Autosomal Dominant Alzheimer’s Disease: Underlying Causes



Knowledge about genetics of Alzheimer’s disease (AD), the most prevalent form of dementia, is important to manage challenges of aging populations. So far, genetic analyses of families with autosomal dominant AD, presenting with early-onset dementia (<65 years of age), have found three causal genes: APP, PSEN1, and PSEN2. The possibility to detect carriers of causal mutations could help to evaluate the efficacy of different treatments at either asymptomatic or early stages of dementia. Such individuals are currently enrolled in a longitudinal clinical trial, named the Dominantly Inherited Alzheimer Network (DIAN). We provide an overview for the molecular genetic findings available for causal AD genes, discuss how this knowledge can be applied in clinical practice, and highlight the strategies to detect novel AD genes (e.g., TREM2 and PLD3).


Gene Alzheimer’s disease APP PSEN1 PSEN2 TREM2 PLD3 



We are grateful for the support from the Canadian Institutes of Health Research, W. Garfield Weston Foundation, Ontario Research Fund, and Alzheimer Society of Ontario.


  1. 1.
    Dementia statistics. Available at: Accessed 3 Jan 2014.
  2. 2.
    Miyoshi K. What is ‘early onset dementia’? Psychogeriatrics. 2009;9(2):67–72 [Review].PubMedGoogle Scholar
  3. 3.
    Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488(7409):96–9.PubMedGoogle Scholar
  4. 4.
    Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81–104 [Review].PubMedGoogle Scholar
  5. 5.
    Stefanacci RG. The costs of Alzheimer’s disease and the value of effective therapies. Am J Manag Care. 2011;17 Suppl 13:S356–62 [Review].PubMedGoogle Scholar
  6. 6.
    Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5 [Review].PubMedGoogle Scholar
  7. 7.
    St George-Hyslop PH, Petit A. Molecular biology and genetics of Alzheimer’s disease. C R Biol. 2005;328(2):119–30 [Review].Google Scholar
  8. 8.
    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
  9. 9.
    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.PubMedGoogle Scholar
  10. 10.
    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.PubMedGoogle Scholar
  11. 11.
    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.PubMedGoogle Scholar
  12. 12.
    Guyant-Marechal L, Campion D, Hannequin D. Alzheimer disease: autosomal dominant forms. Rev Neurol (Paris). 2009;165(3):223–31.Google Scholar
  13. 13.
    Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004;25(5):641–50.PubMedGoogle Scholar
  14. 14.
    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.PubMedCentralPubMedGoogle Scholar
  15. 15.
    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
  16. 16.
    Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, et al. Replication of CLU, CR1, and PICALM associations with Alzheimer disease. Arch Neurol. 2010;67(8):961–4.PubMedCentralPubMedGoogle Scholar
  17. 17.
    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.PubMedCentralPubMedGoogle Scholar
  18. 18.
    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.PubMedCentralPubMedGoogle Scholar
  19. 19.
    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.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, et al. Extended meta-analysis of 74,538 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8.Google Scholar
  21. 21.
    Bignante EA, Heredia F, Morfini G, Lorenzo A. Amyloid beta precursor protein as a molecular target for amyloid beta-induced neuronal degeneration in Alzheimer’s disease. Neurobiol Aging. 2013;34:2525–37.PubMedGoogle Scholar
  22. 22.
    Postina R. Activation of alpha-secretase cleavage. J Neurochem. 2012;120 Suppl 1:46–54 [Review].PubMedGoogle Scholar
  23. 23.
    Allinson TM, Parkin ET, Turner AJ, Hooper NM. ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res. 2003;74(3):342–52.PubMedGoogle Scholar
  24. 24.
    Nicolaou M, Song YQ, Sato CA, Orlacchio A, Kawarai T, Medeiros H, et al. Mutations in the open reading frame of the beta-site APP cleaving enzyme (BACE) locus are not a common cause of Alzheimer’s disease. Neurogenetics. 2001;3(4):203–6.PubMedGoogle Scholar
  25. 25.
    Cruts M, Dermaut B, Rademakers R, Roks G, Van den Broeck M, Munteanu G, et al. Amyloid beta secretase gene (BACE) is neither mutated in nor associated with early-onset alzheimer’s disease. Neurosci Lett. 2001;313(1–2):105–7.Google Scholar
  26. 26.
    Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature. 1992;360(6405):672–4.PubMedGoogle Scholar
  27. 27.
    Wolfe MS. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry. 2006;45(26):7931–9 [Review].PubMedGoogle Scholar
  28. 28.
    Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane. Cell. 2007;131(2):215–21 [Review].PubMedGoogle Scholar
  29. 29.
    Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, et al. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell. 1999;97(3):395–406.PubMedGoogle Scholar
  30. 30.
    Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, et al. A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat Med. 2000;6(4):397–404.PubMedGoogle Scholar
  31. 31.
    Sisodia SS, St George-Hyslop PH. gamma-Secretase, Notch, Abeta and Alzheimer’s disease: where do the presenilins fit in? Nat Rev Neurosci. 2002;3(4):281–90.PubMedGoogle Scholar
  32. 32.
    Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat. 2012;33(9):1340–4.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248(4959):1124–6.PubMedGoogle Scholar
  34. 34.
    Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, Wehnert A, et al. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). Science. 1990;248(4959):1120–2.PubMedGoogle Scholar
  35. 35.
    Fernandez-Madrid I, Levy E, Marder K, Frangione B. Codon 618 variant of Alzheimer amyloid gene associated with inherited cerebral hemorrhage. Ann Neurol. 1991;30(5):730–3.PubMedGoogle Scholar
  36. 36.
    Bornebroek M, Haan J, Maat-Schieman ML, Van Duinen SG, Roos RA. Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D): I–A review of clinical, radiologic and genetic aspects. Brain Pathol. 1996;6(2):111–4 [Review].PubMedGoogle Scholar
  37. 37.
    Bugiani O, Giaccone G, Rossi G, Mangieri M, Capobianco R, Morbin M, et al. Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch Neurol. 2010;67(8):987–95.PubMedGoogle Scholar
  38. 38.
    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.PubMedCentralPubMedGoogle Scholar
  39. 39.
    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.PubMedGoogle Scholar
  40. 40.
    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(3):377–87.PubMedGoogle Scholar
  41. 41.
    Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001;49(6):697–705.PubMedGoogle Scholar
  42. 42.
    Greenberg SM, Shin Y, Grabowski TJ, Cooper GE, Rebeck GW, Iglesias S, et al. Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology. 2003;60(6):1020–2.PubMedGoogle Scholar
  43. 43.
    Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992;1(3):218–21.PubMedGoogle Scholar
  44. 44.
    Roks G, Van Harskamp F, De Koning I, Cruts M, De Jonghe C, Kumar-Singh S, et al. Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain. 2000;123(Pt 10):2130–40.PubMedGoogle Scholar
  45. 45.
    Kumar-Singh S, Cras P, Wang R, Kros JM, van Swieten J, Lubke U, et al. Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am J Pathol. 2002;161(2):507–20.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, et al. APP locus duplication causes autosomal dominant early-onset alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38(1):24–6.Google Scholar
  47. 47.
    Guyant-Marechal I, Berger E, Laquerriere A, Rovelet-Lecrux A, Viennet G, Frebourg T, et al. Intrafamilial diversity of phenotype associated with app duplication. Neurology. 2008;71(23):1925–6.PubMedGoogle Scholar
  48. 48.
    Domingues-Montanari S, Pares M, Hernandez-Guillamon M, Fernandez-Cadenas I, Mendioroz M, Ortega G, et al. No evidence of APP point mutation and locus duplication in individuals with cerebral amyloid angiopathy. Eur J Neurol. 2011;18(10):1279–81.PubMedGoogle Scholar
  49. 49.
    Haass C, Hung AY, Selkoe DJ, Teplow DB. Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem. 1994;269(26):17741–8.PubMedGoogle Scholar
  50. 50.
    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 A beta(42) in Alzheimer’s disease. Hum Mol Genet. 2000;9(18):2589–98.PubMedGoogle Scholar
  51. 51.
    De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, 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.PubMedGoogle Scholar
  52. 52.
    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.PubMedGoogle Scholar
  53. 53.
    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.PubMedGoogle Scholar
  54. 54.
