Davis PB, Morris JC, White DL. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging. 1991;12(4):295–312. https://doi.org/10.1016/0197-4580(91)90006-6.CrossRefPubMed

41.

Ryan NS, Rossor MN. Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomark Med. 2010;4(1):99–112. https://doi.org/10.2217/bmm.09.92.CrossRefPubMed

42.

Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992;1(5):345–7. https://doi.org/10.1038/ng0892-345.CrossRefPubMed

43.

Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature. 1992;360(6405):672–4. https://doi.org/10.1038/360672a0.CrossRef

44.

Chen W-T, Hong C-J, Lin Y-T, Chang W-H, Huang H-T, Liao J-Y, et al. Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies. PLoS ONE. 2012;7(4): e35807. https://doi.org/10.1371/journal.pone.0035807.CrossRefPubMedPubMedCentral

45.

Kaden D, Harmeier A, Weise C, Munter LM, Althoff V, Rost BR, et al. Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers: Aβ K16N heteromeric oligomers are highly toxic. EMBO Mol Med. 2012;4(7):647–59. https://doi.org/10.1002/emmm.201200239.CrossRefPubMedPubMedCentral

46.

Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, et al. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005;6(2):85–9. https://doi.org/10.1007/s10048-005-0211-x.CrossRefPubMed

47.

Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001;4(9):887–93. https://doi.org/10.1038/nn0901-887.CrossRefPubMed

48.

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30. https://doi.org/10.1038/s41588-019-0358-2.CrossRefPubMedPubMedCentral

49.

Czeh M, Gressens P, Kaindl AM. The yin and yang of microglia. Dev Neurosci. 2011;33(3–4):199–209. https://doi.org/10.1159/000328989.CrossRefPubMed

50.

Paresce DM, Ghosh RN, Maxfield FR. Microglial cells internalize aggregates of the Alzheimer’s disease amyloid β-protein via a scavenger receptor. Neuron. 1996;17(3):553–65. https://doi.org/10.1016/s0896-6273(00)80187-7.CrossRefPubMed

51.

Lee CYD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna). 2010;117(8):949–60. https://doi.org/10.1007/s00702-010-0433-4.CrossRef

52.

Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci. 2008;28(33):8354–60. https://doi.org/10.1523/jneurosci.0616-08.2008.CrossRefPubMedPubMedCentral

53.

Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang L-C, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16(12):1896–905. https://doi.org/10.1038/nn.3554.CrossRefPubMedPubMedCentral

54.

Khachaturian ZS. 40 Years of Alzheimer’s research failure: now what? MedpageToday. 2018. https://www.medpagetoday.com/neurology/alzheimersdisease/75075. Accessed 7 Oct 2021.

55.

Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368(9533):387–403. https://doi.org/10.1016/S0140-6736(06)69113-7.CrossRefPubMed

56.

Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006;26(19):4985–94. https://doi.org/10.1523/jneurosci.5476-05.2006.CrossRefPubMedPubMedCentral

57.

Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, 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. https://doi.org/10.1074/jbc.m407963200.CrossRefPubMed

58.

Tokuda T, Calero M, Matsubara E, Vidal R, Kumar A, Permanne B, et al. Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid β peptides. Biochem J. 2000;348(2):359–65. https://doi.org/10.1042/bj3480359.CrossRefPubMedPubMedCentral

59.

Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, et al. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 2000;6(2):143–50. https://doi.org/10.1038/72237.CrossRefPubMed

60.

Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, et al. Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40(6):1087–93. https://doi.org/10.1016/s0896-6273(03)00787-6.CrossRefPubMed

61.

Michaelson DM, Dolev I. P2–297 differential and isoform-specific effects of apolipoprotein E4 on the initiation of deposition and on the reversible dissolution and fibrillization of Ab in vivo. Neurobiol Aging. 2004;25:S317. https://doi.org/10.1016/s0197-4580(04)81042-x.CrossRef

62.

Rogers J, Strohmeyer R, Kovelowski CJ, Li R. Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia. 2002;40(2):260–9. https://doi.org/10.1002/glia.10153.CrossRefPubMed

63.

