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The genetics and neuropathology of Alzheimer’s disease

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Abstract

Here we review the genetic causes and risks for Alzheimer’s disease (AD). Early work identified mutations in three genes that cause AD: APP, PSEN1 and PSEN2. Although mutations in these genes are rare causes of AD, their discovery had a major impact on our understanding of molecular mechanisms of AD. Early work also revealed the ε4 allele of the APOE as a strong risk factor for AD. Subsequently, SORL1 also was identified as an AD risk gene. More recently, advances in our knowledge of the human genome, made possible by technological advances and methods to analyze genomic data, permit systematic identification of genes that contribute to AD risk. This work, so far accomplished through single nucleotide polymorphism arrays, has revealed nine new genes implicated in AD risk (ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4E/MS4A6A, and PICALM). We review the relationship between these mutations and genetic variants and the neuropathologic features of AD and related disorders. Together, these discoveries point toward a new era in neurodegenerative disease research that impacts not only AD but also related illnesses that produce cognitive and behavioral deficits.

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References

  1. Abraham R, Moskvina V, Sims R, Hollingworth P et al (2008) A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC Med Genomics 1:44

    Article  PubMed  CAS  Google Scholar 

  2. Adams RH, Klein R (2000) Eph receptors and ephrin ligands. Essential mediators of vascular development. Trends Cardiovasc Med 10:183–188

    Article  PubMed  CAS  Google Scholar 

  3. Andersen OM, Reiche J, Schmidt V, Gotthardt M et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA 102:13461–13466

    Article  PubMed  CAS  Google Scholar 

  4. Andersen OM, Schmidt V, Spoelgen R, Gliemann J et al (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45:2618–2628

    Article  PubMed  CAS  Google Scholar 

  5. Basun H, Bogdanovic N, Ingelsson M, Almkvist O et al (2008) Clinical and neuropathological features of the Arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol 65:499–505

    Article  PubMed  Google Scholar 

  6. Beecham GW, Martin ER, Li YJ, Slifer MA et al (2009) Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet 84:35–43

    Article  PubMed  CAS  Google Scholar 

  7. Beecham GW, Naj AC, Gilbert JR, Haines JL et al (2010) PCDH11X variation is not associated with late-onset Alzheimer disease susceptibility. Psychiatr Genet 20:321–324

    Article  PubMed  Google Scholar 

  8. Bergmans BA, De Strooper B (2010) gamma-secretases: from cell biology to therapeutic strategies. Lancet Neurol 9:215–226

    Article  PubMed  CAS  Google Scholar 

  9. Bertram L, Lange C, Mullin K, Parkinson M et al (2008) Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 83:623–632

    Article  PubMed  CAS  Google Scholar 

  10. Bettens K, Brouwers N, Engelborghs S, De Deyn PP et al (2008) SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat 29:769–770

    Article  PubMed  Google Scholar 

  11. Bornebroek M, Haan J, MaatSchieman MLC, VanDuinen SG et al (1996) Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D).1. A review of clinical, radiologic and genetic aspects. Brain Pathol 6:111–114

    Article  PubMed  CAS  Google Scholar 

  12. Bu GJ (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344

    Article  PubMed  CAS  Google Scholar 

  13. Calabia-Linares C, Robles-Valero J, de la Fuente H, Perez-Martinez M et al (2011) Endosomal clathrin drives actin accumulation at the immunological synapse. J Cell Sci 124:820–830

    Article  PubMed  CAS  Google Scholar 

  14. Cao H, Crocker PR (2011) Evolution of CD33-related siglecs: regulating host immune functions and escaping pathogen exploitation? Immunology 132:18–26

    Article  PubMed  CAS  Google Scholar 

  15. Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL et al (2009) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet 41:192–198

    Article  PubMed  CAS  Google Scholar 

  16. Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329–1333

    Article  PubMed  Google Scholar 

  17. Chibnik LB, Shulman JM, Leurgans SE, Schneider JA et al (2011) CR1 is associated with amyloid plaque burden and age-related cognitive decline. Ann Neurol 69:560–569

    Article  PubMed  CAS  Google Scholar 

  18. Chu SH, Roeder K, Ferrell RE, Devlin B et al (2011) TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. Neurobiol Aging 32:2328.e1–2328.e9

    Article  CAS  Google Scholar 

  19. Coon KD, Myers AJ, Craig DW, Webster JA et al (2007) A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry 68:613–618

