Advertisement

Current Genetic Medicine Reports

, Volume 8, Issue 1, pp 1–16 | Cite as

Alzheimer’s Disease Genetics: Review of Novel Loci Associated with Disease

  • Miguel Tábuas-Pereira
  • Isabel Santana
  • Rita GuerreiroEmail author
  • José Brás
Neurogenetics and Psychiatric Genetics (C Cruchaga and C Karch, Section Editors)
  • 21 Downloads
Part of the following topical collections:
  1. Neurogenetics and Psychiatric Genetics

Abstract

Purpose of the Review

The amyloid cascade hypothesis has shaped the Alzheimer’s disease (AD) research field for the last 30 years. Originally hinged on mutations in the APP pathway, its linearity has become limited to explain all the disease subtypes and features. The understanding of the disease has evolved significantly, now being viewed as a polygenic disease, with more and more risk genes uncovered by several approaches, namely, by genome-wide association studies. Here we reviewed the literature for the latest loci reported to be associated with Alzheimer’s disease using genome-wide association studies and discussed the possible involvement of specific genes located at these loci, in the disease.

Recent Findings

The largest genome-wide association studies for AD have been published in the last year, adding more loci of interest: ADAM10, ADAMTS1, ADAMTS4, ACE/PSMC5, APH1B, WWOX/MAF, HESX1, HS3ST1/CLNK, ANKRD31, CNTNAP2, NDUFAF6, ECHDC3, SPPL2A, KAT8/BCKDK, IQCK, SCIMP, BRZAP-1/BZRAP1-AS1, ALPK2, BHMG1.

Summary

The definite association with AD for some of the reported genes needs further evidence. Regardless, the implicated genes add support for the involvement of several pathways, such as lipids homeostasis and immune pathways. These also point to synaptic dysfunction and cell-cycle dysregulation as mechanisms involved in the disease, extending the understanding of Alzheimer’s disease pathophysiology.

Keywords

Alzheimer’s disease Dementia Genome-wide association studies GWAS Genetics Pathways 

Notes

Compliance with ethical standards

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

40142_2020_182_MOESM1_ESM.docx (108 kb)
ESM 1 (DOCX 108 kb)

