A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis.

Brain atrophy and cognitive dysfunction are neurodegenerative features of Multiple Sclerosis (MS). We used a candidate gene approach to address whether genetic variants implicated in susceptibility to late onset Alzheimer's Disease (AD) influence brain volume and cognition in MS patients. MS subjects were genotyped for five single nucleotide polymorphisms (snps) associated with susceptibility to AD: PICALM, CR1, CLU, PCK1, and ZNF224. We assessed brain volume using Brain Parenchymal Fraction (BPF) measurements obtained from Magnetic Resonance Imaging (MRI) data and cognitive function using the Symbol Digit Modalities Test (SDMT). Genotypes were correlated with cross-sectional BPF and SDMT scores using linear regression after adjusting for sex, age at symptom onset, and disease duration. 722 MS patients with a mean (±SD) age at enrollment of 41 (±10) years were followed for 44 (±28) months. The AD risk-associated allele of a non-synonymous SNP in the PCK1 locus (rs8192708G) is associated with a smaller average brain volume (P=0.0047) at the baseline MRI, but it does not impact our baseline estimate of cognition. PCK1 is additionally associated with higher baseline T2-hyperintense lesion volume (P=0.0088). Finally, we provide technical validation of our observation in a subset of 641 subjects that have more than one MRI study, demonstrating the same association between PCK1 and smaller average brain volume (P=0.0089) at the last MRI visit. Our study provides suggestive evidence for greater brain atrophy in MS patients bearing the PCK1 allele associated with AD-susceptibility, yielding new insights into potentially shared neurodegenerative process between MS and late onset AD.