    Article  PubMed  CAS  Google Scholar 

  20. Coppus A, Evenhuis H, Verberne GJ, Visser F et al (2006) Dementia and mortality in persons with Down’s syndrome. J Intellect Disabil Res 50:768–777

    Article  PubMed  CAS  Google Scholar 

  21. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE et al (1993) Gene dose of apolipoprotein-E Type-4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

    Article  PubMed  CAS  Google Scholar 

  22. Cramer PE, Cirrito JR, Wesson DW, Lee CY et al (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335:1503–1506

    Article  PubMed  CAS  Google Scholar 

  23. Cras P, van Harskamp F, Hendriks L, Ceuterick C et al (1998) Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala → Gly mutation. Acta Neuropathol 96:253–260

    Article  PubMed  CAS  Google Scholar 

  24. Crehan H, Holton P, Wray S, Pocock J et al (2011) Complement receptor 1 (CR1) and Alzheimer’s disease. Immunobiology 217:244–250

    Article  PubMed  CAS  Google Scholar 

  25. Crocker PR, Paulson JC, Varki A (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7:255–266

    Article  PubMed  CAS  Google Scholar 

  26. Cruchaga C, Nowotny P, Kauwe JS, Ridge PG et al (2011) Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Arch Neurol 68:1013–1019

    Article  PubMed  Google Scholar 

  27. Davidson YS, Raby S, Foulds PG, Robinson A et al (2011) TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol 122:703–713

    Article  PubMed  Google Scholar 

  28. De Jager PL, Shulman JM, Chibnik LB, Keenan BT et al (2012) A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiol Aging 33(5):1017.e1–e15

    Google Scholar 

  29. Depaepe V, Suarez-Gonzalez N, Dufour A, Passante L et al (2005) Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435:1244–1250

    Article  PubMed  CAS  Google Scholar 

  30. Diedrich JF, Minnigan H, Carp RI, Whitaker JN et al (1991) Neuropathological changes in scrapie and Alzheimer’s disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol 65:4759–4768

    PubMed  CAS  Google Scholar 

  31. Dowling JJ, Gibbs EM, Feldman EL (2008) Membrane traffic and muscle: lessons from human disease. Traffic 9:1035–1043

    Article  PubMed  CAS  Google Scholar 

  32. Duffy SL, Coulthard MG, Spanevello MD, Herath NI et al (2008) Generation and characterization of EphA1 receptor tyrosine kinase reporter knockout mice. Genesis 46:553–561

    Article  PubMed  CAS  Google Scholar 

  33. Dustin ML, Olszowy MW, Holdorf AD, Li J et al (1998) A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94:667–677

    Article  PubMed  CAS  Google Scholar 

  34. Farrer LA, Cupples LA, Haines JL, Hyman B et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 278:1349–1356

    Article  PubMed  CAS  Google Scholar 

  35. Genin E, Hannequin D, Wallon D, Sleegers K et al (2011) APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 16:903–907

    Article  PubMed  CAS  Google Scholar 

  36. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890

    Article  PubMed  CAS  Google Scholar 

  37. Goate A, Chartier-Harlin M-C, Mullan M, Brown J et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706

    Article  PubMed  CAS  Google Scholar 

  38. Gomez-Isla T, Growdon WB, McNamara MJ, Nochlin D et al (1999) The impact of different presenilin 1 and presenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer’s disease brain—evidence for other phenotype-modifying factors. Brain 122:1709–1719

    Article  PubMed  Google Scholar 

  39. Grabowski TJ, Cho HS, Vonsattel JPG, Rebeck GW et al (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurology 49:697–705

    Article  CAS  Google Scholar 

  40. Grupe A, Abraham R, Li Y, Rowland C et al (2007) Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet 16:865–873

    Article  PubMed  CAS  Google Scholar 

  41. Guardia-Laguarta C, Pera M, Clarimon J, Molinuevo JL et al (2010) Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation. J Neuropathol Exp Neurol 69:53–59

    Article  PubMed  CAS  Google Scholar 

  42. Hafner C, Meyer S, Langmann T, Schmitz G et al (2005) Ephrin-B2 is differentially expressed in the intestinal epithelium in Crohn’s disease and contributes to accelerated epithelial wound healing in vitro. World J Gastroenterol 11:4024–4031

    PubMed  CAS  Google Scholar 

  43. Halliday G, Brooks W, Arthur H, Creasey H et al (1997) Further evidence for an association between a mutation in the APP gene and Lewy body formation. Neurosci Lett 227:49–52