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349(6311):704–6.PubMedGoogle Scholar
  2. 2.
    Zhu JB, Tan CC, Tan L, Yu JT. State of play in Alzheimer’s disease genetics. J Alzheimers Dis. 2017;58(3):631–59.PubMedGoogle Scholar
  3. 3.
    Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168–74.PubMedGoogle Scholar
  4. 4.
    Escott-Price V, Shoai M, Pither R, Williams J, Hardy J. Polygenic score prediction captures nearly all common genetic risk for Alzheimer’s disease. Neurobiol Aging. 2017;49:214 e217–1.Google Scholar
  5. 5.
    Ridge PG, Mukherjee S, Crane PK, Kauwe JS. Alzheimer’s disease genetics C: Alzheimer’s disease: analyzing the missing heritability. PLoS One. 2013;8(11):e79771.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8.PubMedPubMedCentralGoogle Scholar
  7. 7.
    •• Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51(3):404–13. The largest GWAS in AD to date, uncovering 8 additional novel loci to a total of 29 AD-associated loci. PubMedGoogle Scholar
  8. 8.
    •• Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD, et al. GWAS on family history of Alzheimer’s disease. Transl Psychiatry. 2018;8(1):99. A GWAS that integrated for the first time a proxy-approach on AD investigation, reaching a sample of almost 400,000 subjects. Most findings match other GWAS, supporting the validity of this approach. PubMedPubMedCentralGoogle Scholar
  9. 9.
    •• 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 Abeta, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30. The largest GWAS in AD including only cases and controls, without proxies. It revealed an association of 26 loci, 5 of which were novel. PubMedGoogle Scholar
  10. 10.
    • Moreno-Grau S, de Rojas I, Hernandez I, Quintela I, Montrreal L, Alegret M, Hernandez-Olasagarre B, Madrid L, Gonzalez-Perez A, Maronas O et al. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project. Alzheimer's Dement 2019. A case-control GWAS including AD and mixed dementia, uncovering 4 novel loci. Google Scholar
  11. 11.
    • Witoelar A, Rongve A, Almdahl IS, Ulstein ID, Engvig A, White LR, et al. Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci. Sci Rep. 2018;8(1):18088. A case-control GWAS adding one additional locus to the previous studies. PubMedPubMedCentralGoogle Scholar
  12. 12.
    Brodie A, Azaria JR, Ofran Y. How far from the SNP may the causative genes be? Nucleic Acids Res. 2016;44(13):6046–54.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Lemarchant S, Wojciechowski S, Vivien D, Koistinaho J. ADAMTS-4 in central nervous system pathologies. J Neurosci Res. 2017;95(9):1703–11.PubMedGoogle Scholar
  14. 14.
    Hayashi K, Kadomatsu K, Muramatsu T. Requirement of chondroitin sulfate/dermatan sulfate recognition in midkine-dependent migration of macrophages. Glycoconj J. 2001;18(5):401–6.PubMedGoogle Scholar
  15. 15.
    Rolls A, Shechter R, London A, Segev Y, Jacob-Hirsch J, Amariglio N, et al. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 2008;5(8):e171.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Stanton H, Melrose J, Little CB, Fosang AJ. Proteoglycan degradation by the ADAMTS family of proteinases. Biochim Biophys Acta. 2011;1812(12):1616–29.PubMedGoogle Scholar
  17. 17.
    Lemarchant S, Pruvost M, Hebert M, Gauberti M, Hommet Y, Briens A, et al. tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury. Neurobiol Dis. 2014;66:28–42.PubMedGoogle Scholar
  18. 18.
    Krstic D, Rodriguez M, Knuesel I. Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PLoS One. 2012;7(10):e47793.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Doehner J, Knuesel I. Reelin-mediated signaling during normal and pathological forms of aging. Aging Dis. 2010;1(1):12–29.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Kocherhans S, Madhusudan A, Doehner J, Breu KS, Nitsch RM, Fritschy JM, et al. Reduced reelin expression accelerates amyloid-beta plaque formation and tau pathology in transgenic Alzheimer’s disease mice. J Neurosci. 2010;30(27):9228–40.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Satoh K, Suzuki N, Yokota H. ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) is transcriptionally induced in beta-amyloid treated rat astrocytes. Neurosci Lett. 2000;289(3):177–80.PubMedGoogle Scholar
  22. 22.
    Rolls A, Shechter R, Schwartz M. The bright side of the glial scar in CNS repair. Nat Rev Neurosci. 2009;10(3):235–41.PubMedGoogle Scholar
  23. 23.
    Martinez-Barbera JP, Rodriguez TA, Beddington RS. The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation. Dev Biol. 2000;223(2):422–30.PubMedGoogle Scholar
  24. 24.
    Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet. 1998;19(2):125–33.PubMedGoogle Scholar
  25. 25.
