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Methods

The genes identified in a number of recent genomewide association studies are available at the GWAS repository at the National Human Genome Research Institute http://www .genome.gov/gwastudies/ [32] and, along with pre-GWAS genes and environmental risk factors, at http://www.polygenicpathways.co.uk/alzenvrisk.htm. The genes returned from very large sample sets (N > 10, 000) include ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A2, MS4A4A, MS4A4E, MS4A6A, and PICALM whose pro perties in relation to diverse pathogens were identified by literature survey. While it is recognised that such genes, particularly APOE, ABCA7, CR1, and clusterin, which are involved in lipoprotein function and/or amyloid processing (see below), may exert effects on other relevant branches of Alzheimer's disease pathophysiology, the focus of this paper is on pathogens and the immune system, which appear to be the common factors integrating this network. Throughout the text, these and other genes implicated in Alzheimer's disease from the GWAS and pre-GWAS era are highlighted in bold and appended to the various processes in which they are involved (derived from a KEGG pathway analysis of these genes http://www.polygenicpathways.co.uk/alzkegg.htm) Herpes simplex binding proteins, and key interactors, currently numbering over 450, are stocked and referenced at http:// www.polygenicpathways.co.uk/herpeshost.html. KEGG pathway analysis of this interactome is provided at http:www .polygenicpathways.co.uk//HERPESKEGG.htm. Expression data are provided in Figure 1 and are also hyperlinked to the BioGPS webserver http://www.biogps.gnf.org/, which provides general gene information and mRNA expression profiles for most human genes, based on custom arrays from 79 human issues [33, 34] . Predicted B-cell epitopes from human beta-amyloid Figure 1 : The mRNA distribution of the major genes derived from GWAS in Alzheimer's disease, as well as that of APP and gamma-secretase components. Data are from the BioGps website. Plasmodium falciparum [37] [38] [39] [40] [41] [42] [43] and is a general clearance receptor for complement opsonised pathogens [44] . Clusterin, predominantly expressed in brain, liver, and testis, (http://www.biogps.org/#goto=genereport&id=1191/) is a ligand for the lipoprotein receptor, megalin (LRP2) that is involved in beta-amyloid clearance, and also a complement inhibitor that prevents the formation of the membrane attack complex, a channel that is inserted into pathogen membranes, killing them by lysis [45] . This complex is also seen in Alzheimer's disease neurones [46, 47] . The herpes simplex virus interacts with other members of the complement cascade, by binding to the complement component and CR1 ligand, C3 and its derivatives and to CD59, a further inhibitor of the formation of the complement membrane attack complex (see review) [48] . C. pneumoniae interacts with this pathway by binding to properdin (CFP), a protein that stabilises the complement C3 and C5 convertase and contributes to the formation of the membrane attack complex [49] . CD59 is also incorporated into chlamydial inclusion bodies [50] . Complement component C3 binds to melanins derived from C. neoformans [51] and cryptococcal capsules bind to C3 and activate the alternative complement pathway [52] . Complement component C3 also binds to the bacterial surface of H. pylori, and the complement pathway is involved in bactericidal effects against this pathogen [53] . P. gingivalis also uses complement receptor 3 (an integrin complex of integrin, alpha M/integrin, beta 2 (ITGAM/ ITGB2)) for entry [54] , and herpes simplex glycoprotein C also binds to this complex [55] as does C. neoformans [56] , while ITGB2 is involved in C. pneumoniae entry in human coronary artery endothelial cells [57] . This macrophage complement receptor, also known as MAC-1, generally mediates the phagocytosis of pathogens coated with complement C3 derivatives [58] . T. C3 also binds to P. gingivalis although the pathogen has devised an elegant escape strategy involving digestion of complement components C3, C4, and C5 by bacterial secreted proteases, known as gingipains [59] . The complement inhibitor CD59 is also a ligand for CD2, and CD59 activation of this receptor, presumably involving CD2AP, activates T cell receptor signalling resulting in the secretion of interleukins (IL1A, IL2 and IL6) and granulocyte macrophage colony stimulating factor (CSF2) [60, 61] .