    Article  PubMed  CAS  Google Scholar 

  44. Harold D, Abraham R, Hollingworth P, Sims R et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093

    Article  PubMed  CAS  Google Scholar 

  45. Heilig EA, Xia W, Shen J, Kelleher RJ 3rd (2010) A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem 285:22350–22359

    Article  PubMed  CAS  Google Scholar 

  46. Hermey G (2009) The Vps10p-domain receptor family. Cell Mol Life Sci 66:2677–2689

    Article  PubMed  CAS  Google Scholar 

  47. Himanen JP, Saha N, Nikolov DB (2007) Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol 19:534–542

    Article  PubMed  CAS  Google Scholar 

  48. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705

    Article  PubMed  CAS  Google Scholar 

  49. Holen HL, Nustad K, Aasheim HC (2010) Activation of EphA receptors on CD4+ CD45RO+ memory cells stimulates migration. J Leukoc Biol 87:1059–1068

    Article  PubMed  CAS  Google Scholar 

  50. Hollingworth P, Harold D, Sims R, Gerrish A et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43:429–435

    Article  PubMed  CAS  Google Scholar 

  51. Hollingworth P, Sweet R, Sims R, Harold D et al (2011) Genome-wide association study of Alzheimer’s disease with psychotic symptoms. Mol Psychiatry. doi:10.1038/mp.2011.125

  52. Holmes D (2011) Mind the IGAP. Lancet Neurol 10:502–503

    Article  PubMed  Google Scholar 

  53. Houlden H, Baker M, McGowan E, Lewis P et al (2000) Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurology 48:806–808

    Article  CAS  Google Scholar 

  54. Houlden H, Crook R, Dolan RJ, McLaughlin J et al (2001) A novel presenilin mutation (M233V) causing very early onset Alzheimer’s disease with Lewy bodies. Neurosci Lett 313:93–95

    Article  PubMed  CAS  Google Scholar 

  55. Innerarity TL, Hui DY, Bersot TP, Mahley RW (1986) Type III hyperlipoproteinemia: a focus on lipoprotein receptor–apolipoprotein E2 interactions. Adv Exp Med Biol 201:273–288

    PubMed  CAS  Google Scholar 

  56. Ishibashi K, Suzuki M, Sasaki S, Imai M (2001) Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and beta subunit of the high-affinity IgE receptor. Gene 264:87–93

    Article  PubMed  CAS  Google Scholar 

  57. Ishii K, Lippa C, Tomiyama T, Miyatake F et al (2001) Distinguishable effects of Presenilin-1 and APP717 mutations on amyloid plaque deposition. Neurobiol Aging 22:367–376

    Article  PubMed  CAS  Google Scholar 

  58. Ishikawa A, Piao YS, Miyashita A, Kuwano R et al (2005) A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer’s disease. Ann Neurol 57:429–434

    Article  PubMed  CAS  Google Scholar 

  59. Ivanov AI, Romanovsky AA (2006) Putative dual role of ephrin–Eph receptor interactions in inflammation. IUBMB Life 58:389–394

    Article  PubMed  CAS  Google Scholar 

  60. Iwamoto N, Abe-Dohmae S, Sato R, Yokoyama S (2006) ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis. J Lipid Res 47:1915–1927

    Article  PubMed  CAS  Google Scholar 

  61. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H et al (1994) Visualization of a-beta-42(43) and a-beta-40 in senile plaques with end-specific a-beta monoclonals—evidence that an initially deposited species is a-beta-42(43). Neuron 13:45–53

    Article  PubMed  CAS  Google Scholar 

  62. Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697

    Article  PubMed  CAS  Google Scholar 

  63. Jayadev S, Leverenz JB, Steinbart E, Stahl J et al (2010) Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133:1143–1154

    Article  PubMed  Google Scholar 

  64. Jones L, Harold D, Williams J (2010) Genetic evidence for the involvement of lipid metabolism in Alzheimer’s disease. Biochim Biophys Acta 1801:754–761

    Article  PubMed  CAS  Google Scholar 

  65. Jun G, Naj AC, Beecham GW, Wang LS et al (2010) Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67:1473–1484

    Article  PubMed  Google Scholar 

  66. Kamino K, Orr HT, Payami H, Wijsamn EM et al (1992) Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet 51:998–1014

    PubMed  CAS  Google Scholar 

  67. Kaneko H, Kakita A, Kasuga K, Nozaki H et al (2007) Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer’s disease. J Neurosci 27:13092–13097