    Yu J, Riou C, Davidson D, Minhas R, Robson JD, Julius M, et al. Synergistic regulation of immunoreceptor signaling by SLP-76-related adaptor Clnk and serine/threonine protein kinase HPK-1. Mol Cell Biol. 2001;21(18):6102–12.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Goitsuka R, Tatsuno A, Ishiai M, Kurosaki T, Kitamura D. MIST functions through distinct domains in immunoreceptor signaling in the presence and absence of LAT. J Biol Chem. 2001;276(38):36043–50.PubMedGoogle Scholar
  27. 27.
    Xu M, Cai C, Sun X, Chen W, Li Q, Zhou H. Clnk plays a role in TNF-alpha-induced cell death in murine fibrosarcoma cell line L929. Biochem Biophys Res Commun. 2015;463(3):275–9.PubMedGoogle Scholar
  28. 28.
    Lan B, Chen P, Jiri M, He N, Feng T, Liu K, et al. WDR1 and CLNK gene polymorphisms correlate with serum glucose and high-density lipoprotein levels in Tibetan gout patients. Rheumatol Int. 2016;36(3):405–12.PubMedGoogle Scholar
  29. 29.
    Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, et al. Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease. Circulation. 2015;131(23):2061–9.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Espinosa A, Hernandez-Olasagarre B, Moreno-Grau S, Kleineidam L, Heilmann-Heimbach S, Hernandez I, et al. Exploring genetic associations of Alzheimer’s disease loci with mild cognitive impairment neurocognitive endophenotypes. Front Aging Neurosci. 2018;10:340.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Hirano K, Sasaki N, Ichimiya T, Miura T, Van Kuppevelt TH, Nishihara S. 3-O-sulfated heparan sulfate recognized by the antibody HS4C3 contributes [corrected] to the differentiation of mouse embryonic stem cells via fas signaling. PLoS One. 2012;7(8):e43440.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Tecle E, Diaz-Balzac CA, Bulow HE. Distinct 3-O-sulfated heparan sulfate modification patterns are required for kal-1-dependent neurite branching in a context-dependent manner in Caenorhabditis elegans. G3. 2013;3(3):541–52.PubMedGoogle Scholar
  33. 33.
    Smits NC, Kobayashi T, Srivastava PK, Skopelja S, Ivy JA, Elwood DJ, et al. HS3ST1 genotype regulates antithrombin’s inflammomodulatory tone and associates with atherosclerosis. Matrix Biol. 2017;63:69–90.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Lucariello M, Vidal E, Vidal S, Saez M, Roa L, Huertas D, et al. Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype. Hum Genet. 2016;135(12):1343–54.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Papanikos F, Clement JAJ, Testa E, Ravindranathan R, Grey C, Dereli I, et al. Mouse ANKRD31 regulates spatiotemporal patterning of meiotic recombination initiation and ensures recombination between X and Y sex chromosomes. Mol Cell. 2019;74(5):1069–85 e1011.PubMedGoogle Scholar
  36. 36.
    Sale JE, Lehmann AR, Woodgate R. Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat Rev Mol Cell Biol. 2012;13(3):141–52.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Bakkaloglu B, O'Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet. 2008;82(1):165–73.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Friedman JI, Vrijenhoek T, Markx S, Janssen IM, van der Vliet WA, Faas BH, et al. CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol Psychiatry. 2008;13(3):261–6.PubMedGoogle Scholar
  39. 39.
    Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry. 2010;15(6):637–46.PubMedGoogle Scholar
  40. 40.
    Hirano A, Ohara T, Takahashi A, Aoki M, Fuyuno Y, Ashikawa K, et al. A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population. Psychiatr Genet. 2015;25(4):139–46.PubMedGoogle Scholar
  41. 41.
    van Abel D, Michel O, Veerhuis R, Jacobs M, van Dijk M, Oudejans CB. Direct downregulation of CNTNAP2 by STOX1A is associated with Alzheimer’s disease. J Alzheimer's Dis. 2012;31(4):793–800.Google Scholar
  42. 42.
    Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, et al. Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron. 1999;24(4):1037–47.PubMedGoogle Scholar
  43. 43.
    Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354(13):1370–7.PubMedGoogle Scholar
  44. 44.
    Logue MW, Schu M, Vardarajan BN, Buros J, Green RC, Go RC, et al. A comprehensive genetic association study of Alzheimer disease in African Americans. Arch Neurol. 2011;68(12):1569–79.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Lemire BD. Evolution, structure and membrane association of NDUFAF6, an assembly factor for NADH:ubiquinone oxidoreductase (Complex I). Mitochondrion. 2017;35:13–22.PubMedGoogle Scholar
  46. 46.
    Escott-Price V, Bellenguez C, Wang LS, Choi SH, Harold D, Jones L, et al. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS One. 2014;9(6):e94661.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, et al. p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol Cell. 2001;8(1):85–94.PubMedGoogle Scholar