Clathrin-Mediated Endocytosis

PICALM, expressed primarily in myeloid and dendritic cells of the immune network http://www.biogps.org/ #goto=genereport&id=8301/, plays a key role in clathrinrelated endocytosis, binding to clathrin heavy chains (CLTC and CLTCL1), and recruiting the clathrin and adaptor protein 2 (AP-2) to the plasma membrane. The AP-2 complex is a heterotetramer consisting of permutations of two large adaptins (alpha (AP2A1, AP2A2)) or beta (AP2B1), a medium adaptin (AP1M1, AP1M2), and a small adaptin (sigma AP2S1). PICALM controls the endocytosis of the cation-independent mannose-6-phosphate IGF2 receptor (IGF2R) [70] , one used by Herpes simplex for entry and cellto-cell transmission [71] and by C. pneumoniae for cellular entry [57] . IGF2R is also a component of late endosomes disrupted by the Helicobacter pylori VacA cytotoxin [72] . The mannose-6-phosphate receptor binds to clusterin. PICALM also binds to a nuclear exportin crm-1 (XPO1) used by the herpes simplex virus during its life cycle [48] .
CD2AP, primarily expressed in dendritic cells and B lymphoblasts http://www.biogps.org/#goto=genereport&id= 23607/, is a scaffolding molecule that regulates the actin cytoskeleton and is primarily associated with the T-lymphocyte marker protein CD2. CD2 stimulates T cell activation and is involved in the creation of contacts between antigen presenting cells and T cells (the immunological synapse), effects mediated via CD2AP and clathrin [74] . CD2AP is also involved in the entry of the helicobacter vacuolating toxin VacA and connects the actin cytoskeleton to early endosomes containing VacA [75] . CD2 is cleaved by gingipain proteases from P. gingivalis [76] .
Bridging integrator 1 (BIN1), also known as amphiphysin 2, is primarily expressed in the pineal and skeletal muscle, or otherwise ubiquitously http://www.biogps.org/ #goto=genereport&id=274/. It is also involved in the clathrin-mediated endocytosis machinery [86] and binds to dynamins that regulate the clathrin network [87] including DNM1 and the herpes simplex binding partner DNM2 [88] and to clathrins and the alpha adaptins, AP2A1 and AP2A2 [89] . BIN1 also participates in phagocytosis in macrophages and is associated, but only transiently, with early phagosomes; however, it is retained on vacuoles containing Chlamydia pneumoniae, an effect that reduces the ability of the macrophage system to kill the bacteria via nitric oxide generation. Macrophages expressing a dominant negative BIN1 internalise C. pneumoniae, but do not allow their killing [90] . BIN1 also binds to a number of alpha integrins (ITGA1, ITGA3, and ITGA6) [91] : integrins are used for attachment by many viruses, bacteria, and fungi and may serve as pattern recognition receptors regulating the immune response [92] . Individual integrins bind to many others, forming heteromeric complexes; for example, ITGA1 binds to ITGA3 or ITGA6, while ITGA3 binds to ITGB1 (a receptor for the H. pylori protein CagA [93] ), ITGB4, or ITGB5, and ITGA6 binds to ITGB1 and ITGB4 (data from NCBI gene).
3.3. The Immune Network (APOE, BIN1, CD2AP, CD33, MS4A2) ( Figure 4) . CD33, mainly expressed in myeloid cells, monocytes, and dendritic cells (http://www.biogps.org/ #goto=genereport&id=945/), is a member of the sialic acid binding Immunoglobulin g-like lectin (SIGLEC) family. CD33-related SIGLECs regulate adaptive immune responses and are also important as macrophage pattern recognition receptors for sialylated pathogens, including enveloped viruses [94] . CD33 binds to alpha2-3-or alpha2-6-linked sialic acids (N-acetyl neuraminic acid) [95] . These particular sialic acids are expressed on the surface envelope glycoproteins (B, D, and H) of the herpes simplex virion, and these residues are required for viral entry into cells [96] . N-acetyl neuraminic acid is expressed by C. neoformans, is involved in fungal adhesion to macrophages [97] , and is also a component of the cell wall of B. burgdorferi [98] , while Helicobacter pylori adhesins also bind to this particular form of sialic acid [99, 100] as does P. gingivalis [101] .
