Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults

Abstract

Introduction: 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.

FIG. 1.

Quantile–quantile (Q-Q) plots for gene expression analysis of Mini-Mental State Examination (MMSE) score at RNA collection. (A) The Q-Q plot for the genome-wide analysis of MMSE at RNA collection is shown. The actual p values (−log₁₀) obtained are given on the y axis, plotted against expected p values (−log₁₀) given on the x axis. This graph shows potential deviations to the p value distribution that might be expected by chance. (B) The Q-Q plot for the focused analysis of inflammatory genes is shown. The actual p values (−log₁₀) obtained are given on the y axis, plotted against expected p values (−log₁₀) given on the x axis. This graph shows potential deviations to the p value distribution that might be expected by chance. The positive association with the CCR2 transcript is evident in both plots.

FIG. 2.

Box plot of CCR2 expression by Mini-Mental State Examination (MMSE) score at RNA collection. The box plot shows CCR2 transcript expression levels (relative units) as plotted on the y axis by MMSE score RNA collection on the x axis.

FIG. 3.

Cubic Spline plots for linearity of association between CCR2 expression and Mini-Mental State Examination (MMSE). (A) CCR2 expression and MMSE at RNA collection. (B) CCR2 expression and delta-MMSE over the preceding 9 years. These penalized cubic regression splines visualize the fitted (adjusted) relationship between CCR2 gene expression and MMSE score, and separately with change in MMSE over 9 years. The relationships are approximately linear after normalization (log-transformed expression data) and adjustment for multiple confounders.