  48. 48.
    Xia X, Lu H, Li C, Huang Y, Wang Y, Yang X, et al. miR-106b regulates the proliferation and differentiation of neural stem/progenitor cells through Tp53inp1-Tp53-Cdkn1a axis. Stem Cell Res Ther. 2019;10(1):282.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, et al. Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimers Dement. 2017;13(7):727–38.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Tesi N, van der Lee SJ, Hulsman M, Jansen IE, Stringa N, van Schoor N, et al. Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer’s disease. Eur J Hum Genet. 2019;27(2):244–53.PubMedGoogle Scholar
  51. 51.
    Brady OA, Zhou X, Hu F. Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). J Biol Chem. 2014;289(28):19670–80.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Martin L, Fluhrer R, Reiss K, Kremmer E, Saftig P, Haass C. Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. J Biol Chem. 2008;283(3):1644–52.PubMedGoogle Scholar
  53. 53.
    Kong XF, Martinez-Barricarte R, Kennedy J, Mele F, Lazarov T, Deenick EK, et al. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol. 2018;19(9):973–85.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Beisner DR, Langerak P, Parker AE, Dahlberg C, Otero FJ, Sutton SE, et al. The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. J Exp Med. 2013;210(1):23–30.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 2010;29(17):3020–32.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014;6(243):243ra286.Google Scholar
  57. 57.
    Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004;113(10):1456–64.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Araki W, Kitaguchi N, Tokushima Y, Ishii K, Aratake H, Shimohama S, et al. Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun. 1991;181(1):265–71.PubMedGoogle Scholar
  59. 59.
    Bell KF, Zheng L, Fahrenholz F, Cuello AC. ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging. 2008;29(4):554–65.PubMedGoogle Scholar
  60. 60.
    Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, et al. Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. Hum Mol Genet. 2009;18(20):3987–96.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Malinverno M, Carta M, Epis R, Marcello E, Verpelli C, Cattabeni F, et al. Synaptic localization and activity of ADAM10 regulate excitatory synapses through N-cadherin cleavage. J Neurosci. 2010;30(48):16343–55.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Marcello E, Gardoni F, Mauceri D, Romorini S, Jeromin A, Epis R, et al. Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J Neurosci. 2007;27(7):1682–91.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Marcello E, Epis R, Saraceno C, Gardoni F, Borroni B, Cattabeni F, et al. SAP97-mediated local trafficking is altered in Alzheimer disease patients’ hippocampus. Neurobiol Aging. 2012;33(2):422 e421–10.Google Scholar
  64. 64.
    Epis R, Marcello E, Gardoni F, Vastagh C, Malinverno M, Balducci C, et al. Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer’s disease. Brain J Neurol. 2010;133(11):3323–35.Google Scholar
  65. 65.
    Marcello E, Saraceno C, Musardo S, Vara H, de la Fuente AG, Pelucchi S, et al. Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease. J Clin Invest. 2013;123(6):2523–38.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Baig S, Joseph SA, Tayler H, Abraham R, Owen MJ, Williams J, et al. Distribution and expression of picalm in Alzheimer disease. J Neuropathol Exp Neurol. 2010;69(10):1071–7.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10. Proc Natl Acad Sci U S A. 2001;98(10):5815–20.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Chen YL, Wang LM, Chen Y, Gao JY, Marshall C, Cai ZY, et al. Changes in astrocyte functional markers and beta-amyloid metabolism-related proteins in the early stages of hypercholesterolemia. Neuroscience. 2016;316:178–91.PubMedGoogle Scholar
  69. 69.
    Jorissen E, Prox J, Bernreuther C, Weber S, Schwanbeck R, Serneels L, et al. The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci. 2010;30(14):4833–44.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Zhuang J, Wei Q, Lin Z, Zhou C. Effects of ADAM10 deletion on Notch-1 signaling pathway and neuronal maintenance in adult mouse brain. Gene. 2015;555(2):150–8.PubMedGoogle Scholar
  71. 71.
    De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003;38(1):9–12.PubMedGoogle Scholar
  72. 72.
    Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565–97.PubMedGoogle Scholar
  73. 73.
    Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003;305(3):502–9.PubMedGoogle Scholar
  74. 74.