    Article  PubMed  CAS  Google Scholar 

  68. Kang J, Lemaire H-G, Unterbeck A, Salbaum JM et al (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

    Article  PubMed  CAS  Google Scholar 

  69. Kasuga K, Shimohata T, Nishimura A, Shiga A et al (2009) Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J Neurol Neurosurg Psychiat 80:1050–1052

    Article  PubMed  CAS  Google Scholar 

  70. Kauwe JS, Jacquart S, Chakraverty S, Wang J et al (2007) Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer’s disease presenilin 1 mutation. Ann Neurol 61:446–453

    Article  PubMed  CAS  Google Scholar 

  71. Keene CD, Cudaback E, Li X, Montine KS et al (2011) Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease. Curr Opin Neurobiol 21:920–928

    Article  PubMed  CAS  Google Scholar 

  72. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303

    Article  PubMed  CAS  Google Scholar 

  73. Kim JM, Wu H, Green G, Winkler CA et al (2003) CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 300:1298–1300

    Article  PubMed  CAS  Google Scholar 

  74. Kim WS, Weickert CS, Garner B (2008) Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem 104:1145–1166

    Article  PubMed  CAS  Google Scholar 

  75. Kimura R, Yamamoto M, Morihara T, Akatsu H et al (2009) SORL1 is genetically associated with Alzheimer disease in a Japanese population. Neurosci Lett 461:177–180

    Article  PubMed  CAS  Google Scholar 

  76. Kolsch H, Jessen F, Wiltfang J, Lewczuk P et al (2009) Association of SORL1 gene variants with Alzheimer’s disease. Brain Res 1264:1–6

    Article  PubMed  CAS  Google Scholar 

  77. Kumar-Singh S, Cras P, Wang R, Kros JM et al (2002) Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am J Pathol 161:507–520

    Article  PubMed  CAS  Google Scholar 

  78. Kwok JBJ, Halliday GM, Brooks WS, Dolios G et al (2003) 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 278:6748–6754

    Article  PubMed  CAS  Google Scholar 

  79. Lai KO, Ip NY (2009) Synapse development and plasticity: roles of ephrin/Eph receptor signaling. Curr Opin Neurobiol 19:275–283

    Article  PubMed  CAS  Google Scholar 

  80. Lambert JC, Heath S, Even G, Campion D et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099

    Article  PubMed  CAS  Google Scholar 

  81. Lambert JC, Sleegers K, Gonzalez-Perez A, Ingelsson M et al (2010) The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer’s disease: a meta-analysis study. J Alzheimers Dis 22:247–255

    PubMed  CAS  Google Scholar 

  82. Lantos PL, Ovenstone IM, Johnson J, Clelland CA et al (1994) Lewy bodies in the brain of two members of a family with the 717 (Val to Ile) mutation of the amyloid precursor protein gene. Neurosci Lett 172:77–79

    Article  PubMed  CAS  Google Scholar 

  83. Laumet G, Chouraki V, Grenier-Boley B, Legry V et al (2010) Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis 20:1181–1188

    PubMed  CAS  Google Scholar 

  84. Le TV, Crook R, Hardy J, Dickson DW (2001) Cotton wool plaques in non-familial late-onset Alzheimer disease. J Neuropathol Exp Neurol 60:1051–1061

    PubMed  CAS  Google Scholar 

  85. Lee JH, Cheng R, Barral S, Reitz C et al (2011) Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch Neurol 68:320–328

    Article  PubMed  Google Scholar 

  86. Lee JH, Cheng R, Honig LS, Vonsattel JPG et al (2008) Association between genetic variants in SORL1 and autopsy-confirmed Alzheimer disease. Neurology 70:887–889

    Article  PubMed  CAS  Google Scholar 

  87. Lee JH, Cheng R, Schupf N, Manly J et al (2007) The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol 64:501–506

    Article  PubMed  Google Scholar 

  88. Lehtonen S, Zhao F, Lehtonen E (2002) CD2-associated protein directly interacts with the actin cytoskeleton. Am J Physiol Renal Physiol 283:F734–F743

    PubMed  Google Scholar 

  89. Leverenz JB, Fishel MA, Peskind ER, Montine TJ et al (2006) Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol 63:370–376

    Article  PubMed  Google Scholar 

  90. Leverenz JB, Raskind MA (1998) Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol 150:296–304

    Article  PubMed  CAS  Google Scholar 

  91. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977

    Article  PubMed  CAS  Google Scholar 

  92. Li H, Wetten S, Li L, St Jean PL et al (2008) Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 65:45–53

    Article  PubMed  Google Scholar 

  93. Li Y, Rowland C, Catanese J, Morris J et al (2008) SORL1 variants and risk of late-onset Alzheimer’s disease. Neurobiol Dis 29:293–296

