Abstract
Motoric cognitive risk (MCR) syndrome is a newly described predementia syndrome characterized by the presence of cognitive complaints and slow gait, which is associated with increased risk of conversion to dementia. The underlying biological mechanisms for MCR have not yet been established. Neuroinflammation mediated through cytokines plays a pivotal role in the pathogenesis of dementia. Hence, our objective was to prospectively examine whether variations in cytokine genes (CRP, IFNG, IL1A, IL1B, IL4, IL6, IL10, IL18, TNF, and IL12A) play a role in MCR incidence in 530 community-dwelling Ashkenazi Jewish adults aged 65 years and older without MCR or dementia at baseline enrolled in the LonGenity study. Over a median follow-up of 2.99 years, 70 participants developed MCR. Single nucleotide polymorphisms (SNPs) in the transcriptional regulatory regions of cytokine IL10, rs1800896 (hazard ratio adjusted for age, gender, and education, aHR: 1.667; 95% CI: 1.198-2.321) and rs3024498 (aHR: 1.926; 95% CI: 1.315-2.822), were associated with incident MCR. Functional analysis using in silico approaches indicated associated SNP rs3024498 "C" allele being the local expression quantitative trait locus. Associated alleles of both the SNPs, rs1800896 and rs3024498, were implicated with overexpression of IL10 gene. None of the variants in the neuroinflammatory pathway studied were associated with incident mild cognitive impairment syndrome. These observations support a role for the IL10 gene in dementia pathogenesis by increasing risk of developing MCR in older adults.