    Biundo F, Ishiwari K, Del Prete D, D'Adamio L. Deletion of the gamma-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia. Oncotarget. 2016;7(11):11923–44.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Barao S, Gartner A, Leyva-Diaz E, Demyanenko G, Munck S, Vanhoutvin T, et al. Antagonistic effects of BACE1 and APH1B-gamma-secretase control axonal guidance by regulating growth cone collapse. Cell Rep. 2015;12(9):1367–76.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Li X, Corsa CA, Pan PW, Wu L, Ferguson D, Yu X, et al. MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol Cell Biol. 2010;30(22):5335–47.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Li X, Li L, Pandey R, Byun JS, Gardner K, Qin Z, et al. The histone acetyltransferase MOF is a key regulator of the embryonic stem cell core transcriptional network. Cell Stem Cell. 2012;11(2):163–78.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Chatterjee A, Seyfferth J, Lucci J, Gilsbach R, Preissl S, Bottinger L, et al. MOF acetyl transferase regulates transcription and respiration in mitochondria. Cell. 2016;167(3):722–38 e723.PubMedGoogle Scholar
  79. 79.
    Fullgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature. 2013;500(7463):468–71.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Huai W, Liu X, Wang C, Zhang Y, Chen X, Chen X, et al. KAT8 selectively inhibits antiviral immunity by acetylating IRF3. J Exp Med. 2019;216(4):772–85.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr. 1998;68(1):72–81.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr. 2005;135(6 Suppl):1527S–30S.PubMedGoogle Scholar
  83. 83.
    Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012;338(6105):394–7.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Krzyszton-Russjan J, Zielonka D, Jackiewicz J, Kusmirek S, Bubko I, Klimberg A, et al. A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington’s disease: looking for biomarkers. J Bioenerg Biomembr. 2013;45(1-2):71–85.PubMedGoogle Scholar
  85. 85.
    Ross KA, Bigham AW, Edwards M, Gozdzik A, Suarez-Kurtz G, Parra EJ. Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. J Hum Genet. 2010;55(9):582–9.PubMedGoogle Scholar
  86. 86.
    Zhang H, Yang L, Feng Q, Fan Y, Zheng H, He Y. Association between VKORC1 gene polymorphisms and ischemic cerebrovascular disease in Chinese Han population. J Mol Neurosci. 2014;53(2):166–70.PubMedGoogle Scholar
  87. 87.
    DeSoto MC. Speculations on vitamin K, VKORC1 genotype and autism. Med Hypotheses. 2016;96:30–3.PubMedGoogle Scholar
  88. 88.
    Kruszka P, Uwineza A, Mutesa L, Martinez AF, Abe Y, Zackai EH, et al. Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)? Mol Genet Genom Med. 2015;3(5):424–32.Google Scholar
  89. 89.
    Mattheisen M, Samuels JF, Wang Y, Greenberg BD, Fyer AJ, McCracken JT, et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry. 2015;20(3):337–44.PubMedGoogle Scholar
  90. 90.
    Bednarek AK, Laflin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer. Cancer Res. 2000;60(8):2140–5.PubMedGoogle Scholar
  91. 91.
    Chang NS, Doherty J, Ensign A, Lewis J, Heath J, Schultz L, et al. Molecular mechanisms underlying WOX1 activation during apoptotic and stress responses. Biochem Pharmacol. 2003;66(8):1347–54.PubMedGoogle Scholar
  92. 92.
    Li MY, Lai FJ, Hsu LJ, Lo CP, Cheng CL, Lin SR, et al. Dramatic co-activation of WWOX/WOX1 with CREB and NF-kappaB in delayed loss of small dorsal root ganglion neurons upon sciatic nerve transection in rats. PLoS One. 2009;4(11):e7820.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Sze CI, Su M, Pugazhenthi S, Jambal P, Hsu LJ, Heath J, et al. Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro. A potential role in Alzheimer’s disease. J Biol Chem. 2004;279(29):30498–506.PubMedGoogle Scholar
  94. 94.
    Wang HY, Juo LI, Lin YT, Hsiao M, Lin JT, Tsai CH, et al. WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3beta. Cell Death Differ. 2012;19(6):1049–59.PubMedGoogle Scholar
  95. 95.
    Lee MH, Lin SR, Chang JY, Schultz L, Heath J, Hsu LJ, et al. TGF-beta induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid beta plaques in Alzheimer's disease. Cell Death Dis. 2010;1:e110.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Mallaret M, Synofzik M, Lee J, Sagum CA, Mahajnah M, Sharkia R, et al. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain J Neurol. 2014;137(Pt 2):411–9.Google Scholar
  97. 97.
    Aldaz CM, Ferguson BW, Abba MC. WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta. 2014;1846(1):188–200.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Xia K, Zhang J, Ahn M, Jha S, Crowley JJ, Szatkiewicz J, et al. Genome-wide association analysis identifies common variants influencing infant brain volumes. Transl Psychiatry. 2017;7(8):e1188.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Cao S, Liu J, Song L, Ma X. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol. 2005;174(6):3484–92.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Yang Y, Cvekl A. Large Maf transcription factors: cousins of AP-1 proteins and important regulators of cellular differentiation. Einstein J Biol Med. 2007;23(1):2–11.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Hale TK, Myers C, Maitra R, Kolzau T, Nishizawa M, Braithwaite AW. Maf transcriptionally activates the mouse p53 promoter and causes a p53-dependent cell death. J Biol Chem. 2000;275(24):17991–9.PubMedGoogle Scholar
