Table 1.
Genome-wide significant AD-associated genes with potential roles in innate and adaptive immunity
| Chr | Gene | Immune-related function | References |
|---|---|---|---|
| 1 | ADAMTS4 | Immunomodulator | Jansen et al., 2019 [22]; Redondo-García et al., 2021 [23] |
| 1 | AGRN | Survival and function of monocytes | Mazzon et al., 2012 [24] |
| 1 | CR1 | Immunity—e.g., microglial phagocytosis and clearance of complement opsonized molecules | Lambert et al., 2009 [25]; Borucki et al., 2020 [26] |
| 1 | PSEN2 | Innate immune system | Agrawal et al., 2016 [27]; Nam et al., 2022 [28]; Fung et al., 2020 [29]; Mendez et al., 2017 [30] |
| 1 | SORT1 | Monocytes and T cells | Bellenguez et al., 2022 [31]; Herda et al., 2012 [32]; Mortensen et al., 2014 [33] |
| 2 | ADAM17 | T cell response | Lambrecht et al., 2018 [34] |
| 2 | BIN1 | Pro-inflammatory response; endocytosis and phagocytosis | Seshadri et al., 2010 [35], Sudwarts et al., 2022 [36] |
| 2 | FHL2 | Wound healing and inflammation | Nordhoff et al., 2012 [37]; Wixler et al., 2019 [38] |
| 2 | INPP5D | Immunity and microglia function | Efthymiou and Goate, 2017 [19]; Lambert et al., 2013 [39] |
| 2 | SPRED2 | NK cells; cytokine/chemokine production | Itakura et al., 2017 [40] |
| 2 | PRKD3 | Thymic selection during T cell development | Ishikawa et al., 2016 [41] |
| 3 | IL17RD | Cytokines | Brigas et al., 2021 [42]; Girondel et al., 2021 [43] |
| 3 | MME | Neutrophils | Schulte-Schrepping et al., 2020 [44] |
| 4 | CLNK | Immune cell-specific adaptors | Utting et al., 2004 [45] |
| 4 | RHOH | TCR signaling | Gu et al., 2006 [46] |
| 4 | SCARB2 | IFN-I production and cholesterol regulation | Guo et al., 2015 [47]; Heybrock et al., 2019 [48] |
| 5 | APC | T cell migration | Mastrogiovanni et al., 2022 [49] |
| 5 | HAVCR2 | Viral receptor; T cells | Zhai et al., 2021 [50]; Wightman et al., 2021 [51] |
| 5 | HBEGF | T cells | Macdonald et al., 2021 [52] |
| 5 | MEF2C | B cell proliferation, regulate microglia, and antigen presentation | Sao et al., 2018 [53] |
| 5 | PFDN1/HBEGF | Macrophage-mediated cellular proliferation | Higashiyama et al., 1991 [54] |
| 5 | RASGEF1C | Macrophages; microglia | Srinivasan et al., 2020 [55] |
| 5 | TNIP1 | NF-κB regulation | G'Sell et al., 2016 [56]; Gurevich et al., 2011 [57] |
| 6 | CD2AP | T lymphocyte | Raju et al., 2018 [58]; Tao et al., 2019 [59] |
| 6 |
HLA-DRB5/ HLA-DRB1 |
Immunity—e.g., antigen presentation | Lambert et al., 2013 [39]; Lu et al., 2017 [60] |
| 6 | TREM2 | Phagocytosis, and cellular metabolism in myeloid cells, microglia activation as well as binding to Aβ | Griciuc et al., 2019 [61]; Guerreiro et al., 2013 [13]; Jonsson et al., 2013 [14]; Kunkle et al., 2019 [62]; Bis et al., 2020 [63]; Sims et al., 2017 [64] |
| 7 | EPHA1 | Immunity, BBB permeability, and immune cell trafficking | Ivanov et al., 2006 [65]; Chen et al., 2018 [66] |
| 7 | IKZF1 | T/B cell dysregulation | Hoshino et al., 2022 [67] |
| 7 | PILRA | Immunoglobulin receptor; viral receptor | Agostini et al., 2019 [68] |
| 7 | SEC61G | Antigen presentation | Zehner et al., 2015 [69] |
| 7 | TMEM106B | Innate immune system | Rhinn et al., 2017 [70] |
| 8 | CLU | Immunity, binding to Aβ, and inhibition of complement system | Tschopp et al., 1993 [71]; Lambert et al., 2009 [25]; Zhao et al., 2015 [72] |
| 8 | CTSB | Immune cell infiltration | Ma et al., 2022 [73]; Ha et al., 2008 [74] |
| 8 | PTK2B | Spreading, migration, and function of immune cells | Okigaki et al., 2003 [75]; Lambert et al., 2013 [39] |
| 8 | SHARPIN | Neuroinflammation and NF-κB activation | Asanomi et al., 2019 [76] |
| 9 | ABCA1 | Immune modulation; myeloid cells; dendritic cells | Zamanian-Daryoush et al., 2017 [77]; Westerterp et al., 2017 [78] |
| 10 | BLNK | B cell linker | Fu et al., 1998 [79]; Han et al., 2016 [80] |
