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Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis

  • Celeste M. Karch
    Affiliations
    Department of Psychiatry and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
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  • Alison M. Goate
    Correspondence
    Address correspondence to Alison M. Goate, D.Phil., Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Avenue, Campus Box 8134, St. Louis, MO 63110
    Affiliations
    Department of Psychiatry and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
    Search for articles by this author

      Abstract

      We review the genetic risk factors for late-onset Alzheimer’s disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome—technologic advances in methods to analyze millions of polymorphisms in thousands of subjects—have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.

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      References

        • Hardy J.
        • Selkoe D.J.
        The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.
        Science. 2002; 297: 353-356
        • Holtzman D.M.
        • Morris J.C.
        • Goate A.M.
        Alzheimer’s disease: The challenge of the second century.
        Sci Transl Med. 2011; 3: 77sr71
        • Harold D.
        • Abraham R.
        • Hollingworth P.
        • Sims R.
        • Gerrish A.
        • Hamshere M.L.
        • et al.
        Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease.
        Nat Genet. 2009; 41: 1088-1093
        • Naj A.C.
        • Jun G.
        • Beecham G.W.
        • Wang L.-S.
        • Vardarajan B.N.
        • 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: 436-441
        • Hollingworth P.
        • Harold D.
        • Sims R.
        • Gerrish A.
        • Lambert J.-C.
        • Carrasquillo M.M.
        • et al.
        Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease.
        Nat Genet. 2011; 43: 429-435
        • Lambert J.C.
        • Ibrahim-Verbaas C.A.
        • Harold D.
        • Naj A.C.
        • 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: 1452-1458
        • Bertram L.
        • Lange C.
        • Mullin K.
        • Parkinson M.
        • Hsiao M.
        • Hogan M.F.
        • et al.
        Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE.
        Am J Hum Genet. 2008; 83: 623-632
        • Kim M.
        • Suh J.
        • Romano D.
        • Truong M.H.
        • Mullin K.
        • Hooli B.
        • et al.
        Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity.
        Hum Mol Genet. 2009; 18: 3987-3996
        • 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: 117-127
        • Jonsson T.
        • Stefansson H.
        • Steinberg S.
        • Jonsdottir I.
        • Jonsson P.V.
        • Snaedal J.
        • et al.
        Variant of TREM2 associated with the risk of Alzheimer’s disease.
        N Engl J Med. 2013; 368: 107-116
        • Cruchaga C.
        • Karch C.M.
        • Jin S.C.
        • Benitez B.A.
        • Cai Y.
        • Guerreiro R.
        • et al.
        Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease.
        Nature. 2014; 505: 550-554
        • Zhang B.
        • Gaiteri C.
        • Bodea L.G.
        • Wang Z.
        • McElwee J.
        • Podtelezhnikov A.A.
        • et al.
        Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease.
        Cell. 2013; 153: 707-720
        • Lambert J.C.
        • 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: 1094-1099
        • Cruchaga C.
        • Kauwe J.S.K.
        • Mayo K.
        • Spiegel N.
        • Bertelsen S.
        • Nowotny P.
        • et al.
        SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer’s disease.
        PLoS Genet. 2010; 6: e1001101
        • Cruchaga C.
        • Kauwe J.S.
        • Harari O.
        • Jin S.C.
        • Cai Y.
        • Karch C.M.
        • et al.
        GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease.
        Neuron. 2013; 78: 256-268
        • Kauwe J.S.K.
        • Cruchaga C.
        • Bertelsen S.
        • Mayo K.
        • Latu W.
        • Nowotny P.
        • et al.
        Validating predicted biological effects of Alzheimer’s disease associated SNPs using CSF biomarker levels.
        J Alzheimers Dis. 2010; 21: 833-842
        • Kauwe J.S.K.
        • Cruchaga C.
        • Karch C.M.
        • Sadler B.
        • Lee M.
        • Mayo K.
        • et al.
        Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer’s disease.
        PLoS One. 2011; 6: e15918
        • Kauwe J.S.K.
        • Cruchaga C.
        • Mayo K.
        • Fenoglio C.
        • Bertelsen S.
        • Nowotny P.
        • et al.
        Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition.
        Proc Natl Acad Sci U S A. 2008; 105: 8050-8054
        • Biffi A.
        • Anderson C.D.
        • Desikan R.S.
        • Sabuncu M.
        • Cortellini L.
        • Schmansky N.
        • et al.
        Genetic variation and neuroimaging measures in Alzheimer disease.