  102. 102.
    Su W, Hopkins S, Nesser NK, Sopher B, Silvestroni A, Ammanuel S, et al. The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf. J Immunol. 2014;192(1):358–66.PubMedGoogle Scholar
  103. 103.
    Nakayama H, Yamasaki H, Nishizawa M, Goto N. Tissue distribution of the DNA binding oncoprotein Maf during chicken development. Int J Dev Biol. 1995;39(6):957–64.PubMedGoogle Scholar
  104. 104.
    Luo L, Bokil NJ, Wall AA, Kapetanovic R, Lansdaal NM, Marceline F, et al. SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. Nat Commun. 2017;8:14133.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Draber P, Vonkova I, Stepanek O, Hrdinka M, Kucova M, Skopcova T, et al. SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling. Mol Cell Biol. 2011;31(22):4550–62.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Kralova J, Fabisik M, Pokorna J, Skopcova T, Malissen B, Brdicka T. The transmembrane adaptor protein SCIMP facilitates sustained dectin-1 signaling in dendritic cells. J Biol Chem. 2016;291(32):16530–40.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Rock J, Schneider E, Grun JR, Grutzkau A, Kuppers R, Schmitz J, et al. CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2. Eur J Immunol. 2007;37(12):3564–75.PubMedGoogle Scholar
  108. 108.
    Delunardo F, Margutti P, Pontecorvo S, Colasanti T, Conti F, Rigano R, et al. Screening of a microvascular endothelial cDNA library identifies rabaptin 5 as a novel autoantigen in Alzheimer’s disease. J Neuroimmunol. 2007;192(1-2):105–12.PubMedGoogle Scholar
  109. 109.
    Perez SE, He B, Nadeem M, Wuu J, Ginsberg SD, Ikonomovic MD, et al. Hippocampal endosomal, lysosomal, and autophagic dysregulation in mild cognitive impairment: correlation with abeta and tau pathology. J Neuropathol Exp Neurol. 2015;74(4):345–58.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Grauel MK, Maglione M, Reddy-Alla S, Willmes CG, Brockmann MM, Trimbuch T, et al. RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. Proc Natl Acad Sci U S A. 2016;113(41):11615–20.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Kleino I, Jarviluoma A, Hepojoki J, Huovila AP, Saksela K. Preferred SH3 domain partners of ADAM metalloproteases include shared and ADAM-specific SH3 interactions. PLoS One. 2015;10(3):e0121301.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Tanabe C, Hotoda N, Sasagawa N, Sehara-Fujisawa A, Maruyama K, Ishiura S. ADAM19 is tightly associated with constitutive Alzheimer’s disease APP alpha-secretase in A172 cells. Biochem Biophys Res Commun. 2007;352(1):111–7.PubMedGoogle Scholar
  113. 113.
    Galiegue S, Jbilo O, Combes T, Bribes E, Carayon P, Le Fur G, et al. Cloning and characterization of PRAX-1. A new protein that specifically interacts with the peripheral benzodiazepine receptor. J Biol Chem. 1999;274(5):2938–52.PubMedGoogle Scholar
  114. 114.
    Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer’s and other CNS pathologies. J Neurosci. 2008;28(47):12255–67.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009;5(6):e1000536.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Arregui A, Perry EK, Rossor M, Tomlinson BE. Angiotensin converting enzyme in Alzheimer’s disease increased activity in caudate nucleus and cortical areas. J Neurochem. 1982;38(5):1490–2.PubMedGoogle Scholar
  117. 117.
    Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, et al. Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol. 2005;162(4):305–17.PubMedGoogle Scholar
  118. 118.
    Wang XB, Cui NH, Yang J, Qiu XP, Gao JJ, Yang N, et al. Angiotensin-converting enzyme insertion/deletion polymorphism is not a major determining factor in the development of sporadic Alzheimer disease: evidence from an updated meta-analysis. PLoS One. 2014;9(10):e111406.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 2001;276(51):47863–8.PubMedGoogle Scholar
  120. 120.
