Advertisement

Genetic Markers of Alzheimer’s Disease

  • Matea Nikolac Perkovic
  • Nela PivacEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1192)

Abstract

Alzheimer’s disease is a complex and heterogeneous, severe neurodegenerative disorder and the predominant form of dementia, characterized by cognitive disturbances, behavioral and psychotic symptoms, progressive cognitive decline, disorientation, behavioral changes, and death. Genetic background of Alzheimer’s disease differs between early-onset familial Alzheimer’s disease, other cases of early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease. Rare cases of early-onset familial Alzheimer’s diseases are caused by high-penetrant mutations in genes coding for amyloid precursor protein, presenilin 1, and presenilin 2. Late-onset Alzheimer’s disease is multifactorial and associated with many different genetic risk loci (>20), with the apolipoprotein E ε4 allele being a major genetic risk factor for late-onset Alzheimer’s disease. Genetic and genomic studies offer insight into many additional genetic risk loci involved in the genetically complex nature of late-onset Alzheimer’s disease. This review highlights the contributions of individual loci to the pathogenesis of Alzheimer’s disease and suggests that their exact contribution is still not clear. Therefore, the use of genetic markers of Alzheimer’s disease, for monitoring development, time course, treatment response, and prognosis of Alzheimer’s disease, is still far away from the clinical application, because the contribution of genetic variations to the relative risk of developing Alzheimer’s disease is limited. In the light of prediction and prevention of Alzheimer’s disease, a novel approach could be found in the form of additive genetic risk scores, which combine additive effects of numerous susceptibility loci.

Keywords

Alzheimer’s disease Genetics GWAS Late-onset Markers 

References

  1. 1.
    Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Reitz C (2016) Toward precision medicine in Alzheimer’s disease. Ann Transl Med. 2016;4(6):107.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Hampel H, O’Bryant S, Durrleman S, Younesi E, Rojkova K, Escott-Price V, et al. A precision medicine Initiative for Alzheimer’s disease: the road ahead to biomarker-guided integrative disease modeling. Climacteric. 2017;20(2):107–18.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Nikolac Perkovic M, Svob Strac D, Tudor L, Konjevod M, Nedic Erjavec G, Pivac N. Catechol-O-methyltransferase, cognition and Alzheimer’s disease. Curr Alzheimer Res. 2018;15(5):408–19.CrossRefGoogle Scholar
  5. 5.
    Duarte A, Santos MS, Oliveira CR. Moreira P. Brain insulin signalling, glucose metabolism and females’ reproductive aging: a dangerous triad in Alzheimer’s disease. Neuropharmacology. 2018;136(Pt B):223–42.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2015;18(5):421–30.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Kopan R, Goate A. A common enzyme connects Notch signaling and Alzheimer’s disease. Genes Dev. 2000;14(22):2799–806.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, et al. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002;21(8):1948–56.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Lleó A, Waldron E, von Arnim CA, Herl L, Tangredi MM, Peltan ID, et al. Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for gamma-secretase. J Biol Chem. 2005;280:27303–9.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Vidal GA, Naresh A, Marrero L, Jones FE. Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities. J Biol Chem. 2005;280:19777–83.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Dai MH, Zheng H, Zeng LD, Zhang Y. The genes associated with early-onset Alzheimer’s disease. Oncotarget. 2017;9(19):15132–43.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Larsson M, Duffy DL, Zhu G, Liu JZ, Macgregor S, McRae AF, et al. GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development. Am J Hum Genet. 2011;89(2):334–43.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Liu Y, Yu JT, Wang HF, Hao XK, Yang YF, Jiang T, et al. Association between NME8 locus polymorphism and cognitive decline, cerebrospinal fluid and neuroimaging biomarkers in Alzheimer’s disease. PLoS ONE. 2014;9:e114777.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ruiz A, Heilmann S, Becker T, Hernández I, Wagner H, Thelen M, et al. Follow-up of loci from the International Genomics of Alzheimer’s Disease Project identifies TRIP4 as a novel susceptibility gene. Transl Psychiatry. 2014;4:e358.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Rosenthal SL, Barmada MM, Wang X, Demirci FY, Kamboh MI. Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer’s disease GWAS findings. PLoS ONE. 2014;9(4):e95152.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Allen M, Kachadoorian M, Carrasquillo MM, Karhade A, Manly L, Burgess JD, et al. Late-onset Alzheimer disease risk variants mark brain regulatory loci. Neurol Genet. 2015;1(2):e15.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Jiao B, Liu X, Zhou L. Polygenic analysis of late-onset Alzheimer’s disease from mainland China. PLoS ONE. 2015;10:e0144898.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Phillips MC. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life. 2014;66(9):616–23.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Lai MK, Tsang SW, Garcia-Alloza M, Minger SL, Nicoll JA, Esiri MM, et al. Selective effects of the APOE ε4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer’s disease. Neurobiol Dis. 2006;22(3):555–61.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180–4.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Tiraboschi P, Hansen LA, Masliah E, Alford M, Thal LJ, Corey-Bloom J. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004;62(11):1977–83.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Liu Y, Paajanen T, Westman E, Zhang Y, Wahlund LO, Simmons A, et al. APOE ε2 allele is associated with larger regional cortical thicknesses and volumes. Dement Geriatr Cogn Disord. 2010;30(3):229–37.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, et al. ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118(12):4002–13.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Matukumalli SR, Tangirala R, Rao CM. Clusterin: full-length protein and one of its chains show opposing effects on cellular lipid accumulation. Sci Reports. 2017;7:41235.CrossRefGoogle Scholar
  27. 27.
    Li X, Ma Y, Wei X, Li Y, Wu H, Zhuang J, Zhao Z. Clusterin in Alzheimer’s disease: a player in the biological behaviour of amyloid-beta. Neurosci Bull. 2014;30(1):162–8.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Zlokovic BV. Cerebrovascular transport of Alzheimer’s amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. Life Sci. 1996;59:1483–97.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1088–93.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR29 associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1094–9.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Szymanski M, Wang R, Bassett SS, Avramopoulos D. Alzheimer’s risk variants in the clusterin gene are associated with alternative splicing. Transl Psychiatry. 2011;1(7):e18.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Bettens K, Brouwers N, Engelborghs S, Lambert JC, Rogaeva E, Vandenberghe R, et al. Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. Mol Neurodegener. 2012;16(7):3.CrossRefGoogle Scholar
  33. 33.
    Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, et al. The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci. 2006;26(5):1596–603.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39(2):168–77.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, et al. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015;77:215–27.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, et al. Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell. 2015;16(4):373–85.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Vasquez JB, Fardo DW, Estus S. ABCA7 expression is associated with Alzheimer’s disease polymorphism and disease status. Neurosci Lett. 2013;556:58–62.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat Genet. 2015;47(5):445–7.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303(18):1832–40.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Xiao Q, Gil SC, Yan P, Wang Y, Han S, Gonzales E, et al. Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem. 2012;287:21279–89.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015;18:978–87.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, et al. PICALM modulates autophagy activity and tau accumulation. Nat Commun. 2014;5:4998.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert JC, Bettens K, Le Bastard N, et al. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry. 2012;17(2):223–33.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Hazrati LN, Van Cauwenberghe C, Brooks PL, Brouwers N, Ghani M, Sato C, et al. Genetic association of CR45 with Alzheimer’s disease: a tentative disease mechanism. Neurobiol Aging. 2012;33(12):2949.e5–12.CrossRefGoogle Scholar
  47. 47.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Karch CM, Jeng AT, Nowotny P, Cady J, Cruchaga C, Goate AM. Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PLoS ONE. 2012;7:e50976.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013;78(4):631–43.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Zuccolo J, Deng L, Unruh TL, Sanyal R, Bau JA, Storek J, et al. Expression of MS4A and TMEM176 genes in human B lymphocytes. Front Immunol. 2013;4:195.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, et al. The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk. BioRxiv. 2018.  https://doi.org/10.1101/352179.
  53. 53.
    Antunez C, Boada M, González-Pérez A, Gayán J, Ramírez-Lorca R, Marín J, et al. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer’s disease. Genome Med. 2011;3(5):33.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Ulrich JD, Ulland TK, Colonna M, Holtzman DM. Elucidating the Role of TREM2 in Alzheimer’s disease. Neuron. 2017;94:237–48.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Shulman JM, Chen K, Keenan BT, Chibnik LB, Fleisher A, Thiyyagura P, et al. Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurol. 2013;70(9):1150–7.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA. 1997;278(16):1349–56.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Hooli BV, Mohapatra G, Mattheisen M, Parrado AR, Roehr JT, Shen Y, et al. Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology. 2012;78(16):1250–7.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kasuga K, Shimohata T, Nishimura A, Shiga A, Mizuguchi T, Tokunaga J, et al. Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80(9):1050–2.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    McNaughton D, Knight W, Guerreiro R, Ryan N, Lowe J, Poulter M, et al. Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series. Neurobiol Aging. 2012;33(2):426.e13–21.CrossRefGoogle Scholar
  60. 60.
    Thonberg H, Fallström M, Björkström J, Schoumans J, Nennesmo I, Graff C. Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient. BMC Res Notes. 2011;4:476.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, et al. The French series of autosomal dominant early onset Alzheimer’s disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012;30(4):847–56.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Brouwers N, Sleegers K, Van Broeckhoven C. Molecular genetics of Alzheimer’s disease: an update. Ann Med. 2008;40(8):562–83.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, et al. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992;51(5):998–1014.PubMedPubMedCentralGoogle Scholar
  64. 64.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Nilsberth C, Westlind-Danielsson A, Eckman CB, Forsell C, Axelman K, Luthman J, et al. The Arctic APP mutation (E693G) causes Alzheimer’s disease through a novel mechanism: increased amyloid β protofibril formation and decreased amyloid β levels in plasma and conditioned media. Neurobiol Aging. 2000;21 Suppl 1:S58.CrossRefGoogle Scholar
  66. 66.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, et al. A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann Neurol. 2008;63:377–87.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Wakutani Y, Watanabe K, Adachi Y, Wada-Isoe K, Urakami K, Ninomiya H, et al. Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;75(7):1039–42.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Wakutani Y. Gene symbol: APP. Disease: Familial Alzheimer’s disease. Hum Genet. 2005;117(2–3):299.Google Scholar
  70. 70.
    Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, et al. Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 → Met betaAPP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci USA. 1999;96(7):4119–24.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, et al. Pilot whole-exome sequencing of a German early-onset Alzheimer’s disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016;37(208):e11–7.Google Scholar
  72. 72.
    Brooks WS, Martins RN, De Voecht J, Nicholson GA, Schofield PR, Kwok JB, et al. A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer’s disease. Neurosc Lett. 1995;199(3):183–6.CrossRefGoogle Scholar
  73. 73.
    Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, Serneels S, Kamali K, et al. Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer’s disease. Brain. 2006;129(Pt 11):2984–91.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Campion D, Brice A, Hannequin D, Charbonnier F, Dubois B, Martin C, et al. No founder effect in three novel Alzheimer’s disease families with APP 717 Val → Ile mutation. Clerget-darpoux. French Alzheimer’s Disease Study Group. J Med Genet. 1996;33(8):661–4.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65(3):664–70.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, et al. Mutations of the presenilin I gene in families with early-onset Alzheimer’s disease. Hum Mol Genet. 1995;4(12):2373–7.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, et al. Genetic screening in a large cohort of early-onset Alzheimer’s disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimer Dement. 2008;4 Supp 2:T583.Google Scholar
  78. 78.
    Cruts M, Dermaut B, Kumar-Singh S, Rademakers R, Van den Broeck M, Stögbauer F, et al. Novel German APP V715A mutation associated with presenile Alzheimer’s disease. Neurobiol Aging. 2002;23(1S):S327.Google Scholar
  79. 79.
    Cruts M, Dermaut B, Rademakers R, Van den Broeck M, Stogbauer F, Van Broeckhoven C. Novel APP mutation V715A associated with presenile Alzheimer’s disease in a German family. J Neurol. 2003;250(11):1374–5.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    De Jonghe C, Kumar-Singh S, Cruts M, Kleinert R, Vanderstichele H, Vanmechelen EJM, et al. Unusual Aβ amyloid deposition in Alzheimer’s disease due tu an APP T714I mutation at the γ42-secretase site. Neurobiol Aging. 2000;21(1):S200.CrossRefGoogle Scholar
  81. 81.
