CANDIDATE GENES FOR VERY LATE ONSET ALZHEIMERS DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the next several years, genetic research will greatly impact patient care for individuals with Alzheimer's disease (AD), leading to new diagnostic tools and biological interventions to delay or prevent disease onset. Our goal is to identify novel genetic loci that influence the initiation or progression of AD. Toward this end, we evaluated a genome scan of 262 affected sib pairs (ASPs) collected as part of the NIMH AD Genetics Initiative, and included ApoE genotype and age as covariates. We identified two regions with peak lod scores of 5.54 and 4.09, where the oldest ASPs have the highest recurrence risk, and are most likely to share the regions identical-by-descent. These regions are on chromosome 21 near the APP locus (Olson, Goddard & Dudek, 2001), and on chromosome 20p (Olson, Goddard & Dudek, 2002). Our aim is to identify candidate genes in these regions and others as additional candidate regions are identified. We have established collaborations with NIMH, the Oregon Brain and Aging Study (OBAS), and the Aging and Memory Center at CWRU (UMAC) to continue these investigations into the genetics of AD. Recently, we reported evidence of linkage on chromosome 20 for AD using a novel statistical approach to incorporate covariates (e.g., age, ApoE genotype) into the analysis. These results suggest that very elderly subjects (85 years), and individuals who carry an e2 allele at the ApoE locus are more likely to be linked to this candidate region. The region on chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has previously been associated with AD in case-control studies. We investigated these findings further by genotyping additional markers to narrow the candidate region, and to identify evidence of linkage disequilibrium as additional support for a susceptibility locus on chromosome 20 (Goddard et al.2004). We selected 43 elderly sibships (89 subjects) from the NIMH AD Genetics Initiative based on current age older than 84 years, and identified 129 unrelated control subjects who were older than 84 years from the Oregon Brain Aging Study to conduct linkage and association studies in this region. Fourteen additional markers were evaluated, including four markers located within or near CST3. We narrowed the candidate region on chromosome 20 to an 11.8 cM region between markers D20S174 and D20S471, which includes the CST3 candidate gene. In addition, we observed evidence of association for markers located near the CST3 candidate gene, with p-values between 0.002 and 0.08 for two-locus haplotypes. These results support the presence of a susceptibility locus for AD in the vicinity of CST3 for very elderly subjects with AD.