    Zou K, Yamaguchi H, Akatsu H, Sakamoto T, Ko M, Mizoguchi K, et al. Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition. J Neurosci. 2007;27(32):8628–35.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Koronyo-Hamaoui M, Shah K, Koronyo Y, Bernstein E, Giani JF, Janjulia T, et al. ACE overexpression in myelomonocytic cells: effect on a mouse model of Alzheimer’s disease. Curr Hypertens Rep. 2014;16(7):444.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Miners S, Ashby E, Baig S, Harrison R, Tayler H, Speedy E, et al. Angiotensin-converting enzyme levels and activity in Alzheimer’s disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am J Transl Res. 2009;1(2):163–77.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Eckman EA, Adams SK, Troendle FJ, Stodola BA, Kahn MA, Fauq AH, et al. Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme. J Biol Chem. 2006;281(41):30471–8.PubMedGoogle Scholar
  124. 124.
    Savaskan E, Hock C, Olivieri G, Bruttel S, Rosenberg C, Hulette C, et al. Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia. Neurobiol Aging. 2001;22(4):541–6.PubMedGoogle Scholar
  125. 125.
    Mateos L, Ismail MA, Gil-Bea FJ, Leoni V, Winblad B, Bjorkhem I, et al. Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer’s disease. J Alzheimer's Dis. 2011;24(4):669–79.Google Scholar
  126. 126.
    Hoyle J, Tan KH, Fisher EM. Localization of genes encoding two human one-domain members of the AAA family: PSMC5 (the thyroid hormone receptor-interacting protein, TRIP1) and PSMC3 (the Tat-binding protein, TBP1). Hum Genet. 1997;99(2):285–8.PubMedGoogle Scholar
  127. 127.
    Bhat KP, Turner JD, Myers SE, Cape AD, Ting JP, Greer SF. The 19S proteasome ATPase Sug1 plays a critical role in regulating MHC class II transcription. Mol Immunol. 2008;45(8):2214–24.PubMedGoogle Scholar
  128. 128.
    Conejero-Goldberg C, Hyde TM, Chen S, Dreses-Werringloer U, Herman MM, Kleinman JE, et al. Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer’s disease as based on APOE genotype. Mol Psychiatry. 2011;16(8):836–47.PubMedGoogle Scholar
  129. 129.
    Smirnikhina SA, Lavrov AV, Chelysheva EY, Adilgereeva EP, Shukhov OA, Turkina A, et al. Whole-exome sequencing reveals potential molecular predictors of relapse after discontinuation of the targeted therapy in chronic myeloid leukemia patients. Leuk Lymphoma. 2016;57(7):1669–76.PubMedGoogle Scholar
  130. 130.
    Yoshida Y, Tsunoda T, Doi K, Fujimoto T, Tanaka Y, Ota T, et al. ALPK2 is crucial for luminal apoptosis and DNA repair-related gene expression in a three-dimensional colonic-crypt model. Anticancer Res. 2012;32(6):2301–8.PubMedGoogle Scholar
  131. 131.
    Chu J, Li JG, Joshi YB, Giannopoulos PF, Hoffman NE, Madesh M, et al. Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer’s disease. Biol Psychiatry. 2015;77(8):720–8.PubMedGoogle Scholar
  132. 132.
    Gellert-Kristensen H, Dalila N, Fallgaard Nielsen S, Gronne Nordestgaard B, Tybjaerg-Hansen A, Stender S. Identification and replication of six loci associated with gallstone disease. Hepatology. 2019;70(2):597–609.PubMedGoogle Scholar
  133. 133.
    Yee AS, Paulson EK, McDevitt MA, Rieger-Christ K, Summerhayes I, Berasi SP, et al. The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene. 2004;336(1):1–13.PubMedGoogle Scholar
  134. 134.
    Tevosian SG, Shih HH, Mendelson KG, Sheppard KA, Paulson KE, Yee AS. HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family. Genes Dev. 1997;11(3):383–96.PubMedGoogle Scholar
  135. 135.
    Watanabe N, Kageyama R, Ohtsuka T. Hbp1 regulates the timing of neuronal differentiation during cortical development by controlling cell cycle progression. Development. 2015;142(13):2278–90.PubMedGoogle Scholar
  136. 136.
    Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K. Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J Biol Chem. 1997;272(1):556–62.PubMedGoogle Scholar
  137. 137.
    Shindo T, Kurihara H, Kuno K, Yokoyama H, Wada T, Kurihara Y, et al. ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function. J Clin Invest. 2000;105(10):1345–52.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Kuno K, Okada Y, Kawashima H, Nakamura H, Miyasaka M, Ohno H, et al. ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan. FEBS Lett. 2000;478(3):241–5.PubMedGoogle Scholar
  139. 139.
    Howell MD, Torres-Collado AX, Iruela-Arispe ML, Gottschall PE. Selective decline of synaptic protein levels in the frontal cortex of female mice deficient in the extracellular metalloproteinase ADAMTS1. PLoS One. 2012;7(10):e47226.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Miguel RF, Pollak A, Lubec G. Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as Down syndrome, Alzheimer’s and Pick’s disease. Brain Res Mol Brain Res. 2005;133(1):1–5.PubMedGoogle Scholar
  141. 141.
    DeWitt DA, Silver J, Canning DR, Perry G. Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer’s disease. Exp Neurol. 1993;121(2):149–52.PubMedGoogle Scholar
  142. 142.
    Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595–608.PubMedPubMedCentralGoogle Scholar
  143. 143.
    De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell. 2016;164(4):603–15.PubMedGoogle Scholar
  144. 144.