| 10 | ECHDC3 | NK, monocyte differentiation, cell infiltration | Zhao et al., 2022 [81] |
| 10 | TSPAN14 | Mast cell function | Orinska et al., 2020 [82] |
| 11 | MS4A | Expressed in immune cells, TREM2 regulation, phagocytosis, regulation of complement system | Deming et al., 2019 [83]; Kuek et al., 2016 [84] |
| 11 | PICALM | Endocytosis and Aβ clearance | Zhao et al., 2015 [72]; Harold et al., 2009 [85] |
| 11 | SORL1 | Microglia, monocyte migration, pro-inflammatory cytokines regulation and phagocytosis | Talbot et al., 2018 [86]; Knupp et al., 2020 [87] |
| 11 | SPI1 | PU.1, altered microglia function | Jones et al., 2021 [88] |
| 12 | TPCN1 | Antigen-presenting cells | He et al., 2020 [89] |
| 14 | FERMT2 | Immune cell infiltration | Su et al., 2021 [90] |
| 14 | IGHG1 | Antigen and immunoglobulin receptor binding activity | Lekhraj et al., 2022 [91] |
| 14 | PSEN1 | Microglial hyperactivation | Lee et al., 2002 [92] |
| 15 | ADAM10 | Immune cell function | Lambrecht et al., 2018 [34] |
| 15 | CTSH | Autoimmune inflammation, macrophages and phagocytosis, cytokines | Faraco et al., 2013 [93]; Conus et al., 2010 [94]; Zavašnik-Bergant et al., 2004 [95], Li et al., 2010 [96] |
| 15 | IGF1R | Stimulates regulatory T cells, autoimmunity | Bilbao et al., 2014 [97]; Andersson et al., 2018 [98] |
| 15 | RORA | Inflammatory response; lymphoid cell development; T cell survival; autoimmunity and chronic inflammatory response | Oh et al., 2019 [99]; Lo et al., 2016 [100]; Chi et al., 2021 [101]; Wang et al., 2021 [102] |
| 15 | SPPL2A | Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-α | Fluhrer et al., 2006 [103] |
| 16 | IL34 | Proliferation, survival and differentiation of monocytes and macrophages | Foucher et al., 2013 [104]; Lin et al., 2008 [105] |
| 16 | KAT8 | Viral immunity | Huai et al., 2019 [106] |
| 16 | MAF | Regulates IL-10 | Gabryšová et al., 2018 [107] |
| 16 | PLCG2 | Involved in multiple pathways in immune cells | Sims et al., 2017 [64]; Magno et al., 2021 [108] |
| 16 | ZNF423 | B cell differentiation | Harder et al., 2013 [109] |
| 17 | ABI3 | Immunity, regulation of actin polymerization, and microglia function | Sims et al., 2017 [64]; Satoh et al., 2017 [110] |
| 17 | ACE | Innate and adaptive immune system | Bernstein et al., 2018 [111] |
| 17 | SCIMP | MHC class II signaling transduction | Draber et al., 2011 [112] |
| 17 | TSPOAP1 | Microglia-associated gene; IFN signaling | Bhatt et al., 2020 [113] |
| 19 | ABCA7 | Microglia Aβ clearance and cholesterol metabolism | Hollingworth et al., 2011 [11]; Kim et al., 2006 [114]; Steinberg et al., 2015 [115] |
| 19 | APOE | Lipid metabolism; T cell activation | Saunders et al., 1993 [116]; Bonacina et al., 2018 [117] |
| 19 | CD33 | Immunity, phagocytosis, and transmembrane receptor in myeloid cells | Bertram et al., 2008 [10]; Griciuc et al., 2013 [118]; Griciuc et al., 2019 [61]; Crocker et al., 2007 [119] |
| 19 | LILRB2 | Immunoglobulin-like receptor; influence immune activation | Deng et al., 2021 [120] |
| 20 | RBCK1 | Immunodeficiency disorders; LUBAC inhibits TNF-α signaling, dousing inflammation | Boisson et al., 2012 [121]; Bellenguez et al., 2022 [31] |
| 20 | CASS4 | Eosinophil asthma response | Esnault et al., 2013 [122] |
| 21 | ADAMTS1 | Immunomodulator | Rodríguez-Baena et al., 2018 [123]; Kunkle et al., 2019 [62] |
| 21 | APP | Antimicrobial peptide | Kumar et al., 2016 [124]; Eimer et al., 2018 [125]; Jonsson et al., 2012 [126] |
The selected genes were implicated based on independent genetic loci with genome-wide significance in at least one GWAS in AD [12, 22, 25, 31, 39, 51, 85, 127–130] and a potential role in the immune system. IFN-I type I interferon; NK cell natural killer cell; TCR T cell receptor; MHC major histocompatibility complex; NF-κB nuclear factor kappa B; LUBAC linear ubiquitination assembly complex