        Arch Neurol. 2010; 67: 677-685
        • Shulman J.M.
        • Chen K.
        • Keenan B.T.
        • Chibnik L.B.
        • Fleisher A.
        • Thiyyagura P.
        • et al.
        Genetic susceptibility for Alzheimer disease neuritic plaque pathology.
        JAMA Neurol. 2013; 70: 1150-1157
        • Weiner M.W.
        • Veitch D.P.
        • Aisen P.S.
        • Beckett L.A.
        • Cairns N.J.
        • Green R.C.
        • et al.
        The Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception.
        Alzheimers Dement. 2013; 9: e111-e194
        • Guerreiro R.J.
        • Gustafson D.R.
        • Hardy J.
        The genetic architecture of Alzheimer’s disease: Beyond APP, PSENs and APOE.
        Neurobiol Aging. 2012; 33: 437-456
        • Thinakaran G.
        • Koo E.H.
        Amyloid precursor protein trafficking, processing, and function.
        J Biol Chem. 2008; 283: 29615-29619
        • Mattson M.P.
        • Cheng B.
        • Culwell A.R.
        • Esch F.S.
        • Lieberburg I.
        • Rydel R.E.
        Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein.
        Neuron. 1993; 10: 243-254
        • Ring S.
        • Weyer S.W.
        • Kilian S.B.
        • Waldron E.
        • Pietrzik C.U.
        • Filippov M.A.
        • et al.
        The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice.
        J Neurosci. 2007; 27: 7817-7826
        • Cruchaga C.
        • Haller G.
        • Chakraverty S.
        • Mayo K.
        • Vallania F.L.
        • Mitra R.D.
        • et al.
        Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families.
        PLoS One. 2012; 7: e31039
        • Benitez B.A.
        • Karch C.M.
        • Cai Y.
        • Jin S.C.
        • 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: e1003685
        • Jin S.C.
        • Pastor P.
        • Cooper B.
        • Cervantes S.
        • Benitez B.A.
        • Razquin C.
        • 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: 34
        • Jonsson T.
        • Atwal J.K.
        • Steinberg S.
        • Snaedal J.
        • Jonsson P.V.
        • Bjornsson S.
        • et al.
        A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline.
        Nature. 2012; 488: 96-99
        • Kuhn P.H.
        • Wang H.
        • Dislich B.
        • Colombo A.
        • Zeitschel U.
        • Ellwart J.W.
        • et al.
        ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons.
        EMBO J. 29. 2010: 3020-3032
        • Suh J.
        • Choi S.H.
        • Romano D.M.
        • Gannon M.A.
        • Lesinski A.N.
        • Kim D.Y.
        • et al.
        ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function.
        Neuron. 2013; 80: 385-401
        • Corder E.H.
        • Saunders A.M.
        • Strittmatter W.J.
        • Schmechel D.E.
        • Gaskell P.C.
        • Small G.W.
        • et al.
        Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.
        Science. 1993; 261: 921-923
        • Strittmatter W.J.
        • Weisgraber K.H.
        • Huang D.Y.
        • Dong L.M.
        • Salvesen G.S.
        • Pericak-Vance M.
        • et al.
        Binding of human apolipoprotein E to synthetic amyloid beta peptide: Isoform-specific effects and implications for late-onset Alzheimer disease.
        Proc Natl Acad Sci U S A. 1993; 90: 8098-8102
        • Mahley R.W.
        Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology.
        Science. 1988; 240: 622-630
        • Kim J.
        • Basak J.M.
        • Holtzman D.M.
        The role of apolipoprotein E in Alzheimer’s disease.
        Neuron. 2009; 63: 287-303
        • Castellano J.M.
        • Kim J.
        • Stewart F.R.
        • Jiang H.
        • DeMattos R.B.
        • Patterson B.W.
        • et al.
        Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance.
        Sci Transl Med. 2011; 3: 89ra57
        • Verghese P.B.
        • Castellano J.M.
        • Garai K.
        • Wang Y.
        • Jiang H.
        • Shah A.
        • et al.
        ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions.
        Proc Natl Acad Sci U S A. 2013; 110: E1807-E1816
        • Bales K.R.
        • Verina T.
        • Dodel R.C.
        • Du Y.
        • Altstiel L.
        • Bender M.
        • et al.
        Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition.
        Nat Genet. 1997; 17: 263-264
        • Fryer J.D.
        • Simmons K.
        • Parsadanian M.
        • Bales K.R.
        • Paul S.M.
        • Sullivan P.M.
        • et al.
        Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model.
        J Neurosci. 2005; 25: 2803-2810
        • Holtzman D.M.
        • Bales K.R.
        • Tenkova T.
        • Fagan A.M.
        • Parsadanian M.
        • Sartorius L.J.
        • et al.
        Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease.
        Proc Natl Acad Sci U S A. 2000; 97: 2892-2897
        • Fagan A.M.
        • Watson M.
        • Parsadanian M.
        • Bales K.R.
        • Paul S.M.
        • Holtzman D.M.
        Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease.
        Neurobiol Dis. 2002; 9: 305-318
        • Rebeck G.W.
        • Reiter J.S.
        • Strickland D.K.
        • Hyman B.T.
        Apolipoprotein E in sporadic Alzheimer’s disease: Allelic variation and receptor interactions.
        Neuron. 1993; 11: 575-580
        • Morris J.C.
        • Roe C.M.
        • Xiong C.
        • Fagan A.M.
        • Goate A.M.
        • Holtzman D.M.
        • et al.
        APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging.
        Ann Neurol. 2010; 67: 122-131
        • Reiman E.M.
        • Chen K.
        • Liu X.
        • Bandy D.
        • Yu M.
        • Lee W.
        • et al.
        Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease.
        Proc Natl Acad Sci U S A. 2009; 106: 6820-6825
        • Jones S.E.
        • Jomary C.
        Clusterin.
        Int J Biochem Cell Biol. 2002; 34: 427-431
        • Rizzi F.
        • Caccamo A.E.
        • Belloni L.
        • Bettuzzi S.
        Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells.
        J Cell Physiol. 2009; 219: 314-323
        • Szymanski M.
        • Wang R.
        • Bassett S.S.
        • Avramopoulos D.
        Alzheimer’s risk variants in the clusterin gene are associated with alternative splicing.
        Transl Psychiatry 1.pii. 2011; : e18
        • Xing Y.Y.
        • Yu J.T.
        • Cui W.Z.
        • Zhong X.L.
        • Wu Z.C.
        • Zhang Q.
        • et al.
        Blood clusterin levels, rs9331888 polymorphism, and the risk of Alzheimer’s disease.
        J Alzheimers Dis. 2012; 29: 515-519
        • Schurmann B.
        • Wiese B.
        • Bickel H.
        • Weyerer S.
        • Riedel-Heller S.G.
        • Pentzek M.
        • et al.
        Association of the Alzheimer’s disease clusterin risk allele with plasma clusterin concentration.
        J Alzheimers Dis. 2011; 25: 421-424
        • Thambisetty M.
        • Simmons A.
        • Velayudhan L.
        • Hye A.
        • Campbell J.
        • Zhang Y.
        • et al.
        Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.
        Arch Gen Psychiatry. 2010; 67: 739-748
        • Schrijvers E.M.
        • Koudstaal P.J.
        • Hofman A.
        • Breteler M.M.
        Plasma clusterin and the risk of Alzheimer disease.
        JAMA. 2011; 305: 1322-1326
        • Kiddle S.J.
        • Sattlecker M.
        • Proitsi P.
        • Simmons A.
        • Westman E.
        • Bazenet C.
        • et al.
        Candidate blood proteome markers of Alzheimer’s disease onset and progression: A systematic review and replication study.
        J Alzheimers Dis. 2014; 38: 515-531
        • Karch C.M.
        • Jeng A.T.
        • Nowotny P.
        • Cady J.
        • Cruchaga C.
        • Goate A.M.
        Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains.
        PLoS One. 2012; 7: e50976
        • Allen M.
        • Zou F.
        • Chai H.S.
        • Younkin C.S.
        • Crook J.
        • Pankratz V.S.
        • et al.
        Novel late-onset Alzheimer disease loci variants associate with brain gene expression.
        Neurology. 2012; 79: 221-228
        • May P.C.
        • Lampert-Etchells M.
        • Johnson S.A.
        • Poirier J.
        • Masters J.N.
        • Finch C.E.
        Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer’s disease and in response to experimental lesions in rat.
        Neuron. 1990; 5: 831-839
        • Calero M.
        • Rostagno A.
        • Matsubara E.
        • Zlokovic B.
        • Frangione B.
        • Ghiso J.
        Apolipoprotein J (clusterin) and Alzheimer’s disease.
        Microsc Res Tech. 2000; 50: 305-315
        • Matsubara E.
        • Frangione B.
        • Ghiso J.
        Characterization of apolipoprotein J-Alzheimer’s A beta interaction.