    Goedert M, Spillantini MG. Propagation of Tau aggregates. Mol Brain. 2017;10(1):18.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Dourlen P, Kilinc D, Malmanche N, Chapuis J, Lambert JC. The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathol. 2019;138(2):221–36.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368(2):117–27.PubMedGoogle Scholar
  147. 147.
    Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368(2):107–16.PubMedGoogle Scholar
  148. 148.
    Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci. 2013;16(7):848–50.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43(5):436–41.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Thambisetty M, An Y, Nalls M, Sojkova J, Swaminathan S, Zhou Y, et al. Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. Biol Psychiatry. 2013;73(5):422–8.PubMedGoogle Scholar
  151. 151.
    Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1094–9.PubMedGoogle Scholar
  152. 152.
    Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43(5):429–35.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Liang Y, Tedder TF. Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse. Genomics. 2001;72(2):119–27.PubMedGoogle Scholar
  154. 154.
    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.PubMedGoogle Scholar
  155. 155.
    Currais A, Hortobagyi T, Soriano S. The neuronal cell cycle as a mechanism of pathogenesis in Alzheimer’s disease. Aging. 2009;1(4):363–71.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Lee HG, Casadesus G, Zhu X, Castellani RJ, McShea A, Perry G, et al. Cell cycle re-entry mediated neurodegeneration and its treatment role in the pathogenesis of Alzheimer’s disease. Neurochem Int. 2009;54(2):84–8.PubMedGoogle Scholar
  157. 157.
    Freeman RS, Estus S, Johnson EM Jr. Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death. Neuron. 1994;12(2):343–55.PubMedGoogle Scholar
  158. 158.
    Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J, et al. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron. 2003;38(4):555–65.PubMedGoogle Scholar
  159. 159.
    Toccaceli V, Fagnani C, Gigantesco A, Brescianini S, D'Ippolito C, Stazi MA. Attitudes and willingness to donate biological samples for research among potential donors in the Italian Twin Register. J Empir Res Human Res Ethics. 2014;9(3):39–47.Google Scholar
  160. 160.
    Davies G, Marioni RE, Liewald DC, Hill WD, Hagenaars SP, Harris SE, et al. Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151). Mol Psychiatry. 2016;21(6):758–67.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Davies G, Armstrong N, Bis JC, Bressler J, Chouraki V, Giddaluru S, et al. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). Mol Psychiatry. 2015;20(2):183–92.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Lencz T, Knowles E, Davies G, Guha S, Liewald DC, Starr JM, et al. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol Psychiatry. 2014;19(2):168–74.PubMedGoogle Scholar
  163. 163.
    Coolen MW, van Loo KM, van Bakel NN, Ellenbroek BA, Cools AR, Martens GJ. Reduced Aph-1b expression causes tissue- and substrate-specific changes in gamma-secretase activity in rats with a complex phenotype. FASEB J. 2006;20(1):175–7.PubMedGoogle Scholar
  164. 164.
    Calvin CM, Deary IJ, Fenton C, Roberts BA, Der G, Leckenby N, et al. Intelligence in youth and all-cause-mortality: systematic review with meta-analysis. Int J Epidemiol. 2011;40(3):626–44.PubMedGoogle Scholar
  165. 165.
    Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Bush WS, et al. Sex differences in the genetic predictors of Alzheimer’s pathology. Brain J Neurol. 2019;142(9):2581–9.Google Scholar
  166. 166.
    Khramtsova EA, Davis LK, Stranger BE. The role of sex in the genomics of human complex traits. Nat Rev Genet. 2019;20(3):173–90.PubMedGoogle Scholar
  167. 167.
    Chen Z, Ng HK, Li J, Liu Q, Huang H. Detecting associated single-nucleotide polymorphisms on the X chromosome in case control genome-wide association studies. Stat Methods Med Res. 2017;26(2):567–82.PubMedGoogle Scholar
  168. 168.
    Lord J, Lu AJ, Cruchaga C. Identification of rare variants in Alzheimer’s disease. Front Genet. 2014;5:369.PubMedPubMedCentralGoogle Scholar
  169. 169.
    Ridge PG, Kauwe JSK. Mitochondria and Alzheimer’s disease: the role of mitochondrial genetic variation. Curr Genet Med Rep. 2018;6(1):1–10.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of NeurologyCentro Hospitalar e Universitário de CoimbraCoimbraPortugal
  2. 2.Faculty of MedicineUniversidade de CoimbraCoimbraPortugal
  3. 3.Center for Neurodegenerative ScienceVan Andel InstituteGrand RapidsUSA
  4. 4.Division of Psychiatry and Behavioral MedicineMichigan State University College of Human MedicineGrand RapidsUSA

Personalised recommendations