Cao G, Bales KR, DeMattos RB, Paul SM. Liver X receptor-mediated gene regulation and cholesterol homeostasis in brain: relevance to Alzheimer’s disease therapeutics. Curr Alzheimer Res. 2007;4(2):179–84. https://doi.org/10.2174/156720507780362173.CrossRefPubMed

64.

Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76(8):915–24. https://doi.org/10.1001/jamaneurol.2019.1424.CrossRefPubMedPubMedCentral

65.

Naseri NN, Wang H, Guo J, Sharma M, Luo W. The complexity of tau in Alzheimer’s disease. Neurosci Lett. 2019;705:183–94. https://doi.org/10.1016/j.neulet.2019.04.022.CrossRefPubMedPubMedCentral

66.

Bakota L, Ussif A, Jeserich G, Brandt R. Systemic and network functions of the microtubule-associated protein tau: implications for tau-based therapies. Mol Cell Neurosci. 2017;84:132–41. https://doi.org/10.1016/j.mcn.2017.03.003.CrossRefPubMed

67.

Lu Q, Wood JG. Functional studies of Alzheimer’s disease tau protein. J Neurosci. 1993;13(2):508–15. https://doi.org/10.1523/jneurosci.13-02-00508.1993.CrossRefPubMedPubMedCentral

68.

Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91(12):5562–6. https://doi.org/10.1073/pnas.91.12.5562.CrossRefPubMedPubMedCentral

69.

Duyckaerts C, Delatour B, Potier M-C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118(1):5–36. https://doi.org/10.1007/s00401-009-0532-1.CrossRefPubMed

70.

Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59. https://doi.org/10.1007/bf00308809.CrossRefPubMed

71.

Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121(2):171–81. https://doi.org/10.1007/s00401-010-0789-4.CrossRefPubMed

72.

Wegmann S, Nicholls S, Takeda S, Fan Z, Hyman BT. Formation, release, and internalization of stable tau oligomers in cells. J Neurochem. 2016;139(6):1163–74. https://doi.org/10.1111/jnc.13866.CrossRefPubMedPubMedCentral

73.

Merezhko M, Brunello CA, Yan X, Vihinen H, Jokitalo E, Uronen R-L, et al. Secretion of Tau via an unconventional non-vesicular mechanism. Cell Rep. 2018;25(8):2027-2035.e4. https://doi.org/10.1016/j.celrep.2018.10.078.CrossRefPubMed

74.

Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287(6):3842–9. https://doi.org/10.1074/jbc.m111.277061.CrossRefPubMed

75.

Simón D, García-García E, Royo F, Falcón-Pérez JM, Avila J. Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett. 2011;586(1):47–54. https://doi.org/10.1016/j.febslet.2011.11.022.CrossRefPubMed

76.

Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24(1):1121–59. https://doi.org/10.1146/annurev.neuro.24.1.1121.CrossRefPubMed

77.

Duka V, Lee J-H, Credle J, Wills J, Oaks A, Smolinsky C, et al. Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer’s diseases. PLoS ONE. 2013;8(9): e75025. https://doi.org/10.1371/journal.pone.0075025.CrossRefPubMedPubMedCentral

78.

Hampel H, Blennow K, Shaw LM, Hoessler YC, Zetterberg H, Trojanowski JQ. Total and phosphorylated tau protein as biological markers of Alzheimer’s disease. Exp Gerontol. 2010;45(1):30–40. https://doi.org/10.1016/j.exger.2009.10.010.CrossRefPubMed

79.

Li QS, De Muynck L. Differentially expressed genes in Alzheimer’s disease highlighting the roles of microglia genes including OLR1 and astrocyte gene CDK2AP1. Brain Behav Immun Health. 2021;13(100227): 100227. https://doi.org/10.1016/j.bbih.2021.100227.CrossRefPubMedPubMedCentral

80.

Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269(5226):973–7. https://doi.org/10.1126/science.7638622.CrossRefPubMed

81.

Saura CA, Choi S-Y, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004;42(1):23–36. https://doi.org/10.1016/s0896-6273(04)00182-5.CrossRefPubMed

82.

Dumanchin C, Czech C, Campion D, Cuif MH, Poyot T, Martin C, et al. Presenilins interact with Rab11, a small GTPase involved in the regulation of vesicular transport. Hum Mol Genet. 1999;8(7):1263–9. https://doi.org/10.1093/hmg/8.7.1263.CrossRefPubMed

83.