        J Biol Chem. 1995; 270: 7563-7567
        • Oda T.
        • Wals P.
        • Osterburg H.H.
        • Johnson S.A.
        • Pasinetti G.M.
        • Morgan T.E.
        • et al.
        Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress.
        Exp Neurol. 1995; 136: 22-31
        • Matsubara E.
        • Soto C.
        • Governale S.
        • Frangione B.
        • Ghiso J.
        Apolipoprotein J and Alzheimer’s amyloid beta solubility.
        Biochem J. 1996; 316: 671-679
        • Demattos R.B.
        • O’Dell M.A.
        • Parsadanian M.
        • Taylor J.W.
        • Harmony J.A.K.
        • Bales K.R.
        • et al.
        Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease.
        Proc Natl Acad Sci U S A. 2002; 99: 10843-10848
        • DeMattos R.B.
        • Cirrito J.R.
        • Parsadanian M.
        • May P.C.
        • O’Dell M.A.
        • Taylor J.W.
        • et al.
        ApoE and clusterin cooperatively suppress Abeta levels and deposition: Evidence that ApoE regulates extracellular Abeta metabolism in vivo.
        Neuron. 2004; 41: 193-202
        • Kim W.S.
        • Weickert C.S.
        • Garner B.
        Role of ATP-binding cassette transporters in brain lipid transport and neurological disease.
        J Neurochem. 2008; 104: 1145-1166
        • Ikeda Y.
        • Abe-Dohmae S.
        • Munehira Y.
        • Aoki R.
        • Kawamoto S.
        • Furuya A.
        • et al.
        Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release.
        Biochem Biophys Res Commun. 2003; 311: 313-318
        • Vasquez J.B.
        • Fardo D.W.
        • Estus S.
        ABCA7 expression is associated with Alzheimer’s disease polymorphism and disease status.
        Neurosci Lett. 2013; 556: 58-62
        • Kim W.S.
        • Guillemin G.J.
        • Glaros E.N.
        • Lim C.K.
        • Garner B.
        Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells.
        Neuroreport. 2006; 17: 891-896
        • Kim W.S.
        • Fitzgerald M.L.
        • Kang K.
        • Okuhira K.
        • Bell S.A.
        • Manning J.J.
        • et al.
        Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels.
        J Biol Chem. 2005; 280: 3989-3995
        • Kim W.S.
        • Li H.
        • Ruberu K.
        • Chan S.
        • Elliott D.A.
        • Low J.K.
        • et al.
        Deletion of Abca7 increases cerebral amyloid-beta accumulation in the J20 mouse model of Alzheimer’s disease.
        J Neurosci. 2013; 33: 4387-4394
        • Chan S.L.
        • Kim W.S.
        • Kwok J.B.
        • Hill A.F.
        • Cappai R.
        • Rye K.A.
        • et al.
        ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro.
        J Neurochem. 2008; 106: 793-804
        • Jehle A.W.
        • Gardai S.J.
        • Li S.
        • Linsel-Nitschke P.
        • Morimoto K.
        • Janssen W.J.
        • et al.
        ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages.
        J Cell Biol. 2006; 174: 547-556
        • Tanaka N.
        • Abe-Dohmae S.
        • Iwamoto N.
        • Fitzgerald M.L.
        • Yokoyama S.
        HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7.
        Atherosclerosis. 2011; 217: 407-414
        • Tanaka N.
        • Abe-Dohmae S.
        • Iwamoto N.
        • Yokoyama S.
        Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system.
        J Atheroscler Thromb. 2011; 18: 274-281
        • Wildsmith K.R.
        • Holley M.
        • Savage J.C.
        • Skerrett R.
        • Landreth G.E.
        Evidence for impaired amyloid beta clearance in Alzheimer’s disease.
        Alzheimers Res Ther. 2013; 5: 33
        • Krych-Goldberg M.
        • Moulds J.M.
        • Atkinson J.P.
        Human complement receptor type 1 (CR1) binds to a major malarial adhesin.
        Trends Mol Med. 2002; 8: 531-537
        • Liu D.
        • Niu Z.X.
        The structure, genetic polymorphisms, expression and biological functions of complement receptor type 1 (CR1/CD35).
        Immunopharmacol Immunotoxicol. 2009; 31: 524-535
        • Eikelenboom P.
        • Stam F.C.
        Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study.
        Acta Neuropathol. 1982; 57: 239-242
        • Shen Y.
        • Li R.
        • McGeer E.G.
        • McGeer P.L.
        Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain.
