[S30.001] Alzheimer's Disease Risk Alleles in PCDH11X and SORL1 Are Associated with the Rate of Cognitive Decline in Subjects with Multiple Sclerosis

Zongqi Xia, Lori B. Chibnik, Joshua M. Shulman, Boston, MA, Cristin Aubin, Cambridge, MA, Dong Tran, Boston, MA, Bonnie I. Glanz, Brookline, MA, Charles R. G. Guttmann, Samia Khoury, Tanuja Chitnis, Howard L. Weiner, Philip L. De Jager, Boston, MA

OBJECTIVE: To examine whether candidate single nucleotide polymorphisms (SNPs) associated with Alzheimer's Disease influence the rate of decline in brain volume and cognitive function in multiple sclerosis (MS). BACKGROUND: Several independent genome-wide association studies (GWAS) have identified genetic variants associated with susceptibility to late-onset sporadic Alzheimer Disease (AD) in the PCDH11X, PICALM, CLU, SORL1, and CR1 loci. DESIGN/METHODS: Participants from Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) were genotyped for candidate SNPs. Brain volume was assessed using the Brain Parenchymal Fraction (BPF) measurements obtained from MRI studies and cognitive function was examined using the Symbol Digit Modalities Test (SDMT) over yearly intervals. Genotype and the cross-sectional outcome of brain volume and cognition at baseline were correlated using ANCOVAs, whereas linear mixed models were used to correlate genotype and the rate of change in brain volume and cognition over time. All models were adjusted for age and sex. RESULTS: 275 MS patients were genotyped with a mean (SD) age at enrollment of 45 (10) years and a mean (SD) time of follow-up of 16.4 (10.6) months. No significant difference in baseline BPF or SDMT was detected for the candidate SNPs. AD risk alleles in the PCDH11X (rs6656401, =-0.19, 95% CI [-0.30, -0.07], P=0.0017) and SORL1 (rs1010159, =-0.18, 95% CI [-0.35, -0.01], P=0.0356) loci are associated with a faster rate of decline in SDMT when compared to the reference alleles. CONCLUSIONS/RELEVANCE: Our study provides suggestive evidence for an accelerated rate of cognitive decline in individuals with MS bearing PCDH11X and SORL1 variants, yielding new insights into the neurodegenerative component of MS. Supported by: Grants from NIH and NMSS.
Category - MS and Related Diseases - Clinical Science

Wednesday, April 14, 2010 2:00 PM

Scientific Sessions: Multiple Sclerosis: Genetics and Human Immunopathogenesis (2:00 PM-4:00 PM)