LaFerla FM. Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci. 2002;3(11):862–72. https://doi.org/10.1038/nrn960.CrossRefPubMed

84.

Mattson MP. ER calcium and Alzheimer’s disease: in a state of flux. Sci Signal. 2010;3(114): e10. https://doi.org/10.1126/scisignal.3114pe10.CrossRef

85.

Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, et al. Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett. 1999;265(1):61–3. https://doi.org/10.1016/s0304-3940(99)00187-1.CrossRefPubMed

86.

Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996;17(1):181–90. https://doi.org/10.1016/s0896-6273(00)80291-3.CrossRefPubMed

87.

Capell A, Grünberg J, Pesold B, Diehlmann A, Citron M, Nixon R, et al. The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. J Biol Chem. 1998;273(6):3205–11. https://doi.org/10.1074/jbc.273.6.3205.CrossRefPubMed

88.

Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat. 2012;33(9):1340–4. https://doi.org/10.1002/humu.22117.CrossRefPubMedPubMedCentral

89.

Rossor MN, Fox NC, Beck J, Campbell TC, Collinge J. Incomplete penetrance of familial Alzheimer’s disease in a pedigree with a novel presenilin-1 gene mutation. Lancet. 1996;347(9014):1560. https://doi.org/10.1016/s0140-6736(96)90715-1.CrossRefPubMed

90.

Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2016;114(4):E476–85. https://doi.org/10.1073/pnas.1618657114.CrossRefPubMedPubMedCentral

91.

Tang N, Dehury B, Kepp KP. Computing the pathogenicity of Alzheimer’s disease presenilin 1 mutations. J Chem Inf Model. 2019;59(2):858–70. https://doi.org/10.1021/acs.jcim.8b00896.CrossRefPubMed

92.

Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu C-E, et al. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010;133(Pt 4):1143–54. https://doi.org/10.1093/brain/awq033.CrossRefPubMedPubMedCentral

93.

Somavarapu AK, Kepp KP. The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access. Neurobiol Dis. 2016;89:147–56. https://doi.org/10.1016/j.nbd.2016.02.008.CrossRefPubMed

94.

Duncan R, Song B, Koulen P. Presenilins as drug targets for Alzheimer’s disease—recent insights from cell biology and electrophysiology as novel opportunities in drug development. Int J Mol Sci. 2018;19(6):1621. https://doi.org/10.3390/ijms19061621.CrossRefPubMedCentral

95.

Reddy PH. Increased mitochondrial fission and neuronal dysfunction in Huntington’s disease: implications for molecular inhibitors of excessive mitochondrial fission. Drug Discov Today. 2014;19(7):951–5. https://doi.org/10.1016/j.drudis.2014.03.020.CrossRefPubMedPubMedCentral

96.

Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298–300. https://doi.org/10.1093/geronj/11.3.298.CrossRefPubMed

97.

Bhardwaj S, Kesari KK, Rachamalla M, Mani S, Ashraf GM, Jha SK, et al. CRISPR/Cas9 gene editing: new hope for Alzheimer’s disease therapeutics. J Adv Res. 2021. https://doi.org/10.1016/j.jare.2021.07.001.CrossRef

98.

Van Giau V, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Sci Rep. 2019;9(1):8368. https://doi.org/10.1038/s41598-019-44848-2.CrossRefPubMedPubMedCentral

99.

Prokopenko D, Morgan SL, Mullin K, Hofmann O, Chapman B, Kirchner R, et al. Whole-genome sequencing reveals new Alzheimer’s disease-associated rare variants in loci related to synaptic function and neuronal development. Alzheimers Dement. 2021;17(9):1509–27. https://doi.org/10.1002/alz.12319.CrossRefPubMedPubMedCentral

100.

Kim H-R, Jung S-H, Kim J, Jang H, Kang SH, Hwangbo S, et al. Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population. Alzheimers Res Ther. 2021;13(1):117. https://doi.org/10.1186/s13195-021-00854-z.CrossRefPubMedPubMedCentral

101.

Park J-H, Park I, Youm EM, Lee S, Park J-H, Lee J, et al. Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers. Transl Psychiatry. 2021;11(1):296. https://doi.org/10.1038/s41398-021-01412-9.CrossRefPubMedPubMedCentral

102.

