R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia

Slattery, Catherine F.Catherine F.SlatteryBeck, Jonathan A.Jonathan A.BeckHarper, LornaLornaHarperAdamson, GaryGaryAdamsonAbdi, ZeinabZeinabAbdiUphill, JamesJamesUphillCampbell, TracyTracyCampbellDruyeh, RonRonDruyehMahoney, Colin J.Colin J.MahoneyRohrer, Jonathan D.Jonathan D.RohrerKenny, JannaJannaKennyLowe, JessicaJessicaLoweLeung, Kelvin K.Kelvin K.LeungBarnes, JosephineJosephineBarnesClegg, Shona L.Shona L.CleggBlair, MelanieMelanieBlairNicholas, Jennifer M.Jennifer M.NicholasGuerreiro, Rita J.Rita J.GuerreiroRowe, James B.James B.RowePonto, ClaudiaClaudiaPontoZerr, IngaIngaZerrKretzschmar, Hans A.Hans A.KretzschmarGambetti, PierluigiPierluigiGambettiCrutch, Sebastian J.Sebastian J.CrutchWarren, Jason D.Jason D.WarrenRossor, Martin N.Martin N.RossorFox, Nick C.Nick C.FoxCollinge, JohnJohnCollingeSchott, Jonathan M.Jonathan M.SchottMead, SimonSimonMead2018-11-072018-11-072014https://resolver.sub.uni-goettingen.de/purl?gro-2/31839Background: Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD). Methods: We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD). Results: We confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P =.03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from "typical" sporadic AD. Conclusion: We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease. (C) 2014 The Alzheimer's Association. All rights reserved.R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementiajournal_article10.1016/j.jalz.2014.05.175125160042000345310800004