    De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, et al. Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001;10(16):1665–71.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Dobricic V, Stefanova E, Jankovic M, Gurunlian N, Novakovic I, Hardy J, et al. Genetic testing in familial and young-onset Alzheimer’s disease: mutation spectrum in a Serbian cohort. Neurobiol Aging. 2012;3(1481):e7–12.Google Scholar
  83. 83.
    Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997;6(12):2087–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, et al. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005;64(2):377–9.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Fidani L, Rooke K, Chartier-Harlin MC, Hughes D, Tanzi R, Mullan M, et al. Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer’s disease: identification of a further family with APP717 Val → Ile. Hum Mol Genet. 1992;1(3):165–8.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Finckh U, Muller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, et al. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000;66(1):110–7.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Ghetti B, Hake AM, Murrell JR, Epperson F, Farlow MR, Vidal R, Spina S. Familial Alzheimer disease associated with the V717L amyloid precursor protein gene mutation: Neuropathological characterization. Alzheimers Dement. 2008;4 Suppl 4:T585.Google Scholar
  89. 89.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Godbolt AK, Beck JA, Collinge JC, Cipolotti L, Fox NC, Rossor MN. A second family with familial AD and the V717L APP mutation has a later age at onset. Neurology. 2006;66(4):611–2.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Guardia-Laguarta C, Pera M, Clarimón J, Molinuevo JL, Sánchez-Valle R, Lladó A, et al. Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation. J Neuropathol Exp Neurol. 2010;69(1):53–9.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Hardy J, Mullan M, Chartier-Harlin M-C, Brown J, Goate A, Rossor M, Collinge J, et al. Molecular classification of Alzheimer’s disease. Lancet. 1991;337(8753):1342–3.Google Scholar
  94. 94.
    Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, et al. Early onset familial Alzheimer’s disease: mutation frequency in 31 families. Neurobiol Aging. 2002;23(1):S311.Google Scholar
  95. 95.
    Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, et al. Early onset familial Alzheimer’s disease: mutation frequency in 31 families. Neurology. 2003;60(2):235–9.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Jiao B, Tang B, Liu X, Xu J, Wang Y, Zhou L, et al. Mutational analysis in early-onset familial Alzheimer’s disease in Mainland China. Neurobiol Aging. 2014;35(8):1957.e1–6.CrossRefGoogle Scholar
  97. 97.
    Kumar-Singh S, De Jonghe C, Cruts M, Kleinert R, Wang R, Mercken M, et al. Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated abeta(42) in Alzheimer’s disease. Hum Mol Genet. 2000;9(18):2589–98.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Kwok JBJ, Li Q-X, Hallupp M, Milward L, Whyte S, Schofield PR. Novel familial early-onset Alzheimer’s disease mutation (Leu723Pro) in amyloid precursor protein (APP) gene increases production of 42(43) amino-acid isoform of amyloid beta peptide. Neurobiol Aging. 1998;19(4):S91.Google Scholar
  99. 99.
    Kwok JB, Li QX, Hallupp M, Whyte S, Ames D, Beyreuther K, Masters CL, Schofield PR. Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol. 2000;47(2):249–53.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Matsumura Y, Kitamura E, Miyoshi K, Yamamoto Y, Furuyama J, Sugihara T. Japanese siblings with missense mutation (717Val → Ile) in amyloid precursor protein of early-onset Alzheimer’s disease. Neurology. 1996;46(6):1721–3.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science. 1991;254(5028):97–9.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B. Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000;57:885–7.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, et al. Mis-sense mutation Val → Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer’s disease. Lancet. 1991;337(8747):978–9.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Park HK, Na DL, Lee JH, Kim JW, Ki CS. Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer’s disease. J Korean Med Sci. 2008;23(2):213–7.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Raux G, Guyant-Marechal L, Martin C, Bou J, Penet C, Brice A, et al. Molecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update. J Med Genet. 2005;42(10):793–5.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, et al. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer’s disease. Neurobiol Aging. 2014;35(10):2422.e13–6.PubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, et al. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer’s disease. Neurobiol Aging. 2014;35(12):2881.e1–6.CrossRefGoogle Scholar
  108. 108.
    Sorbi S, Nacmias B, Forleo P, Piacentini S, Amaducci L, Provinciali L. APP717 and Alzheimer’s disease in Italy. Nat Genet. 1993;4(1):10.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Sorbi S, Nacmias B, Forleo P, Piacentini S, Latorraca S, Amaducci L. Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer’s disease. Ann Neurol. 1995;38(1):124–7.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Tedde A, Nacmias B, Ciantelli M, Forleo P, Cellini E, Bagnoli S, et al. Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003;60(11):1541–4.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Terreni L, Fogliarino S, Franceschi, Forloni G. Novel pathogenic mutation in an Italian patient with familial Alzheimer’s disease detected in APP gene. Neurobiol Aging. 2002;23(1):S319.Google Scholar
  112. 112.
    Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y. The 717Val → Ile substitution in amyloid precursor protein is associated with familial Alzheimer’s disease regardless of ethnic groups. Biochem Biophys Res Commun. 1991;178(3):1141–6.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Yoshizawa T, Komatsuzaki Y, Iwamoto H, Mizusawa H, Kanazawa I. Screening of the mis-sense mutation producing the 717Val → Ile substitution in the amyloid precursor protein in Japanese familial and sporadic Alzheimer’s disease. J Neurol Sci. 1993;117(1–2):12–5.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Zekanowski C, Styczynska M, Peplonska B, Gabryelewicz T, Religa D, Ilkowski J, et al. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer’s disease in Poland. Exp Neurol. 2003;184(2):991–6.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, et al. Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006;27(9):888–96.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Alberici A, Bonato C, Borroni B, Cotelli M, Mattioli F, Binetti G, et al. Dementia, delusions and seizures: storage disease or genetic AD. Eur J Neurol. 2007;14(9):1057–9.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Aldudo J, Bullido MJ, Arbizu T, Oliva R, Valdivieso F. Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer’s disease. Neurosci Lett. 1998;240(3):174–6.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Aldudo J, Bullido MJ, Valdivieso F. DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer’s disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433–9.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Antonell A, Balasa M, Oliva R, Lladó A, Bosch B, Fabregat N, et al. A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer’s disease. Neurosci Lett. 2011;496(1):40–2.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Aoki M, Abe K, Oda N, Ikeda M, Tsuda T, Kanai M, et al. A presenilin-1 mutation in a Japanese family with Alzheimer’s disease and distinctive abnormalities on cranial MRI. Neurology. 1997;48(4):1118–20.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Arai N, Kishino A, Takahashi Y, Morita D, Nakamura K, Yokoyama T, et al. Familial cases presenting very early onset autosomal dominant Alzheimer’s disease with I143T in presenilin-1 gene: implication for genotype-phenotype correlation. Neurogenetics. 2008;9(1):65–7.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Arango D, Cruts M, Torres O, Backhovens H, Serrano ML, Villareal E, et al. Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001;103(2):138–43.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, et al. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001;286(18):2256–63.CrossRefGoogle Scholar
  124. 124.