Xiaodong P, Murong Y, Jingjing X, Qi P, Menghao Y, Jing X, et al. Identification of novel gene variants in patients with Alzheimer’s disease by whole exome sequencing. Ann Alzheimers Dement Care. 2020;4(1):001–4.CrossRef

103.

de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, et al. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nat Commun. 2021;12(1):3417. https://doi.org/10.1038/s41467-021-22491-8.CrossRefPubMedPubMedCentral

104.

Lawingco T, Chaudhury S, Brookes KJ, Guetta-Baranes T, Guerreiro R, Bras J, et al. Genetic variants in glutamate-, Aβ-, and tau-related pathways determine polygenic risk for Alzheimer’s disease. Neurobiol Aging. 2021;101:299.e13-299.e21. https://doi.org/10.1016/j.neurobiolaging.2020.11.009.CrossRef

105.

Ou Y-N, Yang Y-X, Deng Y-T, Zhang C, Hu H, Wu B-S, et al. Identification of novel drug targets for Alzheimer’s disease by integrating genetics and proteomes from brain and blood. Mol Psychiatry. 2021. https://doi.org/10.1038/s41380-021-01251-6.CrossRefPubMed

106.

He L, Loika Y, Park Y, Genotype Tissue Expression (GTEx) consortium, Bennett DA, Kellis M, et al. Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer’s disease. Transl Psychiatry. 2021;11(1):146. https://doi.org/10.1038/s41398-021-01263-4

107.

Bossaerts L, Hens E, Hanseeuw B, Vandenberghe R, Cras P, De Deyn PP, et al. Premature termination codon mutations in ABCA7 contribute to Alzheimer’s disease risk in Belgian patients. Neurobiol Aging. 2021;106:307.e1-307.e7. https://doi.org/10.1016/j.neurobiolaging.2021.04.023.CrossRef

108.

Lyssenko NN, Praticò D. ABCA7 and the altered lipidostasis hypothesis of Alzheimer’s disease. Alzheimers Dement. 2021;17(2):164–74. https://doi.org/10.1002/alz.12220.CrossRefPubMed

109.

Aikawa T, Ren Y, Holm M-L, Asmann YW, Alam A, Fitzgerald ML, et al. ABCA7 regulates brain fatty acid metabolism during LPS-induced acute inflammation. Front Neurosci. 2021;15: 647974. https://doi.org/10.3389/fnins.2021.647974.CrossRefPubMedPubMedCentral

110.

Aikawa T, Ren Y, Yamazaki Y, Tachibana M, Johnson MR, Anderson CT, et al. ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain. Proc Natl Acad Sci U S A. 2019;116(47):23790–6. https://doi.org/10.1073/pnas.1908529116.CrossRefPubMedPubMedCentral

111.

Liu Y, Thalamuthu A, Mather KA, Crawford J, Ulanova M, Wong MWK, et al. Plasma lipidome is dysregulated in Alzheimer’s disease and is associated with disease risk genes. Transl Psychiatry. 2021;11(1):344. https://doi.org/10.1038/s41398-021-01362-2.CrossRefPubMedPubMedCentral

112.

Hung C, Tuck E, Stubbs V, van der Lee SJ, Aalfs C, van Spaendonk R, et al. SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network. Cell Rep. 2021;35(11): 109259. https://doi.org/10.1016/j.celrep.2021.109259.CrossRefPubMedPubMedCentral

113.

Monti G, Kjolby M, Jensen AMG, Allen M, Reiche J, Møller PL, et al. Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer’s disease. Acta Neuropathol Commun. 2021;9(1):43. https://doi.org/10.1186/s40478-021-01140-7.CrossRefPubMedPubMedCentral

114.

Andersen OM, Bøgh N, Landau AM, Pløen GG, Jensen AMG, Monti G, et al. In vivo evidence that SORL1, encoding the endosomal recycling receptor SORLA, can function as a causal gene in Alzheimer’s Disease. bioRxiv. 2021. https://doi.org/10.1101/2021.07.13.452149.CrossRefPubMedPubMedCentral

115.

Mishra S, Knupp A, Szabo M, Kinoshita C, Hailey DW, Wang Y, et al. The Alzheimer’s gene SORL1 is a key regulator of endosomal recycling in human neurons. bioRxiv. 2021. https://doi.org/10.1101/2021.07.26.453861.CrossRef

116.

Cuccaro ML, Carney RM, Zhang Y, Bohm C, Kunkle BW, Vardarajan BN, et al. SORL1 mutations in early- and late-onset Alzheimer disease. Neurol Genet. 2016;2(6): e116. https://doi.org/10.1212/NXG.0000000000000116.CrossRefPubMedPubMedCentral

117.

Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med. 2020;26(1):131–42. https://doi.org/10.1038/s41591-019-0695-9.CrossRefPubMedPubMedCentral

118.

Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med. 2020. https://doi.org/10.1084/jem.20200785.CrossRefPubMedPubMedCentral

119.

Ellwanger DC, Wang S, Brioschi S, Shao Z, Green L, Case R, et al. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2021;118(3): e2017742118. https://doi.org/10.1073/pnas.2017742118.CrossRefPubMedPubMedCentral

120.

McQuade A, Kang YJ, Hasselmann J, Jairaman A, Sotelo A, Coburn M, et al. Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease. Nat Commun. 2020;11(1):5370. https://doi.org/10.1038/s41467-020-19227-5.CrossRefPubMedPubMedCentral

121.

Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019;22(2):191–204. https://doi.org/10.1038/s41593-018-0296-9.CrossRefPubMedPubMedCentral

122.

Li Z, Shue F, Zhao N, Shinohara M, Bu G. APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease. Mol Neurodegener. 2020;15(1):63. https://doi.org/10.1186/s13024-020-00413-4.CrossRefPubMedPubMedCentral

123.

Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ, et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11(1):667. https://doi.org/10.1038/s41467-019-14279-8.CrossRefPubMedPubMedCentral

124.

Shinohara M, Kanekiyo T, Tachibana M, Kurti A, Shinohara M, Fu Y, et al. APOE2 is associated with longevity independent of Alzheimer’s disease. Elife. 2020. https://doi.org/10.7554/eLife.62199.CrossRefPubMedPubMedCentral

125.

Salvadó G, Grothe MJ, Groot C, Moscoso A, Schöll M, Gispert JD, et al. Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia. Eur J Nucl Med Mol Imaging. 2021;48(7):2212–24. https://doi.org/10.1007/s00259-021-05192-8.CrossRefPubMedPubMedCentral

126.

Lefterov I, Wolfe CM, Fitz NF, Nam KN, Letronne F, Biedrzycki RJ, et al. APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res Therapy. 2019;11(1):113. https://doi.org/10.1186/s13195-019-0558-0.CrossRef

127.

Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577–90. https://doi.org/10.1016/S0140-6736(20)32205-4.CrossRefPubMed

128.

Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488(7409):96–9. https://doi.org/10.1038/nature11283.CrossRefPubMed

129.

Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373–84. https://doi.org/10.1038/ng.3916.CrossRefPubMedPubMedCentral

130.

Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217(2):459–72. https://doi.org/10.1083/jcb.201709069.CrossRefPubMedPubMedCentral

131.

Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron. 2016;91(2):328–40. https://doi.org/10.1016/j.neuron.2016.06.015.CrossRefPubMed

132.

Lemprière S. Genome-wide association study identifies new risk loci for Alzheimer disease. Nat Rev Neurol. 2021. https://doi.org/10.1038/s41582-021-00575-9.CrossRefPubMedPubMedCentral

133.

Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276–82. https://doi.org/10.1101/2020.11.20.20235275.CrossRefPubMed

134.

Bruni AC, Bernardi L, Gabelli C. From beta amyloid to altered proteostasis in Alzheimer’s disease. Ageing Res Rev. 2020;64(101126): 101126. https://doi.org/10.1016/j.arr.2020.101126.CrossRefPubMed

Title: An insight into Alzheimer’s disease and its on-setting novel genes
Authors: Jaanaky Vigneswaran
Sivaloganathan Anogh Muthukumar
Mohamed Shafras
Geetika Pant
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: The Egyptian Journal of Neurology, Psychiatry and Neurosurgery / Issue 1/2021
Electronic ISSN: 1687-8329
DOI: https://doi.org/10.1186/s41983-021-00420-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

An insight into Alzheimer’s disease and its on-setting novel genes

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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