Novel genetic risk factor for Alzheimer's disease progression [abstract]

Researchers at Washington University have identified a novel genetic variant that strongly correlates with disease progression. Dr. Alison Goate and collaborators used an established biomarker for the decline of AD patients (cerebrospinal fluid tau phosphorylated at threonine 181, ptau181) to find genetic variants that influence levels of ptau181 in the cerebrospinal fluid. The study found a highly significant association between ptau181levels and the rs1868402 SNP located within a regulatory subunit of PPP3R1 (calcineurin B), a gene previously linked to AD pathogenesis. Carriers of the rs1868402 risk allele showed a 6-fold faster rate of disease progression than AD patients without the variant. In addition, individuals carrying allele rs1868402 and rs3785883, a second allele identified in the study, showed an even more pronounced rate of decline. Direct examination of brain samples from AD cases and controls revealed that rs1868402is in fact associated with reduced PPP3R1 mRNA levels and increased tangle formation, providing biological validation for the genome-wide association study and further implicating PPP3R1 in disease pathology. rs1868402 showed no association with risk for AD or age at onset, but there was a very significant association with rate of progression of disease that is consistent in two independent series. As the first genetic variant associated with rate of AD progression to be reported, its use in clinical trial design and patient care will translate into a significant benefit to patients. Potential Areas of Applications: * Diagnostic for individuals with rapid decline in Alzheimer's disease * New protein pathway for drug therapies for treating Alzheimer's disease progression Patent Status: Patent pending Inventor(s): Carlos Cruchaga, Alison Goate, David Holtzman Contact Info: Nichole Mercier, [email protected] (314) 747 190

Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease

BACKGROUND: Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. RESULTS: In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD. CONCLUSION: In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD