P2‐174: Impulsivity in Alzheimer’s Disease as Detected by D‐CPT

Background: Genetic studies identified an association between Alzheimer’s disease (AD) and common polymorphisms in the MS4A and TREM loci, each containing cluster of homologous genes. Methods:We searched for rare coding variants in 15 genes mapped to these loci by next generation sequencing of a North American dataset (210 cases and 233 controls). Results:Analysis of the MS4A gene-cluster revealed loss-of-function variants in 6 controls and 3 cases. Investigation of the TREM gene-cluster detected known AD associated TREM2 substitutions (p.R47H, p.D87N and p.H157Y) affecting both TREM2 isoforms (NM_018965 and NM_001271821). We also identified two cases with novel TREM2 variants (p.L205P and p.G219C), which mapped only to the isoform NM_001271821. A p.S248R substitution in the homologous TREML2 gene was detected in 5 controls and 1 case suggesting a protective effect (pooled p-value 1⁄4 0.033). Conclusions:Our study advocates for the importance of mutation analysis of controls, particularly for GWAS loci containing SNPs with a minor allele frequency higher in controls versus cases (e.g. MS4A locus), to search for functional variants with a protective effect.