MS4A2, expressed mainly in the tonsils, lymph nodes, B cells, and dendritic cells http://www.biogps.org/#goto= genereport&id=931/, is a component of the immunoglobulin E (IgE) receptor, which is involved in allergic responses in which allergens bound to receptor bound IgE result in the activation of allergic mediators such as histamine [108] . Mice immunised with inactivated herpes simplex develop IgE-specific antibodies to the virus [109] . High levels of IgE are also observed in man following recurrent herpes simplex infection [110] and human IgE antibodies are also known to interact with herpes family viruses including HSV-1 and 2 and the Epstein-Barr and cytomegalovirus [111] and also to C. pneumoniae, H. pylori, and B. burgdorferi [ [112] [113] [114] [115] . IgE-related allergic responses are also involved in C. neoformans infection [116] . Other members of this gene cluster (including MS4A4A, MS4A4E, and MS4A6A) are also structurally related to the immunoglobulin E receptor and to CD20 (MS4A1) and also regulate B cell and T cell proliferation and/or differentiation [117, 118] . EPHA1 is an ephrin receptor, primarily expressed in the liver and otherwise ubiquitously (http://www.biogps.org/ #goto=genereport&id=2041/). Only three protein/protein interactions for EPHA1 are reported in the NCBI gene interaction section, including its ligand EFNA1, the anaplastic lymphoma receptor tyrosine kinase (ALK), and a SMADspecific E3 ubiquitin protein ligase 2 (SMURF2). EFNA1 is one of several proteins identified as being important in the entry of C. pneumoniae into human coronary artery endothelial cells [57] . SMURF2 is known to bind to the VP22 tegument protein of herpes simplex [119] and plays a role in clathrin-mediated endocytosis and the subsequent ubiquitin-related proteasomal degradation of TGF beta receptors, to which it binds [120] . Clusterin is a ligand for TGF beta receptors (TGFBR1/TGFBR2) [121] . TGF beta signalling exerts immunosuppressive effects and inhibits host immunosurveillance and the recruitment of immunocompetent cells by chemokines [122] . ALK is ubiquitously expressed (http://www.biogps.org/#goto=gene-report&id=238/). It plays a role in neural development, and its expression decreases with age [123] . ALK is best characterised via its relationship with lymphomas, caused by ALK gene fusion with any of several other housekeeping genes [124] . Its key involvement in lymphoma suggests a role in the immune network although the function of the normal ALK protein is poorly understood. 5 ). ABCA7 is an ATP-binding cassette transporter, predominantly localised in the pineal gland and cells of the immune network (T cells, natural killer cells, and dendritic cells http://www.biogps.org/#goto=genereport&id=10347/). The lipoproteins APOA1 and APOE are substrates for ABCA7, and in cultured HEK-293 cells, plasma membrane-situated ABCA7 increases the efflux of phosphatidylcholine and sphingomyelin efflux to APOA1 and APOE, with no effect on cholesterol efflux [125] . However, cholesterol efflux to lipidladen APOE, but not to lipid free APOE, is increased by ABCA7 expression in HEK-293 cells [126] . Sphingomyelin is enriched in extracellular herpes simplex viral membranes: this sphingomyelin, together with phosphatidylserine, is collected by the viral envelope during viral passage from the nuclear membrane to the exocytosis pathway [127] . Herpes viral infection leads to an increased incorporation of phosphate into membrane sphingomyelin of the host [128] . Inhibition of sphingomyelinase has also been shown to markedly reduce herpes simplex viral reproduction [129] and also inhibits the antifungal effects of neutrophils against C. neoformans infection. Sphingomyelin is a receptor for the Helicobacter toxin VacA [130] and is also incorporated into inclusion bodies in C. pneumoniae-infected cells [131] . Phosphatidylcholine plays an important role in the fusion of herpes simplex glycoproteins B and H with the host cell lipid membrane, a process used in viral entry [132] . Phosphatidylcholine is also able to trigger capsular enlargement in C. neoformans infection [133] .