    Article  PubMed  CAS  Google Scholar 

  94. Liang Y, Tedder TF (2001) Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse. Genomics 72:119–127

    Article  PubMed  CAS  Google Scholar 

  95. Lippa CF, Fujiwara H, Mann DM, Giasson B et al (1998) 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 153:1365–1370

    Article  PubMed  CAS  Google Scholar 

  96. Lippa CF, Saunders AM, Smith TW, Swearer JM et al (1996) Familial and sporadic Alzheimer’s disease: neuropathology cannot exclude a final common pathway. Neurology 46:406–412

    Article  PubMed  CAS  Google Scholar 

  97. Lipsky LPE, Abramson SB, Crofford L, Dubois RN et al (1998) The classification of cyclooxygenase inhibitors. J Rheumatol 25:2298–2303

    PubMed  CAS  Google Scholar 

  98. Liu F, AriasVasquez A, Sleegers K, Aulchenko YS et al (2007) A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet 81:17–31

    Article  PubMed  CAS  Google Scholar 

  99. Lowik MM, Groenen PJ, Levtchenko EN, Monnens LA et al (2009) Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review. Eur J Pediatr 168:1291–1304

    Article  PubMed  CAS  Google Scholar 

  100. Mahley RW, Rall SC Jr (1999) Is epsilon4 the ancestral human apoE allele? Neurobiol Aging 20:429–430

    Article  PubMed  CAS  Google Scholar 

  101. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537

    Article  PubMed  CAS  Google Scholar 

  102. Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50(Suppl):S183–S188

    Article  PubMed  CAS  Google Scholar 

  103. Mann DMA, Iwatsubo T, Cairns NJ, Lantos PL et al (1996) Amyloid beta protein (A beta) deposition in chromosome 14-linked Alzheimer’s disease: predominance of A beta(42(43)). Ann Neurol 40:149–156

    Article  PubMed  CAS  Google Scholar 

  104. Mann DMA, Iwatsubo T, Ihara Y, Cairns NJ et al (1996) Predominant deposition of amyloid-beta(42(43)) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am J Pathol 148:1257–1266

    PubMed  CAS  Google Scholar 

  105. Mann DMA, Iwatsubo T, Nochlin D, Sumi SM et al (1997) Amyloid (A beta) deposition in chromosome 1-linked Alzheimer’s disease: the Volga German families. Ann Neurol 41:52–57

    Article  PubMed  CAS  Google Scholar 

  106. Mann DMA, Pickering-Brown SM, Takeuchi A, Iwatsubo T (2001) Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol 158:2165–2175

    Article  PubMed  CAS  Google Scholar 

  107. Masters CL, Simms G, Weinman NA, Multhaup G et al (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249

    Article  PubMed  CAS  Google Scholar 

  108. McGeer PL, Rogers J (1992) Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology 42:447–449

    Article  PubMed  CAS  Google Scholar 

  109. Meng Y, Lee JH, Cheng R, GeorgeHyslop P et al (2007) Association between SORLI and Alzheimer’s disease in a genome-wide study. NeuroReport 18:1761–1764

    Article  PubMed  CAS  Google Scholar 

  110. Miklossy J, Taddei K, Suva D, Verdile G et al (2003) Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease. Neurobiol Aging 24:655–662

    Article  PubMed  CAS  Google Scholar 

  111. Minster RL, DeKosky ST, Kamboh MI (2008) No association of SORL1 SNPs with Alzheimer’s disease. Neurosci Lett 440:190–192

    Article  PubMed  CAS  Google Scholar 

  112. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE et al (2010) From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466:714–719

    Article  PubMed  CAS  Google Scholar 

  113. Naj AC, Beecham GW, Martin ER, Gallins PJ et al (2010) Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet 6:e1001130

    Article  PubMed  CAS  Google Scholar 

  114. Naj AC, Jun G, Beecham GW, Wang L-S et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43:436–441

    Article  PubMed  CAS  Google Scholar 

  115. Namba Y, Tomonaga M, Kawasaki H, Otomo E et al (1991) Apolipoprotien E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt–Jakob disease. Brain Res 541:163–166

    Article  PubMed  CAS  Google Scholar 

  116. Naslund J, Schierhorn A, Hellman U, Lannfelt L et al (1994) Relative abundance of Alzheimer a-beta amyloid peptide variants in Alzheimer-disease and normal aging. Proc Natl Acad Sci USA 91:8378–8382

