Yokoyama JS, Wang Y, Schork AJ, Thompson WK, Karch CM, Cruchaga C, McEvoy LK, Witoelar A, Chen CH, Holland D, Brewer JB, Franke A, Dillon WP, Wilson DM, Mukherjee P, Hess CP, Miller Z, Bonham LW, Shen J, Rabinovici GD, Rosen HJ, Miller BL, Hyman BT, Schellenberg GD, Karlsen TH, Andreassen OA, Dale AM, Desikan RS, Alzheimer’s Disease Neuroimaging Initiative. Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. JAMA Neurol. 2016 Jun 1;73(6):691-7. PubMed.

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  1. It is clear that neuroimmune response is key to the genetics of Alzheimer’s disease, not just because of the identification of TREM2 as a risk locus but also from the systematic analysis of the GWAS hits (Jones et al., 2010). Interestingly, transgenic mouse work has shown that many of the GWAs hits, and TREM2, are the biggest responders to plaque deposition, and overlaying GWAS loci with the genes in the TREM2 module of co-expression shows just how important this process appears to be (Matarin et al., 2015). These genes do not respond as markedly in response to tangle deposition, suggesting perhaps that the order of events is plaque deposition, immune response, tangle deposition.

    References:

    Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, Pocklington A, Abraham R, Hollingworth P, Sims R, Gerrish A, Pahwa JS, Jones N, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Peters O, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Rüther E, Carrasquillo MM, Pankratz VS, Younkin SG, Hardy J, O'Donovan MC, Owen MJ, Williams J. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One. 2010;5(11):e13950. PubMed.

    Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, Nahaboo Solim MA, Moens TG, Paublete RM, Ali SS, Perona M, Desai R, Smith KJ, Latcham J, Fulleylove M, Richardson JC, Hardy J, Edwards FA. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 2015 Feb 3;10(4):633-44. Epub 2015 Jan 22 PubMed.

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  1. New Genetic Method Connects Immune Genes to Alzheimer’s