    Axelman K, Basun H, Lannfelt L. Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene. Arch Neurol. 1998;55(5):698–702.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Batelli S, Albani D, Prato F, Polito L, Franceschi M, Gavazzi A, Forloni G. Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394V. Alzheimer Dis Assoc Disord. 2008;22(2):184–7.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Boteva K, Vitek M, Mitsuda H, de Silva H, Xu PT, Small G, Gilbert JR. Mutation analysis of presenillin 1 gene in Alzheimer’s disease. Lancet. 1996;347(8994):130–1.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Brouwers N, Sleegers K, Theuns J, Engelborghs S, Bogaerts V, Serneels S, et al. Contribution of dementia genes to Alzheimer’s disease in Belgium. Alzheimer Dement. 2006;2(3):S191.CrossRefGoogle Scholar
  128. 128.
    Cervenakova L, Brown P, Sandoval F, Foncin J-F, Garruto R, Polinsky RJ, et al. Identification of presenilin-1 gene point mutations in early-onset Alzheimer’s disease families. Am J Hum Genet. 1996;59(Suppl):A252.Google Scholar
  129. 129.
    Church A, Prescott J, Lillis S, Rees J, Chance P, Williamson K, Morris HR. A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer’s disease. Neurobiol Aging. 2011;32(556):e1–2.Google Scholar
  130. 130.
    Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, et al. Genetic screening in a large cohort of early-onset Alzheimer’s disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Dement. 2008;4(Supp 2):T583.CrossRefGoogle Scholar
  131. 131.
    Clark RF, Hutton M, Fuldner RA, Froelich S, Karran E, Talbot C, et al. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995;11(2):219–22.CrossRefGoogle Scholar
  132. 132.
    Coleman P, Kurlan R, Crook R, Werner J, Hardy J. A new presenilin Alzheimer’s disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004;364(3):139–40.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Crook R, Ellis R, Shanks M, Thal LJ, Perez-Tur J, Baker M, et al. Early-onset Alzheimer’s disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2. Ann Neurol. 1997;42(1):124–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Cruts M, Backhovens H, Wang SY, Gassen GV, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P, Bruyland M, Datson N, Weissenbach J, den Dunnen JT, Martin J-J, Hendriks L, Van Broeckhoven C. Molecular genetic analysis of familial early-onset Alzheimer’s disease linked to chromosome 14q24.3. Hum Mol Genet. 1995;4(12):2363–72.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, et al. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998;7:43–51.PubMedCrossRefGoogle Scholar
  136. 136.
    Doran M, Larner AJ. Familial Alzheimer’s disease due to presenilin-1 Y115C mutation. J Neurol. 2006;253 Suppl 2:ii91,2006.Google Scholar
  137. 137.
    Dowjat K, Kuchna I, Wisniewski K, Wisniewski T, Wegiel J. Another highly pathogenic Alzheimer presenilin-1 mutation in codon 117: genotype-phenotype comparison of P117S and P117L mutations. Neurobiol Aging. 2002;23(1S):S219.Google Scholar
  138. 138.
    Dowjat WK, Kuchna I, Wisniewski T, Wegiel J. A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations. J Alzheimers Dis. 2004;6(1):31–43.PubMedCrossRefGoogle Scholar
  139. 139.
    Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, et al. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer’s disease cases. French Alzheimer’s Disease Study Group. J Med Genet. 1998;35(8):672–3.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Edwards-Lee T, Wen J, Bell J, Hardy J, Chung J, Momeni P. A presenilin-1 mutation (T245P) in transmembrane domain 6 causes early onset Alzheimer’s disease. Neurosci Lett. 2006;398(3):251–2.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Ezquerra M, Carnero C, Blesa R, Oliva R. A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease. Arch Neurol. 2000;57(4):485–8.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Fang B, Jia L, Jia J. Chinese Presenilin-1 V97L mutation enhanced Abeta42 levels in SH-SY5Y neuroblastoma cells. Neurosci Lett. 2006;406(1–2):33–7.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Fang BY, Jia JP. The effect of two newly Chinese presenilin-1 mutations on the sensitivity to trophic factor withdrawal in human neuroblastoma cells. Zhonghua Yi Xue Za Zhi. 2007;87(5):336–40.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Finckh U, Alberici A, Antoniazzi M, Benussi L, Fedi V, Giannini C, Gal A, Nitsch RM, Binetti G. Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology. 2000;54(10):2006–8.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Forsell C, Froelich S, Axelman K, Vestling M, Cowburn RF, Lilius L, et al. A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer’s disease. Neurosci Lett. 1997;234(1):3–6.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Gallo M, Marcello N, Curcio SA, Colao R, Geracitano S, Bernardi L, et al. A novel pathogenic PSEN1 mutation in a family with Alzheimer’s disease: phenotypical and neuropathological features. J Alzheimers Dis. 2011;25(3):425–31.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Gliebus G, Rosso A, Lippa CF. Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. Am J Alzheimers Dis Other Demen. 2009;24(6):456–60.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Golan M, Lipczynska-Lojkowska W, Krzysko KA, Styczynska M, Luczywek E, Filipek S, et al. Two novel mutations in presenilin 1 (PSEN1) gene connected with atypical familial early-onset Alzheimer’s disease (EOAD). Alzheimer’s and Parkinson’s diseases: insights, progress and perspectives. In: 7th international conference AD/PD 2005 book of abstracts: 24, 2005.Google Scholar
  149. 149.