    Article  PubMed  CAS  Google Scholar 

  117. Natte R, Maat-Schieman MLC, Haan J, Bornebroek M et al (2001) Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol 50:765–772

    Article  PubMed  CAS  Google Scholar 

  118. Nilsberth C, Westlinddanielsson A, Eckman CB, Condron MM et al (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced A beta protofibril formation. Nat Neurosci 4:887–893

    Article  PubMed  CAS  Google Scholar 

  119. Nuutinen T, Suuronen T, Kauppinen A, Salminen A (2009) Clusterin: a forgotten player in Alzheimer’s disease. Brain Res Rev 61:89–104

    Article  PubMed  CAS  Google Scholar 

  120. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204

    Article  PubMed  CAS  Google Scholar 

  121. Pasquale EB (2005) Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6:462–475

    Article  PubMed  CAS  Google Scholar 

  122. Pastor P, Roe CM, Villegas A, Bedoya G et al (2003) Apolipoprotein E epsilon 4 modifies Alzheimer’s disease onset in an E280A PS1 kindred. Ann Neurol 54:163–169

    Article  PubMed  CAS  Google Scholar 

  123. Pennisi E (2011) The biology of genomes. Disease risk links to gene regulation. Science 332:1031

    Google Scholar 

  124. Pericak-Vance MA, Bebout JL, Gaskell PC, Yamaoka LH et al (1991) Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet 48:1034–1050

    PubMed  CAS  Google Scholar 

  125. Poliakov A, Cotrina M, Wilkinson DG (2004) Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev Cell 7:465–480

    Article  PubMed  CAS  Google Scholar 

  126. Prendergast GC, Muller AJ, Ramalingam A, Chang MY (2009) BAR the door: cancer suppression by amphiphysin-like genes. Biochim Biophys Acta 1795:25–36

    PubMed  CAS  Google Scholar 

  127. Rao Y, Haucke V (2011) Membrane shaping by the Bin/amphiphysin/Rvs (BAR) domain protein superfamily. Cell Mol Life Sci 68:3983–3993

    Article  PubMed  CAS  Google Scholar 

  128. Reiman EM, Webster JA, Myers AJ, Hardy J et al (2007) GAB2 alleles modify Alzheimer’s risk in APOE epsilon 4 carriers. Neuron 54:713–720

    Article  PubMed  CAS  Google Scholar 

  129. Reitz C, Cheng R, Rogaeva E, Lee JH et al (2011) Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch Neurol 68:99–106

    Article  PubMed  Google Scholar 

  130. Ren G, Vajjhala P, Lee JS, Winsor B et al (2006) The BAR domain proteins: molding membranes in fission, fusion, and phagy. Microbiol Mol Biol Rev 70:37–120

    Article  PubMed  CAS  Google Scholar 

  131. Revesz T, McLaughlin JL, Rossor MN, Lantos PL (1997) Pathology of familial Alzheimer’s disease with Lewy bodies. J Neural Transm Suppl 51:121–135

    PubMed  CAS  Google Scholar 

  132. Revuz J (2009) Hidradenitis suppurativa. J Eur Acad Dermatol Venereol 23:985–998

    Article  PubMed  CAS  Google Scholar 

  133. Rogaeva E, Meng Y, Lee JH, Gu Y et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177

    Article  PubMed  CAS  Google Scholar 

  134. Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM et al (2010) A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J 10:375–384

    Article  PubMed  CAS  Google Scholar 

  135. Rossi G, Giaccone G, Maletta R, Morbin M et al (2004) A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology 63:910–912

    Article  PubMed  CAS  Google Scholar 

  136. Rovelet-ecruz A, Hannequin D, Raux G, LeMeur N et al (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26

    Article  CAS  Google Scholar 

  137. Sakamoto A, Sugamoto Y, Tokunaga Y, Yoshimuta T et al (2011) Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. J Int Med Res 39:522–527

    PubMed  CAS  Google Scholar 

  138. Scheuner D, Eckman C, Jensen M, Song X et al (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2:864–870

    Article  PubMed  CAS  Google Scholar 

  139. Schjeide BM, McQueen MB, Mullin K, DiVito J et al (2009) Assessment of Alzheimer’s disease case–control associations using family-based methods. Neurogenetics 10:19–25