    Herl L, Thomas AV, Lill CM, Banks M, Deng A, Jones PB, et al. Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase. Mol Cell Neurosci. 2009;41(2):166–74.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci U S A. 1994;91(25):11993–7.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Perez RG, Squazzo SL, Koo EH. Enhanced release of amyloid beta-protein from codon 670/671 “Swedish” mutant beta-amyloid precursor protein occurs in both secretory and endocytic pathways. J Biol Chem. 1996;271(15):9100–7.PubMedGoogle Scholar
  57. 57.
    Kirkitadze MD, Condron MM, Teplow DB. Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol. 2001;312(5):1103–19.PubMedGoogle Scholar
  58. 58.
    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.PubMedGoogle Scholar
  59. 59.
    Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, et al. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science. 2009;323(5920):1473–7.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Ghani M, Sato C, Lee J, Reitz C, Moreno D, Mayeux R, et al. Evidence of recessive Alzheimer’s disease loci in Caribbean Hispanics: genome-wide survey of runs of homozygosity. JAMA Neurol. 2013;70(10):1261–7. doi: 10.1001/jamaneurol.2013.3545.PubMedCentralPubMedGoogle Scholar
  61. 61.
    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.Google Scholar
  62. 62.
    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.PubMedGoogle Scholar
  63. 63.
    Ghani M, Pinto D, Lee JH, Grinberg Y, Sato C, Moreno D, et al. Genome-wide survey of large rare copy number variants in Alzheimer’s disease among Caribbean hispanics. G3 (Bethesda). 2012;2(1):71–8.Google Scholar
  64. 64.
    Hazrati LN, Van Cauwenberghe C, Brooks PL, Brouwers N, Ghani M, Sato C, et al. Genetic association of CR1 with Alzheimer’s disease: a tentative disease mechanism. Neurobiol Aging. 2012;33(12):2949.e5–12.Google Scholar
  65. 65.
    Hooli BV, Kovacs-Vajna ZM, Mullin K, Blumenthal MA, Mattheisen M, Zhang C, et al. Rare autosomal copy number variations in early-onset familial Alzheimer’s disease. Mol Psychiatry. 2013. doi: 10.1038/mp.2013.77. [Epub ahead of print].
  66. 66.
    St George-Hyslop P, McLachlan DC, Tsuda T, Rogaev E, Karlinsky H, Lippa CF, et al. Alzheimer’s disease and possible gene interaction. Science. 1994;263(5146):537.Google Scholar
  67. 67.
    Wilhelmus MM, Otte-Holler I, Davis J, Van Nostrand WE, de Waal RM, Verbeek MM. Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. J Neurosci. 2005;25(14):3621–7.PubMedGoogle Scholar
  68. 68.
    Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, et al. Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science. 1992;258(5082):668–71.PubMedGoogle Scholar
  69. 69.
    St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, et al. Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nat Genet. 1992;2(4):330–4.Google Scholar
  70. 70.
    Hruz T, Laule O, Szabo G, Wessendorp F, Bleuler S, Oertle L, et al. Genevestigator v3: a reference expression database for the meta-analysis of transcriptomes. Adv Bioinformatics. 2008;2008:420747. doi: 10.1155/2008/420747. Epub 2008 Jul 8.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Haass C, De Strooper B. The presenilins in Alzheimer’s disease—proteolysis holds the key. Science. 1999;286(5441):916–9.PubMedGoogle Scholar
  72. 72.
    Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000;407(6800):48–54.PubMedGoogle Scholar
  73. 73.
    St George-Hyslop P, Fraser PE. Assembly of the presenilin gamma-/epsilon-secretase complex. J Neurochem. 2012;120 Suppl 1:84–8 [Review].Google Scholar
  74. 74.
    Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996;17(5):1005–13.PubMedGoogle Scholar
  75. 75.
    Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, et al. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med. 1996;2(10):1146–50.PubMedGoogle Scholar
  76. 76.
    Mann DM, Iwatsubo T, Cairns NJ, Lantos PL, Nochlin D, Sumi SM, et al. Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer’s disease: predominance of Abeta42(43). Ann Neurol. 1996;40(2):149–56.PubMedGoogle Scholar
  77. 77.
    Mann DM, Iwatsubo T, Nochlin D, Sumi SM, Levy-Lahad E, Bird TD. Amyloid (Abeta) deposition in chromosome 1-linked Alzheimer’s disease: the Volga German families. Ann Neurol. 1997;41(1):52–7.PubMedGoogle Scholar
  78. 78.
    Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398(6727):513–7.PubMedGoogle Scholar
  79. 79.
    Fluhrer R, Fukumori A, Martin L, Grammer G, Haug-Kroper M, Klier B, et al. Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J Biol Chem. 2008;283(44):30121–8.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, et al. A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998;4(4):452–5.PubMedGoogle Scholar
  81. 81.
    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.PubMedGoogle Scholar
  82. 82.
    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(8):1529–40.PubMedGoogle Scholar
  83. 83.
    Muller U, Winter P, Graeber MB. A presenilin 1 mutation in the first case of Alzheimer’s disease. Lancet Neurol. 2013;12(2):129–30.PubMedGoogle Scholar
  84. 84.
    Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, et al. The PSEN1, p.E318G Variant Increases the Risk of Alzheimer’s Disease in APOE-epsilon4 Carriers. PLoS Genet. 2013;9(8):e1003685.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, Jervis R, et al. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol. 2005;62(12):1821–30.PubMedGoogle Scholar
  86. 86.
    Yescas P, Huertas-Vazquez A, Villarreal-Molina MT, Rasmussen A, Tusie-Luna MT, Lopez M, et al. Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset alzheimer’s disease in Mexican families. Neurogenetics. 2006;7(3):195–200.Google Scholar
  87. 87.
    Murrell J, Ghetti B, Cochran E, Macias-Islas MA, Medina L, Varpetian A, et al. The A431E mutation in PSEN1 causing familial Alzheimer’s disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics. 2006;7(4):277–9.PubMedCentralPubMedGoogle Scholar
  88. 88.
    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):2257–63.Google Scholar
  89. 89.
    Tang MX, Cross P, Andrews H, Jacobs DM, Small S, Bell K, et al. Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology. 2001;56(1):49–56.PubMedGoogle Scholar
  90. 90.
    Rogaeva E. The solved and unsolved mysteries of the genetics of early-onset alzheimer’s disease. Neuromolecular Med. 2002;2(1):1–10 [Review].Google Scholar
  91. 91.
    Le TV, Crook R, Hardy J, Dickson DW. Cotton wool plaques in non-familial late-onset alzheimer disease. J Neuropathol Exp Neurol. 2001;60(11):1051–61.Google Scholar
  92. 92.
    Yokota O, Terada S, Ishizu H, Ujike H, Ishihara T, Namba M, et al. Variability and heterogeneity in Alzheimer’s disease with cotton wool plaques: a clinicopathological study of four autopsy cases. Acta Neuropathol. 2003;106(4):348–56.PubMedGoogle Scholar
  93. 93.
    Hiltunen M, Helisalmi S, Mannermaa A, Alafuzoff I, Koivisto AM, Lehtovirta M, et al. Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset alzheimer’s disease family: an Alu core sequence-stimulated recombination? Eur J Hum Genet. 2000;8(4):259–66.Google Scholar
  94. 94.
    Smith MJ, Kwok JB, McLean CA, Kril JJ, Broe GA, Nicholson GA, et al. Variable phenotype of Alzheimer’s disease with spastic paraparesis. Ann Neurol. 2001;49(1):125–9.PubMedGoogle Scholar
  95. 95.
    Sinha N, Grimes D, Tokuhiro S, Sato C, Rogaeva E, Woulfe J. Variant Alzheimer’s disease with spastic paraparesis and supranuclear gaze palsy. Can J Neurol Sci. 2013;40(2):249–51.PubMedGoogle Scholar
  96. 96.
    Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J, et al. A novel presenilin 1 mutation associated with Pick’s disease but not beta-amyloid plaques. Ann Neurol. 2004;55(5):617–26 [Research Support, Non-U.S. Gov’t].PubMedGoogle Scholar
  97. 97.
    Sitek EJ, Narozanska E, Peplonska B, Filipek S, Barczak A, Styczynska M, et al. A patient with posterior cortical atrophy possesses a novel mutation in the presenilin 1 gene. PLoS One. 2013;8(4):e61074.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Mahoney CJ, Downey LE, Beck J, Liang Y, Mead S, Perry RJ, et al. The Presenilin 1 P264L Mutation Presenting as non-Fluent/Agrammatic Primary Progressive Aphasia. J Alzheimers Dis. 2013;36:239–43.PubMedGoogle Scholar
  99. 99.