        Brain Res. 1997; 769: 391-395
        • Terai K.
        • Walker D.G.
        • McGeer E.G.
        • McGeer P.L.
        Neurons express proteins of the classical complement pathway in Alzheimer disease.
        Brain Res. 1997; 769: 385-390
        • Gasque P.
        • Ischenko A.
        • Legoedec J.
        • Mauger C.
        • Schouft M.T.
        • Fontaine M.
        Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells.
        J Biol Chem. 1993; 268: 25068-25074
        • Hosokawa M.
        • Klegeris A.
        • Maguire J.
        • McGeer P.L.
        Expression of complement messenger RNAs and proteins by human oligodendroglial cells.
        Glia. 2003; 42: 417-423
        • McGeer P.L.
        • Akiyama H.
        • Itagaki S.
        • McGeer E.G.
        Activation of the classical complement pathway in brain tissue of Alzheimer patients.
        Neurosci Lett. 1989; 107: 341-346
        • Shen Y.
        • Lue L.
        • Yang L.
        • Roher A.
        • Kuo Y.
        • Strohmeyer R.
        • et al.
        Complement activation by neurofibrillary tangles in Alzheimer’s disease.
        Neurosci Lett. 2001; 305: 165-168
        • Schifferli J.A.
        • Paccaud J.P.
        Two isotypes of human C4, C4A and C4B have different structure and function.
        Complement Inflamm. 1989; 6: 19-26
        • Gibson N.C.
        • Waxman F.J.
        Relationship between immune complex binding and release and the quantitative expression of the complement receptor, type 1 (CR1, CD35) on human erythrocytes.
        Clin Immunol Immunopathol. 1994; 70: 104-113
        • Rogers J.
        • Li R.
        • Mastroeni D.
        • Grover A.
        • Leonard B.
        • Ahern G.
        • et al.
        Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes.
        Neurobiol Aging. 2006; 27: 1733-1739
        • Velazquez P.
        • Cribbs D.H.
        • Poulos T.L.
        • Tenner A.J.
        Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer’s disease pathogenesis.
        Nat Med. 1997; 3: 77-79
        • Crocker P.R.
        • Hartnell A.
        • Munday J.
        • Nath D.
        The potential role of sialoadhesin as a macrophage recognition molecule in health and disease.
        Glycoconj J. 1997; 14: 601-609
        • Malik M.
        • Simpson J.F.
        • Parikh I.
        • Wilfred B.R.
        • Fardo D.W.
        • Nelson P.T.
        • et al.
        CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing.
        J Neurosci. 2013; 33: 13320-13325
        • Griciuc A.
        • Serrano-Pozo A.
        • Parrado A.R.
        • Lesinski A.N.
        • Asselin C.N.
        • Mullin K.
        • et al.
        Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta.
        Neuron. 2013; 78: 631-643
        • Linnartz B.
        • Neumann H.
        Microglial activatory (immunoreceptor tyrosine-based activation motif)- and inhibitory (immunoreceptor tyrosine-based inhibition motif)-signaling receptors for recognition of the neuronal glycocalyx.
        Glia. 2013; 61: 37-46
        • Tateno H.
        • Li H.
        • Schur M.J.
        • Bovin N.
        • Crocker P.R.
        • Wakarchuk W.W.
        • et al.
        Distinct endocytic mechanisms of CD22 (Siglec-2) and Siglec-F reflect roles in cell signaling and innate immunity.
        Mol Cell Biol. 2007; 27: 5699-5710
        • Howie D.
        • Nolan K.F.
        • Daley S.
        • Butterfield E.
        • Adams E.
        • Garcia-Rueda H.
        • et al.
        MS4A4B is a GITR-associated membrane adapter, expressed by regulatory T cells, which modulates T cell activation.
        J Immunol. 2009; 183: 4197-4204
        • Zuccolo J.
        • Bau J.
        • Childs S.J.
        • Goss G.G.
        • Sensen C.W.
        • Deans J.P.
        Phylogenetic analysis of the MS4A and TMEM176 gene families.
        PLoS One. 2010; 5: e9369
        • Rohn T.T.
        The triggering receptor expressed on myeloid cells 2: “TREM-ming” the inflammatory component associated with Alzheimer’s disease.
        Oxid Med Cell Longev. 2013; 2013: 860959
        • Colonna M.
        TREMs in the immune system and beyond.
        Nat Rev Immunol. 2003; 3: 445-453
        • Paloneva J.
        • Manninen T.
        • Christman G.
        • Hovanes K.
        • Mandelin J.
