title: Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults.
abstract: BACKGROUND
  Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample.
  
  
  METHODS
  We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models.
  
  
  RESULTS
  In genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=-0.16, p=5.1×10(-6), false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=-0.16, p=5.1×10(-6), q=0.003; and beta=-0.13, p=5.5×10(-5), q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype.
  
  
  CONCLUSIONS
  We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.
authors.affiliation: Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Bradley-Smith
authors.forename: David J
authors.initials: DJ
authors.lastname: Llewellyn
authors.forename: Luke C
authors.initials: LC
authors.lastname: Pilling
authors.forename: Alexander
authors.initials: A
authors.lastname: Fellows
authors.forename: William
authors.initials: W
authors.lastname: Henley
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Jack M
authors.initials: JM
authors.lastname: Guralnik
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: David
authors.initials: D
authors.lastname: Melzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D003071:Cognition; D003072:Cognition Disorders / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: D001057:Apolipoproteins E; C515334:CCR2 protein, human; D054390:Receptors, CCR2