    Braga-Neto P, Pedroso JL, Alessi H, de Souza PV, Bertolucci PH, Barsottini OG. Early-onset familial Alzheimer’s disease related to presenilin 1 mutation resembling autosomal dominant spinocerebellar ataxia. J Neurol. 2013;260(4):1177–9.PubMedGoogle Scholar
  100. 100.
    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.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Bernardi L, Tomaino C, Anfossi M, Gallo M, Geracitano S, Costanzo A, et al. Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia. Neurobiol Aging. 2009;30(11):1825–33.PubMedGoogle Scholar
  102. 102.
    Amtul Z, Lewis PA, Piper S, Crook R, Baker M, Findlay K, et al. A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis. 2002;9(2):269–73.PubMedGoogle Scholar
  103. 103.
    Pickering-Brown SM, Baker M, Gass J, Boeve BF, Loy CT, Brooks WS, et al. Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain. 2006;129(Pt 11):3124–6.PubMedGoogle Scholar
  104. 104.
    Wang B, Yang W, Wen W, Sun J, Su B, Liu B, et al. Gamma-secretase gene mutations in familial acne inversa. Science. 2010;330(6007):1065.PubMedGoogle Scholar
  105. 105.
    Kimberly WT, Xia W, Rahmati T, Wolfe MS, Selkoe DJ. The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J Biol Chem. 2000;275(5):3173–8.PubMedGoogle Scholar
  106. 106.
    Jayadev S, Case A, Eastman AJ, Nguyen H, Pollak J, Wiley JC, et al. Presenilin 2 is the predominant gamma-secretase in microglia and modulates cytokine release. PLoS One. 2010;5(12):e15743.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Li J, Xu M, Zhou H, Ma J, Potter H. Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell. 1997;90(5):917–27.PubMedGoogle Scholar
  108. 108.
    Bird TD, Levy-Lahad E, Poorkaj P, Sharma V, Nemens E, Lahad A, et al. Wide range in age of onset for chromosome 1–related familial Alzheimer’s disease. Ann Neurol. 1996;40(6):932–6.PubMedGoogle Scholar
  109. 109.
    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.Google Scholar
  110. 110.
    Ezquerra M, Lleo A, Castellvi M, Queralt R, Santacruz P, Pastor P, et al. A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset alzheimer disease. Arch Neurol. 2003;60(8):1149–51.Google Scholar
  111. 111.
    Marchani EE, Bird TD, Steinbart EJ, Rosenthal E, Yu CE, Schellenberg GD, et al. Evidence for three loci modifying age-at-onset of Alzheimer’s disease in early-onset PSEN2 families. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(5):1031–41.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Piscopo P, Marcon G, Piras MR, Crestini A, Campeggi LM, Deiana E, et al. A novel PSEN2 mutation associated with a peculiar phenotype. Neurology. 2008;70(17):1549–54.PubMedGoogle Scholar
  113. 113.
    Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998;153(5):1365–70.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68(2):270–81.PubMedGoogle Scholar
  115. 115.
    Kuwano R, Hara N. Personal genomics for Alzheimer’s disease. Brain Nerve. 2013;65(3):235–46.PubMedGoogle Scholar
  116. 116.
    Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106(45):19096–101.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461(7261):272–6.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Pruitt KD, Harrow J, Harte RA, Wallin C, Diekhans M, Maglott DR, et al. The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes. Genome Res. 2009;19(7):1316–23.PubMedCentralPubMedGoogle Scholar
  119. 119.
    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.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset alzheimer disease. Mol Psychiatry. 2012;17(9):87–9.Google Scholar
  121. 121.
    Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature. 2014;505(7484):550–4.Google Scholar
  122. 122.
    MacArthur DG, Tyler-Smith C. Loss-of-function variants in the genomes of healthy humans. Hum Mol Genet. 2011;19(R2):R125–30.Google Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  1. 1.Tanz Centre for Research in Neurodegenerative DiseasesUniversity of TorontoTorontoCanada
  2. 2.Faculty of Medicine, Neurology Division, Tanz Centre for Research in Neurodegenerative DiseasesUniversity of TorontoTorontoCanada

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