    Article  PubMed  Google Scholar 

  140. Seshadri S, DeStefano AL, Au R, Massaro JM et al (2007) Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham Study. BMC Med Genet 8(Suppl 1):S15

    Article  PubMed  CAS  Google Scholar 

  141. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303:1832–1840

    Article  PubMed  CAS  Google Scholar 

  142. Shen J, Kelleher RJ 3rd (2007) The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci USA 104:403–409

    Article  PubMed  CAS  Google Scholar 

  143. Shen L, Kim S, Risacher SL, Nho K et al (2010) Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: a study of the ADNI cohort. Neuroimage 53:1051–1063

    Article  PubMed  CAS  Google Scholar 

  144. Shepherd CE, Gregory GC, Vickers JC, Brooks WS et al (2004) Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques. Neurobiol Dis 15:115–119

    Article  PubMed  CAS  Google Scholar 

  145. Shih NY, Li J, Cotran R, Mundel P et al (2001) CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am J Pathol 159:2303–2308

    Article  PubMed  CAS  Google Scholar 

  146. Sleegers K, Brouwers N, Gijselinck I, Theuns J et al (2006) APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129:2977–2983

    Article  PubMed  Google Scholar 

  147. Sleegers K, Lambert JC, Bertram L, Cruts M et al (2010) The pursuit of susceptibility genes for Alzheimer’s disease: progress and prospects. Trends Genet 26:84–93

    Article  PubMed  CAS  Google Scholar 

  148. Snider BJ, Norton J, Coats MA, Chakraverty S et al (2005) Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol 62:1821–1830

    Article  PubMed  Google Scholar 

  149. Spoelgen R, vonArnim CAF, Thomas AV, Peltan ID et al (2006) Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci 26:418–428

    Article  PubMed  CAS  Google Scholar 

  150. St George-Hyslop P, Crapper McLachlan D, Tuda T, Rogaev E et al (1994) Alzheimer’s disease and possible gene interaction. Science 263:537

    Article  PubMed  CAS  Google Scholar 

  151. Steiner H, Revesz T, Neumann M, Romig H et al (2001) A pathogenic presenilin-1 deletion causes abberrant A beta 42 production in the absence of congophilic amyloid plaques. J Biol Chem 276:7233–7239

    Article  PubMed  CAS  Google Scholar 

  152. Strittmatter WJ, Saunders AM, Schmechel D, Pericak Vance M et al (1993) Apolipoprotein-E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981

    Article  PubMed  CAS  Google Scholar 

  153. Sudo S, Shiozawa M, Cairns NJ, Wada Y (2005) Aberrant accentuation of neurofibrillary degeneration in the hippocampus of Alzheimer’s disease with amyloid precursor protein 717 and presenilin-1 gene mutations. J Neurol Sci 234:55–65

    Article  PubMed  CAS  Google Scholar 

  154. Taira K, Bujo H, Hirayama S, Yamazaki H et al (2001) LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro. Arterioscler Thromb Vasc Biol 21:1501–1506

    Article  PubMed  CAS  Google Scholar 

  155. Takao M, Ghetti B, Hayakawa I, Ikeda E et al (2002) A novel mutation (G217D) in the Presenilin 1 gene (PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol 104:155–170

    Article  PubMed  CAS  Google Scholar 

  156. Tamaoka A, Fraser PE, Ishii K, Sahara N et al (1998) Amyloid-β-protein isoforms in brain of subjects with PS1-linked, βAPP-linked and sporadic Alzheimer disease. Mol Brain Res 56:178–185

    Article  PubMed  CAS  Google Scholar 

  157. Tamaoka A, Odaka A, Ishibashi Y, Usami M et al (1994) App717 missense mutation affects the ratio of amyloid-beta protein species (a-beta-1–42/43 and a-beta-1–40) in familial Alzheimers-disease brain. J Biol Chem 269:32721–32724

    PubMed  CAS  Google Scholar 

  158. Tamaoka A, Sawamura N, Odaka A, Suzuki N et al (1995) Amyloid-beta protein-1–42/43 (a-beta-1–42/43) in cerebellar diffuse plaques—enzyme-linked-immunosorbent-assay and immunocytochemical study. Brain Res 679:151–156

    Article  PubMed  CAS  Google Scholar 

  159. Tan EK, Lee J, Chen CP, Teo YY et al (2009) SORL1 haplotypes modulate risk of Alzheimer’s disease in Chinese. Neurobiol Aging 30:1048–1051

    Article  PubMed  CAS  Google Scholar 

  160. Tebar F, Bohlander SK, Sorkin A (1999) Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol Biol Cell 10:2687–2702

