Conclusions: These results provide valuable clues to understand the role of Blmh in the pathological process of AD . P1-278 RESULTS FROM DENSE SNP GENOTYPING OF THE 9Q22-Q31 CRI IN THE NIMH AND NCRAD AD COHORTS Rodney Perry , Howard Wiener, Rodney Go, University of Alabama at Birmingham, Birmingham, Alabama, United States. Background: Linkage scans of Alzheimer’s disease (AD) families have identified the 9q22 region as a candidate region of interest (CRI). Second to APOE, the 9q22 signal was the most suggestive from the linkage scan of the NIMH Alzheimer’s Disease Genetic Initiative (ADGI). Additional microsatellite markers, narrowed the 1 LOD region to 11.5 cm (91.5-103 Mb). Four candidate genes located between 2-6 Mb proximal to this peak have been found significantly associated with AD. Methods: To determine more precisely the location of these signals, dense SNP genotyping of the 9q21-9q31 region, covering a total of w18 Mb which includes this region and the proximal 6 Mb was performed. Haplotag SNPs and unblocked SNPs were chosen from HapMap. SNPs in reported CNVs from this region, and SNPs covering four genes CRI, CLU, PICALM, and TOMM40 were also genotyped, resulting in a total of w 5800 SNPs. Genotyping used the Illumina iSelect platform. Results: Dense SNP genotyping was performed in the NIMH and NCRAD cohorts. Using Family Based Association Test- ing, besides confirming the APOE/TOMM40 and NTRK2 associations, the strongest and most consistent signals for additive and dominant models were at 86.6 Mb, 91.3 Mb, 93.2 Mb, 96.25 Mb, 97.8 Mb, 100.3 Mb, and 102.5 Mb. Conclusions: HIATL1, HABP4, GABBR2, and PRG-3, are genes in these key regions known to be expressed in brain and involved in synaptic transmission and neuroplasticity. In depth analyses including pos- sible CNVs, and results from deep sequencing of these genes and others to identify causal variants will be presented. P1-279 REST REGULATES DYRK1ATRANSCRIPTION IN A NEGATIVE FEEDBACK LOOP Xiulian Sun, Shandong University, Jinan, China. Background: Dual-specificity tyrosine-(Y)-phosphorylation regulated ki- nase 1A (DYRK1A) has been shown to be involved in learning and memory impairments in Alzheimer’s disease (AD) and Down Syndrome (DS). As a homolog of Drosophila mnb (minibrain) gene, DYRK1A also plays impor- tant roles in neurodevelopment; however, the function and regulatory mech- anism of DYRK1A in neurodevelopment remain elusive. RE1-silencing transcription factor (REST) plays vital roles in neuronal differentiation. Methods: Gene regulation. Post-translational modifications. Results: Here, we found that REST can activate DYRK1A transcription via a neu- ron-restrictive silencer element (NRSE) at bp -833 to -815 of human DYRK1A promoter. The coordinated expression of DYRK1A and REST in mouse brain further supports the cross interaction of DYRK1A and REST during neurodevelopment. Moreover, we showed that DYRK1A dos- age imbalance reduced REST protein stability and transcriptional activity through facilitating ubiquitination and subsequent degradation of REST protein. Conclusions: Therefore, the regulation of DYRK1A by REST in a negative feedback loop suggests that DYRK1A and REST are closely related in neurodevelopment. P1-280 ASSESS THE IMPORTANCE OF THE OBJECTIVE MEMORY DEFICIT IN THE ASSOCIATION OF APOE4 WITH MILD COGNITIVE IMPAIRMENT AND ITS RELATION WITH A FAST-PROGRESSION TO ALZHEIMER’S DISEASE Alberto Marcos, Hospital Cl  ınico San Carlos, Madrid, Spain. Background: Although the association of Mild Cognitive Impairment (MCI) with the presence of the APOE 4 allele has been described, its useful- ness as a marker of evolution is controversial. Our goal was to determine whether in patients with MCI, divided according to their objective memory loss, the presence of the 4 allele could be a marker of rapid progression to Alz- heimer’s disease (AD). Methods: A prospective, longitudinal study was car- ried out in Clinico Hospital, Madrid, Spain from May 2008 to December 2009. We studied 92 patients diagnosed of MCI (according to Petersen criteria). 