During the past four years of this funding cycle we have identified a unique minority cohort of 549 families of aribbean Hispanic ancestry multiply affected with Alzheimer's disease (AD), we have established a DNA and cell bank repository at our institution, completed two genome wide linkage scans, reported several genotyping projects and identified and confirmed that inherited genetic variants in the receptor for sortilin, SORL1, predisposes to AD. The over arching goal for the continuation of this project is continue our efforts to dentify genetic variants that increase the risk of AD and to further characterize and define the genetic defect n SORL1. To accomplish these goals, we will first identify genetic variants that alter neuronal expression of SORL1 protein in brain and conduct deep sequencing of the entire SORL1 gene. We will conduct fine linkage mapping of loci identified in the initial genome wide linkage scan in the first 210 families. Next, we will analyze data from a whole genome wide association study (GWAS) in progress that includes a cohort of 895 patients with AD (probands from this study and sporadic Caribbean Hispanic cases from the Washington Heights Inwood study) and 327 controls from the community to identify new loci and to provide finer genetic mapping of previously identified loci. We will continue to follow-up and expand the entire cohort of existing amilies to confirm diagnoses, assess progression, discuss autopsy permission, re-examine those at risk and adding phenotypic information. We will recuit an addition 100 families and establish a case-control cohort of aribbean Hispanics consisting of 750 patients with AD and 750 controls similar in age and sex to both for replication and aumentaiton of gene discovery. This will allow us to expand our capacity to identify new gene: or confirm any candidate genes from the fine mapping efforts in the independent Caribbean Hispanic families n a replication series of adequate size. Further we will continue to make cells lines and clinical information available to others through the National Cell Repository for Alzheimer's Disease. We will prioritize genes for detailed analysis based high density genotyping and resequencing and by using assays that identify alterations in the production or processing of the amyloid precursor protien or related proteins. Our work plan is divided into three areas: 1) characterization of SORL1 gene including neuronal expression and sequencing 2) fine mapping of existing loci and analysis of the GWAS in progress to guide future gene mapping;3] extensive deep phenotyping by follow-up of the cohort of families, and the ascertainment, clinica assessments and diagnostic criteria for the case-control series to be recruited. Our work over the pas funding cycle has allowed us to reach a critical step in understanding the complete genetics of AD. We believe that the investigation of this unique ethnic group with relatively few founders represents an unprecidented opportunity to identify and characterize genetic variants that increase the risk of AD.