    PubMed  CAS  Google Scholar 

  161. Teslovich TM, Musunuru K, Smith AV, Edmondson AC et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466:707–713

    Article  PubMed  CAS  Google Scholar 

  162. Thaker U, McDonagh AM, Iwatsubo T, Lendon CL et al (2003) Tau load is associated with apolipoprotein E genotype and the amount of amyloid beta protein, A beta(40), in sporadic and familial Alzheimer’s disease. Neuropathol Appl Neurobiol 29:35–44

    Article  PubMed  CAS  Google Scholar 

  163. Tyrrell J, Cosgrave M, McCarron M, McPherson J et al (2001) Dementia in people with Down’s syndrome. Int J Geriatr Psychiatry 16:1168–1174

    Article  PubMed  CAS  Google Scholar 

  164. Ungewickell EJ, Hinrichsen L (2007) Endocytosis: clathrin-mediated membrane budding. Curr Opin Cell Biol 19:417–425

    Article  PubMed  CAS  Google Scholar 

  165. Verkkoniemi A, Kalimo H, Paetau A, Somer M et al (2001) Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. J Neuropathol Exp Neurol 60:483–492

    PubMed  CAS  Google Scholar 

  166. Visscher PM, Brown MA, McCarthy MI, Yang J (2012) Five years of GWAS discovery. Am J Hum Genet 90:7–24

    Article  PubMed  CAS  Google Scholar 

  167. Vitale C, Romagnani C, Falco M, Ponte M et al (1999) Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. Proc Natl Acad Sci USA 96:15091–15096

    Article  PubMed  CAS  Google Scholar 

  168. von Gunten S, Bochner BS (2008) Basic and clinical immunology of Siglecs. Ann N Y Acad Sci 1143:61–82

    Article  CAS  Google Scholar 

  169. Wakabayashi T, De Strooper B (2008) Presenilins: members of the gamma-secretase quartets, but part-time soloists too. Physiology (Bethesda) 23:194–204

    Article  CAS  Google Scholar 

  170. Wang B, Yang W, Wen W, Sun J et al (2010) Gamma-secretase gene mutations in familial acne inversa. Science 330:1065

    Article  PubMed  CAS  Google Scholar 

  171. Wijsman EM, Daw EW, Yu XS, Steinbart EJ et al (2005) APOE and other loci affect age-at-onset in Alzheimer’s disease families with PS2 mutation. Am J Med Genet 132B:14–20

    Article  PubMed  Google Scholar 

  172. Wijsman EM, Pankratz ND, Choi Y, Rothstein JH et al (2011) Genome-wide association of familial late-onset Alzheimer’s disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet 7:e1001308

    Article  PubMed  CAS  Google Scholar 

  173. Wisiewski KE, Wisniewski HM, Wen GY (1985) Occurance of neuropathologic changes and dementia of Alzheimer’s disease in Down syndrome. Ann Neurol 17:278–282

    Article  Google Scholar 

  174. Wollmer MA (2010) Cholesterol-related genes in Alzheimer’s disease. Biochim Biophys Acta 1801:762–773

    Article  PubMed  CAS  Google Scholar 

  175. Yamazaki T, Masuda J, Omori T, Usui R et al (2009) EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility. J Cell Sci 122:243–255

    Article  PubMed  CAS  Google Scholar 

  176. Yeganeh MZ, Mirabzadeh A, Khorshid HRK, Kamali K et al (2010) Novel extreme homozygote haplotypes at the human Caveolin 1 gene upstream purine complex in sporadic Alzheimer’s disease. Am J Med Genet Part B 153B:347–349

    CAS  Google Scholar 

  177. Yokota O, Terada S, Ishizu H, Ujike H et al (2003) Variability and heterogeneity in Alzheimer’s disease with cotton wool plaques: a clinicopathological study of four autopsy cases. Acta Neuropathol 106:348–356

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants from the NIH (U01AG032984, RC2AG036528, and AG05136) and the Nancy and Buster Alvord Endowment. We thank Dr. Kathleen Montine and Dr. Diane Durnam for their editorial assistance.

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  1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6100, USA

    Gerard D. Schellenberg

  2. Department of Pathology, University of Washington, Seattle, WA, USA

    Thomas J. Montine

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Correspondence to Thomas J. Montine.

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Schellenberg, G.D., Montine, T.J. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 124, 305–323 (2012). https://doi.org/10.1007/s00401-012-0996-2

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