        • Adolfsson R.
        • et al.
        Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype.
        Am J Hum Genet. 2002; 71: 656-662
        • Guerreiro R.J.
        • Lohmann E.
        • Bras J.M.
        • Gibbs J.R.
        • Rohrer J.D.
        • Gurunlian N.
        • et al.
        Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.
        JAMA Neurol. 2013; 70: 78-84
        • Giraldo M.
        • Lopera F.
        • Siniard A.L.
        • Corneveaux J.J.
        • Schrauwen I.
        • Carvajal J.
        • et al.
        Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer’s disease.
        Neurobiol Aging. 2013; 34 (e11–e18): 2077
        • Bertram L.
        • Parrado A.R.
        • Tanzi R.E.
        TREM2 and neurodegenerative disease.
        N Engl J Med. 2013; 369: 1565
        • Benitez B.A.
        • Cruchaga C.
        TREM2 and neurodegenerative disease.
        N Engl J Med. 2013; 369: 1567-1568
        • Pottier C.
        • Wallon D.
        • Rousseau S.
        • Rovelet-Lecrux A.
        • Richard A.C.
        • Rollin-Sillaire A.
        • et al.
        TREM2 R47H variant as a risk factor for early-onset Alzheimer’s disease.
        J Alzheimers Dis. 2013; 35: 45-49
        • Guerreiro R.
        • Hardy J.
        TREM2 and neurodegenerative disease.
        N Engl J Med. 2013; 369: 1569-1570
        • Rayaprolu S.
        • Mullen B.
        • Baker M.
        • Lynch T.
        • Finger E.
        • Seeley W.W.
        • et al.
        TREM2 in neurodegeneration: Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease.
        Mol Neurodegener. 2013; 8: 19
        • Cady J.
        • Koval E.D.
        • Benitez B.A.
        • Zaidman C.
        • Jockel-Balsarotti J.
        • Allred P.
        • et al.
        TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis.
        JAMA Neurol. 2014; 71: 449-453
        • Rajagopalan P.
        • Hibar D.P.
        • Thompson P.M.
        TREM2 and neurodegenerative disease.
        N Engl J Med. 2013; 369: 1565-1567
        • Wunderlich P.
        • Glebov K.
        • Kemmerling N.
        • Tien N.T.
        • Neumann H.
        • Walter J.
        Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) by ectodomain shedding and gamma-secretase dependent intramembranous cleavage.
        J Biol Chem. 2013; 288: 33027-33036
        • Ren G.
        • Vajjhala P.
        • Lee J.S.
        • Winsor B.
        • Munn A.L.
        The BAR domain proteins: Molding membranes in fission, fusion, and phagy.
        Microbiol Mol Biol Rev. 2006; 70: 37-120
        • Ramjaun A.R.
        • McPherson P.S.
        Multiple amphiphysin II splice variants display differential clathrin binding: Identification of two distinct clathrin-binding sites.
        J Neurochem. 1998; 70: 2369-2376
        • McMahon H.T.
        • Wigge P.
        • Smith C.
        Clathrin interacts specifically with amphiphysin and is displaced by dynamin.
        FEBS Lett. 1997; 413: 319-322
        • Tsutsui K.
        • Maeda Y.
        • Seki S.
        • Tokunaga A.
        cDNA cloning of a novel amphiphysin isoform and tissue-specific expression of its multiple splice variants.
        Biochem Biophys Res Commun. 1997; 236: 178-183
        • Chapuis J.
        • Hansmannel F.
        • Gistelinck M.
        • Mounier A.
        • Van Cauwenberghe C.
        • Kolen K.V.
        • et al.
        Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
        Mol Psychiatry. 2013; 18: 1225-1234
        • Yang S.
        • Liu T.
        • Li S.
        • Zhang X.
        • Ding Q.
        • Que H.
        • et al.
        Comparative proteomic analysis of brains of naturally aging mice.
        Neuroscience. 2008; 154: 1107-1120
        • Meunier B.
        • Quaranta M.
        • Daviet L.
        • Hatzoglou A.
        • Leprince C.
        The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the microtubule-binding cytoplasmic linker protein 170 (CLIP-170).
        Eur J Cell Biol. 2009; 88: 91-102
        • Pant S.
        • Sharma M.
        • Patel K.
        • Caplan S.
        • Carr C.M.
        • Grant B.D.
        AMPH-1/Amphiphysin/Bin1 functions with RME-1/Ehd1 in endocytic recycling.
        Nat Cell Biol. 2009; 11: 1399-1410
        • Wigge P.