    Goldman JS, Reed B, Gearhart R, Kramer JH, Miller BL. Very early-onset familial Alzheimer’s disease: a novel presenilin 1 mutation. Int J Geriatr Psychiatry. 2002;17(7):649–51.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, et al. Clinical-genetic correlations in familial Alzheimer’s disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873–84.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, et al. Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010;31(5):725–31.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Gustafson L, Brun A, Englund E, Hagnell O, Nilsson K, Stensmyr M, et al. A 50-year perspective of a family with chromosome-14-linked Alzheimer’s disease. Hum Genet. 1998;102(3):253–7.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Hamaguchi T, Morinaga A, Tsukie T, Kuwano R, Yamada M. A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease. J Neurol. 2009;256(9):1575–7.PubMedCrossRefGoogle Scholar
  154. 154.
    Harvey RJ, Ellison D, Hardy J, Hutton M, Roques PK, Collinge J, Fox NC, Rossor MN. Chromosome 14 familial Alzheimer’s disease: the clinical and neuropathological characteristics of a family with a leucine → serine (L250S) substitution at codon 250 of the presenilin 1 gene. J Neurol Neurosurg Psychiatry. 1998;64(1):44–9.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Heckmann J, de Viliers C, Rutherfoord S, Ramesar R, Morris C, Low R, Kalaria R. Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous South African family with early-onset Alzheimer’s disease. Brain. 2004;127(Pt 1):133–42.PubMedCrossRefGoogle Scholar
  156. 156.
    Higuchi S, Yoshino A, Matsui T, Matsushita S, Satoh A, Iimura T, et al. A novel PS1 Mutation (W165G) in a Japanese family with early-onset Alzheimer’s disease. Alzheimers Rep. 2000;3(4):227–31.Google Scholar
  157. 157.
    Houlden H, Crook R, Dolan RJ, McLaughlin J, Revesz T, Hardy J. A novel presenilin mutation (M233V) causing very early onset Alzheimer’s disease with Lewy bodies. Neurosci Lett. 2001;313(1–2):93–5.PubMedCrossRefGoogle Scholar
  158. 158.
    Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, et al. Complete analysis of the presenilin 1 gene in early onset Alzheimer’s disease. NeuroReport. 1996;7(3):801–5.PubMedCrossRefGoogle Scholar
  159. 159.
    Ikeda M, Sharma V, Sumi SM, Rogaeva EA, Poorkaj P, Sherrington R, et al. The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol. 1996;40(6):912–7.PubMedCrossRefGoogle Scholar
  160. 160.
    Ikeda M, Yonemura K, Kakuda S, Tashiro Y, Fujita Y, Takai E, et al. Cerebrospinal fluid levels of phosphorylated tau and Aß1-38/Aß1-40/Aß1-42 in Alzheimer’s disease with PS1 mutations. Amyloid. 2013;20(2):107–12.PubMedCrossRefGoogle Scholar
  161. 161.
    Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, et al. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406 W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43–9.PubMedCrossRefGoogle Scholar
  162. 162.
    Jacquier M, Arango D, Torres O, Cruts M, Serrano M, Matallana M, et al. Presenilin mutations in a Colombian familial and sporadic AD sample. Neurobiol Aging. 2000;21(1):S176.CrossRefGoogle Scholar
  163. 163.
    Janssen JC, Lantos PL, Fox NC, Harvey RJ, Beck J, Dickinson A, et al. Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation. Arch Neurol. 2001;58(6):953–8.PubMedCrossRefGoogle Scholar
  164. 164.
    Jia J, Xu E, Shao Y, Jia J, Sun Y, Li D. One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer’s disease. J Alzheimers Dis. 2005;7(2):119–24.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Jiang HY, Li GD, Dai SX, Bi R, Zhang DF, Li ZF, et al. Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer’s disease. Neurobiol Aging. 2015;36(3):1602.e3–6.CrossRefGoogle Scholar
  166. 166.
    Jin SC, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C, Goate A, et al. Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer’s disease Ibero-American cohort. Alzheimers Res Ther. 2012;4(4):34.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Jorgensen P, Bus C, Pallisgaard N, Bryder M, Jorgensen AL. Familial Alzheimer’s disease co-segregates with a Met146I1e substitution in presenilin-1. Clin Genet. 1996;50(5):281–6.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Kamimura K, Tanahashi H, Yamanaka H, Takahashi K, Asada T, Tabira T. Familial Alzheimer’s disease genes in Japanese. J Neurol Sci. 1998;160(1):76–81.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Kamino K, Sato S, Sakaki Y, Yoshiiwa A, Nishiwaki Y, Takeda M, et al. Three different mutations of presenilin 1 gene in early-onset Alzheimer’s disease families. Neurosci Lett. 1996;208(3):195–8.PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Kasuga K, Ohno T, Ishihara T, Miyashita A, Kuwano R, Onodera O, et al. Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation. J Neurol. 2009;256(8):1351–3.PubMedCrossRefGoogle Scholar
  171. 171.
    Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM, et al. Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer’s disease presenilin 1 mutation. Ann Neurol. 2007;61(5):446–53.PubMedCrossRefGoogle Scholar
  172. 172.
    Kerchner GA, Holbrook K. Novel presenilin-1 Y159F sequence variant associated with early-onset Alzheimer’s disease. Neurosci Lett. 2012;531(2):142–4.PubMedCrossRefGoogle Scholar
  173. 173.
    Kim HJ, Kim HY, Ki CS, Kim SH. Presenilin 1 gene mutation (M139I) in a patient with an early-onset Alzheimer’s disease: clinical characteristics and genetic identification. Neurol Sci. 2010;31(6):781–3.PubMedCrossRefGoogle Scholar
  174. 174.
    Kim J, Bagyinszky E, Chang YH, Choe G, Choi BO, An SS, Kim S. A novel PSEN1 H163P mutation in a patient with early-onset Alzheimer’s disease: clinical, neuroimaging, and neuropathological findings. Neurosci Lett. 2012;530(2):109–14.PubMedCrossRefGoogle Scholar
  175. 175.