Other GWAS Genes

DISC1 is a component of the microtubule-associated dynein motor complex used in viral traffic [163] ; TTLL7 (tubulin tyrosine ligase-like family, member 7) also regulates tubulin phosphorylation [164] and can again be related to viral traffic along the microtubule network (see below). CELF2 (also known as CUGBP2) is a member of the APOBEC1 cytidine deaminase mRNA editing complex that also controls herpes simplex viral replication [165] . GAB2 13 is a member of the GRB2-associated binding protein family which act as adapter hubs transmitting signalling via cytokine and growth factor receptors, and T-and B-cell antigen receptors (definition from NCBI gene), while PAX2 inhibits the expression of the antimicrobial peptide beta defensin (DEFB1) [166] , a gene associated with HSV-1 and cytomegalovirus seropositivity in children with acute lymphoblastic leukaemia [167] , as well as with H. pylori or chlamydial infections [168, 169] , also endowed with antimicrobial activity against C. neoformans and other pathogens [170] . MTHD1L (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like) is involved in the mitochondrial synthesis of tetrahydrofolate which in turn is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine (definition from NCBI gene). Many pathogens, including herpes simplex, express thymidylate kinases, which are important for viral replication and a target for acyclovir [171] . Hyperhomocysteinaemia correlates with C. pneumoniae IgG immunoreactivity in carotid artery atherosclerosis [172] and is also associated with H. pylori infection in the context of atherosclerosis [173] . The apolipoprotein APOC1 is a component of high-density lipoprotein: herpes simplex is present in all lipoprotein blood fractions in blood (VLDL, LDL and HDL) and the lipid component of these lipoproteins binds to viral glycoprotein B [174] (c.f. APOA1, APOA4, APOA5, APOC1, APOC2, APOC3, APOC4, APOD, and APOE). No immediately apparent pathogen-relevant interactions were found for FAM113B (expressed exclusively in T cells, dendritic cells, and natural killer cells http:// www.biogps.org/#goto=genereport&id=91523/), PCDH11X (which is ubiquitously expressed http://www.biogps.org/ #goto=genereport&id=27328/), or SASH1 (primarily expressed in the brain and lung although also in other tissues, including the immune network http://www.biogps.org/#go-to=genereport&id=23328/) although the pathogen/immune theme is clearly carried through, particularly in relation to herpes simplex, in this second rank of Alzheimer's disease susceptibility genes. (Figure 2) . APOE, clusterin, and complement receptor 1 play key roles in beta amyloid clearance as do two further herpes simplex binding proteins APOA1, and alpha-2 macroglobulin (A2M). This is primarily mediated via lipoprotein receptors. A2M, or APOE-bound Aβ, is cleared by the lipoprotein receptor LRP1, while LRP2 (megalin) clears clusterin-bound Aβ. LRP8 is a receptor for both APOE and clusterin. APOA1 is also involved in beta-amyloid clearance via its transporter ABCA1. The role of ABCA7 has not been examined, although APOA1 is also a ligand for this transporter (see above). The Varicella Zoster and herpes simplex glycoprotein E binding protein, insulin-degrading enzyme, are also involved in beta-amyloid degradation, as is caspase-3 which is activated by the herpes simplex viral US3 kinase. The HSV-1 binding protein, complement C3 is also a ligand for LRP1 and LRP8, both of which play a role in C3 cellular uptake. Beta amyloid in the bloodstream is processed by its binding to complement C3, which subsequently binds to complement receptor 1 on erythrocytes. The effects above are referenced in a recent review [48] .

Gamma Secretase: Localisation to Dendritic Cells and Cleavage of Pathogen Receptors.

Gamma secretase is constituted of four components: the presenilins (PSEN1 or PSEN2), anterior pharynx-defective-1 (APH1A), the Presenilin enhancer-2 (PSENEN), and nicastrin (NCSTN) [201] . While all components are expressed in cerebral tissue, the major focus of distribution is within cells of the immune network; dendritic cells, myeloid cells, and monocytes for PSEN1 http://www .biogps.org/#goto=genereport&id=5663/; dendritic cells and natural killer cells for PSENEN http://www.biogps.org/#go-to=genereport&id=55851/, dendritic cells and myeloid cells for nicastrin http://www.biogps.org/#goto=genereport&id= 23385/ and B cells, dendritic cells, natural killer cells, and myeloid cells for APH1A. The substrate, APP, is the only gene in this set that appears to be preferentially distributed in brain compartments, but, as with gamma-secretase components, it is also highly expressed in dendritic cells of the immune system (http://www.biogps.org/#goto=gene-report&id=351/). The primary function of such cells is to process antigens and present them to B cells and T cells. They scout for and recognise pathogens via the agency of numerous pattern recognition receptors, for example, Toll receptors (TLR2, TLR4) , or viral DNA sensors, expressed on their surface [202, 203] .

Autoantibodies Derived from Pathogens as Contributory

Autoantibodies, which are observed in many, if not most human diseases, are often regarded as an epiphenomenon of little consequence. However, they can traverse the blood brain barrier [242] (which is compromised in Alzheimer's disease [243] ) and are also able to enter cells, essentially by hitching a ride on viruses, via high affinity IgG receptors (Fc gamma receptors) (FCER1G) in the case of the rhinovirus, or the SARS coronavirus, or via the tripartite motif protein, TRIM21, in the case of adenoviruses, where they are able to activate an intracellular immune attack. It would appear that the cellular entry of antibody laden viruses is diverted from their usually preferred receptors towards those used by antibodies [244] [245] [246] . This may be relevant to the MS4A family. Fc gamma receptors are localised in microglia and astrocytes in the brain and their expression is upregulated by blood brain barrier disruption [247] , while TRIM21 appears to be exclusively localised in peripheral immunocompetent cells (http://www.biogps.org/#goto=genereport&id=6737/). This ability places autoantibodies in a rather more sinister context, as their targeting of extracellular and intracellular human proteins would be expected to effect protein knockdown, a strictly immunopharmacological effect, as well as immune attack.