        • McMahon H.T.
        The amphiphysin family of proteins and their role in endocytosis at the synapse.
        Trends Neurosci. 1998; 21: 339-344
        • Di Paolo G.
        • Sankaranarayanan S.
        • Wenk M.R.
        • Daniell L.
        • Perucco E.
        • Caldarone B.J.
        • et al.
        Decreased synaptic vesicle recycling efficiency and cognitive deficits in amphiphysin 1 knockout mice.
        Neuron. 2002; 33: 789-804
        • Galderisi U.
        • Di Bernardo G.
        • Cipollaro M.
        • Jori F.P.
        • Piegari E.
        • Cascino A.
        • et al.
        Induction of apoptosis and differentiation in neuroblastoma and astrocytoma cells by the overexpression of Bin1, a novel Myc interacting protein.
        J Cell Biochem. 1999; 74: 313-322
        • Wajapeyee N.
        • Serra R.W.
        • Zhu X.
        • Mahalingam M.
        • Green M.R.
        Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.
        Cell. 2008; 132: 363-374
        • Wixler V.
        • Laplantine E.
        • Geerts D.
        • Sonnenberg A.
        • Petersohn D.
        • Eckes B.
        • et al.
        Identification of novel interaction partners for the conserved membrane proximal region of alpha-integrin cytoplasmic domains.
        FEBS Lett. 1999; 445: 351-355
        • Xiao Q.
        • Gil S.C.
        • 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: 21279-21289
        • Baig S.
        • Joseph S.A.
        • Tayler H.
        • Abraham R.
        • Owen M.J.
        • Williams J.
        • et al.
        Distribution and expression of picalm in Alzheimer disease.
        J Neuropathol Exp Neurol. 2010; 69: 1071-1077
        • Harel A.
        • Wu F.
        • Mattson M.P.
        • Morris C.M.
        • Yao P.J.
        Evidence for CALM in directing VAMP2 trafficking.
        Traffic. 2008; 9: 417-429
        • Wendland B.
        • Emr S.D.
        • Riezman H.
        Protein traffic in the yeast endocytic and vacuolar protein sorting pathways.
        Curr Opin Cell Biol. 1998; 10: 513-522
        • Zhang B.
        • Koh Y.H.
        • Beckstead R.B.
        • Budnik V.
        • Ganetzky B.
        • Bellen H.J.
        Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis.
        Neuron. 1998; 21: 1465-1475
        • Duce J.A.
        • Tsatsanis A.
        • Cater M.A.
        • James S.A.
        • Robb E.
        • Wikhe K.
        • et al.
        Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease.
        Cell. 2010; 142: 857-867
        • Treusch S.
        • Hamamichi S.
        • Goodman J.L.
        • Matlack K.E.
        • Chung C.Y.
        • Baru V.
        • et al.
        Functional links between Abeta toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast.
        Science. 2011; 334: 1241-1245
        • Tian Y.
        • Chang J.C.
        • Fan E.Y.
        • Flajolet M.
        • Greengard P.
        Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer’s APP-CTF for terminal degradation via autophagy.
        Proc Natl Acad Sci U S A. 2013; 110: 17071-17076
        • Dustin M.L.
        • Olszowy M.W.
        • Holdorf A.D.
        • Li J.
        • Bromley S.
        • Desai N.
        • et al.
        A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts.
        Cell. 1998; 94: 667-677
        • Shulman J.M.
        • Chipendo P.
        • Chibnik L.B.
        • Aubin C.
        • Tran D.
        • Keenan B.T.
        • et al.
        Functional screening of Alzheimer pathology genome-wide association signals in Drosophila.
        Am J Hum Genet. 2011; 88: 232-238
        • Cormont M.
        • Meton I.
        • Mari M.
        • Monzo P.
        • Keslair F.
        • Gaskin C.
        • et al.
        CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl.
        Traffic. 2003; 4: 97-112
        • Yamazaki T.
        • Masuda J.
        • Omori T.
        • Usui R.
        • Akiyama H.
        • Maru Y.
        EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility.
        J Cell Sci. 2009; 122: 243-255
        • Martinez A.
        • Otal R.
        • Sieber B.A.
        • Ibanez C.
        • Soriano E.
        Disruption of ephrin-A/EphA binding alters synaptogenesis and neural connectivity in the hippocampus.
        Neuroscience. 2005; 135: 451-461
        • Lai K.O.
        • Ip N.Y.
        Synapse development and plasticity: Roles of ephrin/Eph receptor signaling.