    Klunemann HH, Rogaeva E, Neumann M, Kretzschmar HA, Kandel M, Toulina A, et al. Novel PS1 mutation in a Bavarian kindred with familial Alzheimer disease. Alzheimer Dis Assoc Disord. 2004;18(4):256–8.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Knight WD, Kennedy J, Mead S, Rossor MN, Beck J, Collinge J, Mummery C. A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer’s disease. Eur J Neurol. 2007;14(7):829–31.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, et al. Molecular genetics of Alzheimer’s disease: presenilin 1 gene analysis in a cohort of patients from the Poznan region. J Appl Genet. 2003;44(2):231–4.PubMedPubMedCentralGoogle Scholar
  178. 178.
    Kowalska A, Pruchnik-Wolinska D, Florczak J, Modestowicz R, Szczech J, Kozubski W, et al. Genetic study of familial cases of Alzheimer’s disease. Acta Biochim Pol. 2004;51(1):245–52.PubMedPubMedCentralGoogle Scholar
  179. 179.
    Kowalska A, Pruchnik-Wolinska D, Florczak J, Szczech J, Kozubski W, Rossa G, Wender M. Presenilin 1 mutations in Polish families with early-onset Alzheimer’s disease. Folia Neuropathol. 2004;42(1):9–14.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, et al. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer’s disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. NeuroReport. 1997;8(6):1537–42.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Kwok JB, Halliday GM, Brooks WS, Dolios G, Laudon H, Murayama O, et al. Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer’s disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003;278(9):6748–54.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    La Bella V, Liguori M, Cittadella R, Settipani N, Piccoli T, Manna I, Quattrone A, Piccoli F. A novel mutation (Thr116Ile) in the presenilin 1 gene in a patient with early-onset Alzheimer’s disease. Eur J Neurol. 2004;11(8):521–4.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Lee P, Medina L, Ringman JM. The Thr354Ile substitution in PSEN1: disease-causing mutation or polymorphism? Neurology. 2006;66(12):1955–6.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, et al. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014;2(5):430–7.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Lendon CL, Martinez A, Behrens IM, Kosik KS, Madrigal L, Norton J, et al. E280A PS-1 mutation causes Alzheimer’s disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186–95.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Lindquist S, Schwartz M, Batbayli M, Waldemar G, Nielsen J. Genetic testing in familial AD and FTD: Mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009;76(2):205–9.PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Lladó A, Sánchez-Valle R, Rey MJ, Mercadal P, Almenar C, López-Villegas D, Fortea J, Molinuevo JL. New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer’s disease. Neurologia. 2010;25(1):13–6.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Lleo A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Pena-Casanova J, Rojo A, Oliva R. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002;59(11):1759–63.PubMedCrossRefPubMedCentralGoogle Scholar
  189. 189.
    Lohmann E, Guerreiro RJ, Erginel-Unaltuna N, Gurunlian N, Bilgic B, Gurvit H, et al. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012;33(8):1850.e17–27.CrossRefGoogle Scholar
  190. 190.
    Luedecke D, Becktepe JS, Lehmbeck JT, Finckh U, Yamamoto R, Jahn H, Boelmans K. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease. Neurosci Lett. 2014;566:115–9.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Miklossy J, Taddei K, Suva D, Verdile G, Fonte J, Fisher C, et al. Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease. Neurobiol Aging. 2003;24(5):655–62.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Miravalle L, Murrell JR, Takao M, Glazier B, Piccardo P, Vidal R, Ghetti B. Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002;23(1):S322.Google Scholar
  193. 193.
    Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, et al. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci USA. 2002;99(12):8025–30.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Morelli L, Prat MI, Levy E, Mangone CA, Castano EM. Presenilin 1 Met146Leu variant due to an A → T transversion in an early-onset familial Alzheimer’s disease pedigree from Argentina. Clin Genet. 1998;53(6):469–73.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Norton JB, Cairns NJ, Chakraverty S, Wang J, Levitch D, Galvin JE, Goate A. Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool plaques. Neurology. 2009;73(6):480–2.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer’s disease in the UK. Hum Mutat. 1999;13(3):256.PubMedCrossRefPubMedCentralGoogle Scholar
  197. 197.
    Pantieri R, Pardini M, Cecconi M, Dagna-Bricarelli F, Vitali A, Piccini A, et al. A novel presenilin 1 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer’s disease. Neurol Sci. 2005;26(5):349–50.PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, et al. Missense mutations in the chromosome 14 familial Alzheimer’s disease presenilin 1 gene. Hum Mutat. 1998;11(3):216–21.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Portet F, Dauvilliers Y, Campion D, Raux G, Hauw JJ, Lyon-Caen O, et al. Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu). Neurology. 2003;61(8):1136–7.PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Queralt R, Ezquerra M, Castellvi M, Lleo A, Blesa R, Oliva R. Detection of the presenilin 1 gene mutation (M139T) in early-onset familial Alzheimer disease in Spain. Neurosci Lett. 2001;299(3):239–41.PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Ramirez-Duenas MG, Rogaeva EA, Leal CA, Lin C, Ramirez-Casillas GA, Hernandez-Romo JA, et al. A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease. Ann Genet. 1998;41(3):149–53.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Reznik-Wolf H, Treves TA, Davidson M, Aharon-Peretz J, St George Hyslop PH, Chapman J, et al. A novel mutation of presenilin 1 in familial Alzheimer’s disease in Israel detected by denaturing gradient gel electrophoresis. Hum Genet. 1996;98(6):700–2.PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Ringman JM, Gylys KH, Medina LD, Fox M, Kepe V, Flores DL, et al. Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer’s disease due to a novel PSEN1 mutation. Neurosci Lett. 2011;487(3):287–92.PubMedCrossRefPubMedCentralGoogle Scholar
  204. 204.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376(6543):775–8.PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, et al. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001;57(4):621–5.PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    Romero I, Jorgensen P, Bolwig G, Fraser PE, Rogaeva E, Mann D, et al. A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer’s disease. NeuroReport. 1999;10(11):2255–60.PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  208. 208.
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375(6534):754–60.PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Shrimpton AE, Schelper RL, Linke RP, Hardy J, Crook R, Dickson DW, et al. A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis. Neuropathology. 2007;27(3):228–32.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Smith MJ, Gardner RJ, Knight MA, Forrest SM, Beyreuther K, Storey E, et al. Early-onset Alzheimer’s disease caused by a novel mutation at codon 219 of the presenilin-1 gene. NeuroReport. 1999;10(3):503–7.PubMedCrossRefPubMedCentralGoogle Scholar
  211. 211.