53 of them fulfilled criteria of objective memory loss according to the California Verbal Learning Test (CVLT). Patients were evaluated periodically to com- plete a period of 20 months or until conversion to AD (NINCS-ADRDA cri- teria). We also included a control group of 40 healthy subjects matched for age and sex. The analysis of APOE genotypes by PCR and subsequent restriction enzyme digestion was performed. Results: In the 92 MCI patients, 37 (43.5%) were carriers of allele 4 vs. 5 (14.7%) control subjects (OR 4.5 95% 1.6 to 12.7). When we analyzed 53 patients with objective memory loss, 28 (57.1%) were carriers of APOE4 compared with 4 controls (15.4%) (OR 7.3 95% CI 2.2 to 24.5). 55 of these patients were followed during 20 months. 60% of all carriers of APOE4 and 58.8% of carriers of APOE4 with memory loss, objectified by the CVLT, progressed to AD. Conclusions: The presence of the APOE 4 allele is more related to the risk of MCI with objective memory loss than the patient’s progression to AD. P1-281 MULTILOCUS GENOTYPE PATTERN AT PICALM, CLU AND APOE GENES IS ASSOCIATED WITH EPISODIC MEMORY IN THE NIA-LOAD/NCRAD STUDY David A. Bennett 1 , Thomas Bird 2 , Bradley Boeve 3 , Ramon Diaz-Arrastia 4 , M. Farlow 5 , Tatiana Foroud 5 , Alison Goate 6 , Neill Graff-Radford 3 , Robert Sweet 7 , Robert Wilson 1 , Richard Mayeux 8 , 1 Rush University Medical Center, Chicago, Illinois, United States; 2 University of Washington, Seattle, Washington, United States; 3 Mayo Clinic, Jacksonville, Florida, United States; 4 University of Texas Southwestern Medical Center, Dallas, Texas, United States; 5 Indiana University School of Medicine, Indianapolis, Indiana, United States; 6 Washington University School of Medicine, St. Louis, Missouri, United States; 7 University of Pittsburgh, Pittsburgh, Pennsylvania, United States; 8 Columbia University, NewYork City, New York, United States. Background: Genomewide association studies (GWAS) have identified new susceptibility genes for Late Onset Alzheimer’s Disease (AD). Addi- tional efforts also confirmed endophenotypes as powerful disease’s surrogates that overcome phenotypic heterogeneity. However, GWAS also revealed very modest effect sizes, reinforcing the multi factorial nature of AD, suggesting that single SNP approaches might be underpowered. We combined several ge- netic variants at different AD susceptibility genes into multi-locus genotype patterns (MLGP) and evaluated their association with memory performance. Methods: We used 2091 AD cases and 2200 non demented individuals of Eu- ropean ancestry from the National Institute on Aging-Late Onset Alzheimer’s Disease Family Study (NIA-LOAD)that were genotyped using Illumina 610- quad platform. All participants completed a battery of cognitive tests and a composite measure of episodic memory was used as cognitive endopheno- type. We tabulated multi-locus genotype patterns using genotypes at CLU, PICALM and APOE genes. Using Generalized Estimating Equations (to ad- just for family structure), we modeled episodic memory as the dependent en- dophenotype, MLGPas a predictor variable and sex, age and education as covariates. Analysis was carried in all subjects and in unaffected subjects only. Results: Two of the CLU and PICALM patterns significantly influenced episodic memory performance. The genotypic pattern TT-GG is a nominally significant genetic risk factor of episodic performance in all subjects (ß¼-0.24, SE ¼ 0.12, p ¼ 0.039) and after excluding AD cases (ß¼-0.32, SE ¼ 0.14, p ¼ 0.021). After adding APOE genotype, the effect of the geno- type pattern TT-GG-e4 increased (ß¼-0.47, SE ¼ 0.19, p ¼ 0.016). The ge- notype pattern CC-AG is a nominally significant predictor of a better episodic performance in all subjects (ß¼ 0.15, SE ¼ 0.06, p ¼ 0.020) and showed a trend to significance in unaffected subjects (ß ¼0.15, SE ¼ 0.08, p ¼ 0.057). After adding APOE, the genotype pattern was no longer signifi- cant associated with episodic performance (ß¼-0.09, 0.10, p ¼ 0.354 in all subjects; ß¼-0.15, SE ¼ 0.14, p ¼ 0.305 after excluding AD cases). However, when we considered e3e3 homozygotes, the genotype pattern CC-AG-e3e3 is significant associated with episodic memory performance in all subjects (ß¼0.27, SE ¼ 0.10, p ¼ 0.005) and unaffected subjects (ß¼0.26, SE ¼ Poster Presentation’s P1 S200