A Rare Genetic Variant in the PLCG2 gene Is Associated with a Reduced Risk of All Major Types of Dementia and Associates with an Increased Risk to Reach an Extremely Old Age

VAN DER LEE, SJ; JANSEN, IE; PLETNIKOVA, O; BLAUWENDRAAT, C; HULSMAN, M; DALMASSO, MC; KAWALIA, A; RAMIREZ, A; VAN DER FLIER, WM; SCHELTENS P; REINDERS MJT; HERNANDEZ I; LLEÓ A; FORTEA J; STRINGA N; RUIZ A; ILLÁN-GALA I; MORENAS-RODRÍGUEZ E; CLARIMON J; LAGE C; VAN DEN AKKER E; RODRÍGUEZ E; SÁNCHEZ-JUAN P; PIJNENBURG YAL; VAN SCHOOR N; SIMON-SANCHEZ J; LEMSTRA AW; HEUTINK P; SCHOLZ S; HUISMAN M; SLAGBOOM E; HOLSTEGE H

Chicago

Conferencia; AAIC 2018; 2018

Alzheimer's Association

Background: The genetic variant rs72824905-G(p.Pro522Arg) in the PLCG2 gene(Phospholipase CGamma 2) was previously found to associate with a reduced risk of Alzheimer?s disease (AD). Wehypothesized that the variant might reduce the risk of other neurodegenerative diseases as PLCG2plays an important role in innate immune system signaling, and is expressed in microglial cells inbrain. Therefore, we tested if the variant associated with a reduced risk of Fronto-temporalDementia(FTD), Lewy-body dementia (LBD), Progressive Supranuclear Palsy(PSP), Parkinson?sDisease(PD) and Amyotrophic Lateral Sclerosis(ALS). Additionally, we investigated if carriers had anincreased risk to reach extreme ages in good cognitive health. Methods: We determinedrs72824905-G genotypes in 2,129 AD, 2,273 FTD patients, 1,075 LBD patients, 625 PSP patients allfrom European descent(consortia in author list). We genotyped 464 nonagenarians and 268 selfreportedcognitively healthy centenarians. Patients and aged cases were compared with populationmatchedcontrols(N-max=10,891). Cohorts were analyzed using the score test and if necessary cohortswere meta-analyzed in R with the ?SeqMeta? package. One-sided p-values are reported. Associationresults were extracted from existing meta-analyses of 6,248 PD patients(6,031 controls) and 10,953ALS patients(20,673 controls). Results: We replicated the protective effect of rs72824905-G onAD(OR=0.49; 95%CI 0.33-0.73, P=2.5×10-4), and we found a similar protective effect on FTD, LBD andPSP(aggregate OR=0.65; 95%CI 0.49-0.86, P=1.4×10-3). The effect was comparable for FTD(OR=0.66,95%CI 0.48-0.90, P=4.8×10-3), LBD(OR=0.64, 95%CI 0.35-1.19, P=0.08) and PSP(OR=0.71, 95%CI0.29-1.74, P=0.26). There was no significant effect in the large meta-analysis of PD(OR=0.79, 95%CI0.56-1.12, P=0.10) or ALS(OR=1.07, 95%CI 0.87-1.33, P=0.26). Lastly, we considered the effect onextreme aging. Carriers of rs72824905-G had 1.65-fold(95%CI 0.91-2.99, P=4.8×10-2) increasedchance to become a nonagenarian and 3.2-fold(95%CI 1.49-6.95, P=1.4×10-3) increased chance tobecome a cognitively healthy centenarian. Conclusions: The amino acid substitution Pro522Arg inPLCG2 reduces the risk of AD and non-AD dementias, as well as increase the risk to reach extremeages. No evidence of association with PD and ALS was found, despite large sample sizes. Wespeculate that an improved immune response as consequence of this variant in the PLCG2 genemakes the brain resilient to neurodegenerative processes leading to dementia.