    Sorbi S, Tedde A, Nacmias B, Ciantelli M, Caffarra P, Ghidoni E, et al. Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer’s disease families. Neurobiol Aging. 2002;23(1):S312.Google Scholar
  212. 212.
    Sugiyama N, Suzuki K, Matsumura T, Kawanishi C, Onishi H, Yamada Y, et al. A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer’s disease. Hum Mutat. 1999;14(1):90.PubMedCrossRefPubMedCentralGoogle Scholar
  213. 213.
    Tanahashi H, Kawakatsu S, Kaneko M, Yamanaka H, Takahashi K, Tabira T. Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer’s disease patients. Neurosci Lett. 1996;218(2):139–41.PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Tedde A, Bartoli A, Piaceri I, Ferrara S, Bagnoli S, Serio A, et al. Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-onset Alzheimer’s disease. Neurosci Lett. 2016;610:150–3.PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Terreni L, Valeria C, Calella AM, Gavazzi A, Alberoni M, Grimaldi LM, et al. A novel missense mutation (L219F) in exon 8 of the presenilin 1 gene in an Italian family with presenile familial Alzheimer’s disease. Neurobiol Aging. 2000;21(1):176–7.CrossRefGoogle Scholar
  216. 216.
    Tiedt HO, Lueschow A, Winter P, Müller U. Previously not recognized deletion in presenilin-1 (p.Leu174del.) in a patient with early-onset familial Alzheimer’s disease. Neurosci Lett. 2013;544:115–8.PubMedCrossRefPubMedCentralGoogle Scholar
  217. 217.
    Ting SK, Benzinger T, Kepe V, Fagan A, Coppola G, Porter V, et al. A novel PSEN1 mutation (I238M) associated with early-onset Alzheimer’s disease in an African-American woman. J Alzheimers Dis. 2014;40(2):271–5.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Wasco W, Pettingell WP, Jondro PD, Schmidt SD, Gurubhagavatula S, Rodes L, et al. Familial Alzheimer’s chromosome 14 mutations. Nat Med. 1995;1(9):848.PubMedCrossRefPubMedCentralGoogle Scholar
  219. 219.
    Wisniewski T, Dowjat WK, Buxbaum JD, Khorkova O, Efthimiopoulos S, Kulczycki J, et al. A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer’s disease and leads to death as early as the age of 28 years. NeuroReport. 1998;9(2):217–21.PubMedCrossRefPubMedCentralGoogle Scholar
  220. 220.
    Yagi R, Miyamoto R, Morino H, Izumi Y, Kuramochi M, Kurashige T, et al. Detecting gene mutations in Japanese Alzheimer’s patients by semiconductor sequencing. Neurobiol Aging. 2014;35(7):1780.e1–5.CrossRefGoogle Scholar
  221. 221.
    Yasuda M, Maeda K, Ikejiri Y, Kawamata T, Kuroda S, Tanaka C. A novel missense mutation in the presenilin-1 gene in a familial Alzheimer’s disease pedigree with abundant amyloid angiopathy. Neurosci Lett. 1997;232(1):29–32.PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Yasuda M, Maeda K, Hashimoto M, Yamashita H, Ikejiri Y, Bird TD, et al. A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2. Arch Neurol. 1999;56(1):65–9.PubMedCrossRefPubMedCentralGoogle Scholar
  223. 223.
    Yasuda M, Maeda S, Kawamata T, Tamaoka A, Yamamoto Y, Kuroda S, et al. Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000;68(2):220–3.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Zekanowski C, Golan MP, Krzysko KA, Lipczynska-Lojkowska W, Filipek S, Kowalska A, et al. Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment. Exp Neurol. 2006;200(1):82–8.PubMedCrossRefPubMedCentralGoogle Scholar
  225. 225.
    De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, et al. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer’s disease by increased Abeta42 secretion. Hum Mol Genet. 1999;8(3):1539–40.Google Scholar
  226. 226.
    Guo J, Wei J, Liao S, Wang L, Jiang H, Tang B. A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer’s disease. Neurosci Lett. 2010;468(1):34–7.PubMedCrossRefPubMedCentralGoogle Scholar
  227. 227.
    Tysoe C, Whittaker J, Xuereb J, Cairns NJ, Cruts M, Van Broeckhoven C, et al. A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet. 1998;62(1):70–6.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Puccio G, et al. Late onset familial Alzheimer’s disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008;255(4):604–6.PubMedCrossRefPubMedCentralGoogle Scholar
  229. 229.
    Beyer K, Lao JI, Fernandández-Novoa L, Cacabelos R. Identification of a novel mutation (V148I) in the TM2 domain of the presenilin 2 gene in a patient with late-onset Alzheimer disease. Neurob Aging. 1998;19(4):S87.Google Scholar
  230. 230.
    Ertekin-Taner N, Younkin LH, Yager DM, Parfitt F, Baker MC, Asthana S, et al. Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology. 2008;70(8):596–606.PubMedCrossRefPubMedCentralGoogle Scholar
  231. 231.
    Ezquerra M, Lleo A, Castellvi M, Queralt R, Santacruz P, Pastor P, et al. A novel mutation in the PSEN2 gene (T430 M) associated with variable expression in a family with early-onset Alzheimer disease. Arch Neurol. 2003;60(8):1149–51.PubMedCrossRefPubMedCentralGoogle Scholar
  232. 232.
    Gallo M, Tomaino C, Bernardi L, Maletta R, Anfossi M, Geracitano S, et al. PS1 polymporphism and a novel PS2 mutation in a patient with late-onset familial Alzheimer’s disease. Alzheimers Dement. 2008;4(4):Suppl:T585.Google Scholar
  233. 233.
    Guerreiro RJ, Beck J, Gibbs JR, Santana I, Rossor MN, Schott JM, et al. Genetic variability in CLU and its association with Alzheimer’s disease. PLoS ONE. 2010;5(3):e9510.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Lao JI, Beyer K, Fernandez-Novoa L, Cacabelos R. A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer’s disease. Neurogenetics. 1998;1(4):293–6.PubMedCrossRefPubMedCentralGoogle Scholar
  235. 235.
    Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, et al. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006;79(6):1030–9.PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Lindquist SG, Hasholt L, Bahl JM, Heegaard NH, Andersen BB, Nørremølle A, et al. A novel presenilin 2 mutation (V393 M) in early-onset dementia with profound language impairment. Eur J Neurol. 2008;15(10):1135–9.PubMedCrossRefPubMedCentralGoogle Scholar
  237. 237.
    Lleo A, Blesa R, Gendre J, Castellvi M, Pastor P, Queralt R, Oliva R. A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer’s disease. Neurology. 2001;57(10):1926–8.PubMedCrossRefPubMedCentralGoogle Scholar
  238. 238.
    Müller U, Winter P, Bolender C, Nolte D. Previously unrecognized missense mutation E126 K of PSEN2 segregates with early onset Alzheimer’s disease in a family. J Alzheimers Dis. 2014;42(1):109–13.PubMedCrossRefPubMedCentralGoogle Scholar
  239. 239.
    Niu F, Yu S, Zhang Z, Yi X, Ye L, Tang W, Qiu C, Wen H, Sun Y, Gao J, Guo Y. Novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer’s disease in a Chinese Han family. Neurobiol Aging. 2014;35(10):2420.e1–5.CrossRefGoogle Scholar
  240. 240.
    Piscopo P, Talarico G, Crestini A, Gasparini M, Malvezzi-Campeggi L, Piacentini E, et al. A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer’s disease. J Alzheimers Dis. 2010;20(1):43–7.PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    Piscopo P, Talarico G, Spadoni O, Malvezzi-Campeggi L, Crestini A, Gasparini M, et al. A novel Italian presenilin 2 mutation (S175Y). Alzheimers Dement. 2008;4(4):Suppl 2:T595.Google Scholar
  242. 242.
    Sleegers K, Roks G, Theuns J, Aulchenko YS, Rademakers R, Cruts M, et al. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004;127(Pt7):1641–9.PubMedCrossRefPubMedCentralGoogle Scholar
  243. 243.
    Tomaino C, Bernardi L, Anfossi M, Costanzo A, Ferrise F, Gallo M, et al. Presenilin 2 Ser130Leu mutation in a case of late-onset “sporadic” Alzheimer’s disease. J Neurol. 2007;254(3):391–3.PubMedCrossRefPubMedCentralGoogle Scholar
  244. 244.
    Youn YC, Bagyinszky E, Kim H, Choi BO, An SS, Kim S. Probable novel PSEN2 Val214Leu mutation in Alzheimer’s disease supported by structural prediction. BMC Neurol. 2014;14:105.PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;13;261(5123):921–3.PubMedCrossRefPubMedCentralGoogle Scholar
  246. 246.
    Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S. Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet. 1993;342(8873):697–9.PubMedCrossRefPubMedCentralGoogle Scholar
  247. 247.
    Rebeck GW, Reiter JS, Strickland DK, Hyman BT. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron. 1993;11(4):575–80.PubMedCrossRefPubMedCentralGoogle Scholar
  248. 248.
    Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996;47:387–400.PubMedCrossRefPubMedCentralGoogle Scholar
  249. 249.
    Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43(8):1467–72.PubMedCrossRefPubMedCentralGoogle Scholar
  250. 250.
    Saunders AM. Apolipoprotein E and Alzheimer disease: an update on genetic and functional analyses. J Neuropathol Exp Neurol. 2000;59(9):751–8.PubMedCrossRefPubMedCentralGoogle Scholar
  251. 251.
    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA. 1993;90(5):1977–81.PubMedCrossRefPubMedCentralGoogle Scholar
  252. 252.
    Cuenco KT, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA, et al. Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol. 2008;65(12):1640–8.PubMedCentralCrossRefGoogle Scholar
  253. 253.
    Holton P, Ryten M, Nalls M, Trabzuni D, Weale ME, Hernandez D, et al. Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci. Ann Hum Genet. 2013;77(2):85–105.PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    Tycko B, Feng L, Nguyen L, Francis A, Hays A, Chung WY, et al. Polymorphisms in the human apolipoproteinJ/clusterin gene: ethnic variation and distribution in Alzheimer’s disease. Hum Genet. 1996;98(4):430–6.PubMedCrossRefGoogle Scholar
  255. 255.
    Kok EH, Luoto T, Haikonen S, Goebeler S, Haapasalo H, Karhunen PJ. CLU, CR255 and PICALM genes associate with Alzheimer’s-related senile plaques. Alzheimers Res Ther. 2011;3(2):12.PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, et al. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008;83(5):623–32.PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Malik M, Simpson JF, Parikh I, Wilfred BR, Fardo DW, Nelson PT, Estus S. CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing. J Neurosci. 2013;33(33):13320–5.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Lacher SE, Alazizi A, Wang X, Bell DA, Pique-Regi R, Luca F, Slattery M. A hypermorphic antioxidant response element is associated with increased MS4A6A expression and Alzheimer’s disease. Redox Biol. 2018;14:686–93.PubMedCrossRefGoogle Scholar
  259. 259.
    Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron. 2013;78(2):256–68.PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet. 2014;23(21):5838–46.PubMedPubMedCentralCrossRefGoogle Scholar
  261. 261.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  262. 262.
    Schjeide BM, Schnack C, Lambert JC, Lill CM, Kirchheiner J, Tumani H, et al. The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. Arch Gen Psychiatry. 2011;68(2):207–13.PubMedCrossRefPubMedCentralGoogle Scholar
  263. 263.
    Morgen K, Ramirez A, Frölich L, Tost H, Plichta MM, Kölsch H, et al. Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer’s disease. Alzheimers Dement. 2014;10(5 Suppl):S269–76.PubMedCrossRefPubMedCentralGoogle Scholar
  264. 264.
    Chen H, Wu G, Jiang Y, Feng R, Liao M, Zhang L, et al. Analyzing 54,936 samples supports the association between CD2AP rs9349407 polymorphism and Alzheimer’s disease susceptibility. Mol Neurobiol. 2015;52(1):1–7.PubMedCrossRefPubMedCentralGoogle Scholar
  265. 265.
    Wang HF, Tan L, Hao XK, Jiang T, Tan MS, Liu Y, et al. Effect of EPHA1 genetic variation on cerebrospinal fluid and neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer’s disease cohorts. J Alzheimers Dis. 2015;44(1):115–23.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Division of Molecular MedicineRudjer Boskovic InstituteZagrebCroatia

Personalised recommendations