Role of INPP5D, PTK2B, ZCWPW1 and TREM 2 in Predicting Risk of Progression in Cognitively Impaired Subjects to Alzheimer's Disease (P5.166)

Objective: To examine the correlation between four risk loci and clinical progression to Alzheimer9s Disease. Background: Recent genome-wide association studies have identified several new genetic risk loci for Alzheimer9s Disease (AD), including INPP5D (rs35349669), PTK2B (rs28834970), ZCWPW1 (rs1476679) and TREM2 (rs75932628). Their utility in predicting outcome of patients with cognitive impairment has not been examined. We used two large Canadian cohorts to study the role of these genes in predicting the outcome of patients with cognitive impairment. Methods: In the current analysis, we compared genotype frequency in cognitively stable patients diagnosed as not cognitively impaired (NCI) or cognitively impaired no dementia (CIND) but never declined over the duration of study, to those who progressed to AD. Single nucleotide polymorphisms genotypes for INPP5D, PTK2B, ZCWPW1 and TREM 2 were obtained using TaqMan assays. Genotype frequencies were examined with chi-square tests, and odds ratios were calculated by multivariate logistic regression with age, sex, education, and APOE e4 status as covariates. Results: Within the 2 cohorts, 401 subjects who remained cognitively normal until at the end of the cohort study were used as controls, while 348 diagnosed with AD were cases. Of the 4 SNPs examined in this study, only PTK2B was significant (p=0.042). When we compared the genotypic frequencies between subjects with CIND who remained stable vs. those who progressed to AD (n=134), the significance is even stronger (p<0.001), with an O.R. of 1.75 (95[percnt] C.I 1.13-2.71), which remains constant after adjustment with age, sex, and APOE e4 carrier status. Conclusions: We found that only the PTK2B risk allele was significantly associated with progression from cognitive impairment, which is independent from the effect of age and APOE genotype. These findings contribute to our understanding of the pathogenesis of AD, which may help develop potential novel biomarkers and therapeutic targets. Disclosure: Dr. Hawkins has nothing to disclose. Dr. Fok has nothing to disclose. Dr. Feldman has received personal compensation for activities with Merck, Eli Lilly and Arena and Eisai and Genentech Banne as a member of safety and diagnostic monitoring committees. Dr. Sadovnick has received personal compensation for activities with Biogen Idec, Merck Serono, Teva Neuroscience, and Bayer Pharmaceuticals Corp as a speaker. Dr. Hsiung has received research support from Baxter, Bristol-Myers Squibb, TauRx, Elan, and GlaxoSmithKline.