        Curr Opin Neurobiol. 2009; 19: 275-283
        • Sakamoto A.
        • Sugamoto Y.
        • Tokunaga Y.
        • Yoshimuta T.
        • Hayashi K.
        • Konno T.
        • et al.
        Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells.
        J Int Med Res. 2011; 39: 522-527
        • Rogaeva E.
        • Meng Y.
        • Lee J.H.
        • Gu Y.
        • Kawarai T.
        • Zou F.
        • et al.
        The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.
        Nat Genet. 2007; 39: 168-177
        • Lee J.H.
        • Cheng R.
        • Honig L.S.
        • Vonsattel J.P.
        • Clark L.
        • Mayeux R.
        Association between genetic variants in SORL1 and autopsy-confirmed Alzheimer disease.
        Neurology. 2008; 70: 887-889
        • Spoelgen R.
        • von Arnim C.A.
        • Thomas A.V.
        • Peltan I.D.
        • Koker M.
        • Deng A.
        • et al.
        Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.
        J Neurosci. 2006; 26: 418-428
        • Offe K.
        • Dodson S.E.
        • Shoemaker J.T.
        • Fritz J.J.
        • Gearing M.
        • Levey A.I.
        • et al.
        The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments.
        J Neurosci. 2006; 26: 1596-1603
        • Schmidt V.
        • Sporbert A.
        • Rohe M.
        • Reimer T.
        • Rehm A.
        • Andersen O.M.
        • et al.
        SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1.
        J Biol Chem. 2007; 282: 32956-32964
        • Dodson S.E.
        • Andersen O.M.
        • Karmali V.
        • Fritz J.J.
        • Cheng D.
        • Peng J.
        • et al.
        Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: Evidence for a proximal role in Alzheimer’s disease.
        J Neurosci. 2008; 28: 12877-12886
        • Scherzer C.R.
        • Offe K.
        • Gearing M.
        • Rees H.D.
        • Fang G.
        • Heilman C.J.
        • et al.
        Loss of apolipoprotein E receptor LR11 in Alzheimer disease.
        Arch Neurol. 2004; 61: 1200-1205
        • Dodson S.E.
        • Gearing M.
        • Lippa C.F.
        • Montine T.J.
        • Levey A.I.
        • Lah J.J.
        LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease.
        J Neuropathol Exp Neurol. 2006; 65: 866-872
        • Sager K.L.
        • Wuu J.
        • Leurgans S.E.
        • Rees H.D.
        • Gearing M.
        • Mufson E.J.
        • et al.
        Neuronal LR11/sorLA expression is reduced in mild cognitive impairment.
        Ann Neurol. 2007; 62: 640-647
        • Munck A.
        • Bohm C.
        • Seibel N.M.
        • Hashemol Hosseini Z.
        • Hampe W.
        Hu-K4 is a ubiquitously expressed type 2 transmembrane protein associated with the endoplasmic reticulum.
        FEBS J. 2005; 272: 1718-1726
        • McDermott M.
        • Wakelam M.J.
        • Morris A.J.
        Phospholipase D.
        Biochem Cell Biol. 2004; 82: 225-253
        • Cai D.
        • Zhong M.
        • Wang R.
        • Netzer W.J.
        • Shields D.
        • Zheng H.
        • et al.
        Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer’s disease-linked presenilin-1 mutant neurons.
        Proc Natl Acad Sci U S A. 2006; 103: 1936-1940
        • Cai D.
        • Netzer W.J.
        • Zhong M.
        • Lin Y.
        • Du G.
        • Frohman M.
        • et al.
        Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.
        Proc Natl Acad Sci U S A. 2006; 103: 1941-1946
        • Jin J.K.
        • Ahn B.H.
        • Na Y.J.
        • Kim J.I.
        • Kim Y.S.
        • Choi E.K.
        • et al.
        Phospholipase D1 is associated with amyloid precursor protein in Alzheimer’s disease.
        Neurobiol Aging. 2007; 28: 1015-1027
        • Oliveira T.G.
        • Chan R.B.
        • Tian H.
        • Laredo M.
        • Shui G.
        • Staniszewski A.
        • et al.
        Phospholipase d2 ablation ameliorates Alzheimer’s disease-linked synaptic dysfunction and cognitive deficits.
        J Neurosci. 2010; 30: 16419-16428
        • Guerreiro R.
        • Bras J.
        • Hardy J.
        SnapShot: Genetics of Alzheimer’s disease.
        Cell. 2013; 155 (968–968.e961)