title: Interleukin-6, interleukin-6 receptor gene variant, small-vessel disease and incident dementia.
abstract: OBJECTIVE
  Mixed neurogenerative and vascular dementia has emerged as the leading cause of dementia in the elderly. Inflammation is implicated in atherosclerosis, cerebral small-vessel disease (SVD) as well as cognitive impairment. However, longitudinal data on the predictive value of circulating inflammatory markers including gene variants and magnetic resonance imaging (MRI) findings in incident dementia are scarce. It was investigated whether circulating interleukin-6 (IL-6), C-reactive protein (CRP) and gene variants increase dementia risk.
  
  
  METHODS
  In a cohort of Japanese participants with vascular risk factors in an observational study from 2001, the association between baseline IL-6, CRP levels, gene variants [interleukin-6 receptor (IL-6R), rs2228145; IL-6, rs2097677; CRP, rs3093059] and incident all-cause dementia was evaluated. Baseline MRI was used to determine SVD (lacuna, white matter hyperintensities) and atrophy (medial-temporal lobe atrophy, bicaudate ratio). Cox proportional hazards analyses were performed for predictors of dementia, adjusting for age, sex, apolipoprotein Eε4, education, cerebrovascular events, vascular risk factors and MRI findings.
  
  
  RESULTS
  Of 803 subjects (mean 67.0 ± 8.5 years, males 59%), during a mean of 7.5 ± 3.2 years follow-up, 60 incident dementia patients (Alzheimer's disease 31; vascular dementia 17; mixed-type six; other six) were diagnosed. In multivariable analyses adjusted for age, sex, cerebrovascular events, MRI findings and IL-6R variant (rs2228145), IL-6 levels (relative risk 1.68, P = 0.048) or highest tertile (relative risk 2.38, P = 0.031) for all-cause dementia remained significant. Although subjects with rs2228145 carrier had significantly higher IL-6 levels, a significant association between rs2228145 and dementia was not observed. Conversely, CRP and remaining gene variants were not associated with dementia.
  
  
  CONCLUSIONS
  The deleterious effect of higher IL-6 on dementia remains consistent irrespective of conventional risk factors, MRI findings and IL-6R variant.
authors.affiliation: Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miwa
authors.affiliation: Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kitagawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D059345:Cerebral Small Vessel Diseases / Q000097:blood* / Q000235:genetics; D003704:Dementia / Q000097:blood* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000235:genetics*
chemical_list: C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6
keywords: C-reactive protein; IL-6; IL-6R; dementia; genetic variants; prospective study; single nucleotide polymorphism; small-vessel disease