Serum IGF-BP2 strongly moderates age's effect on cognition: a MIMIC analysis.

We have used structural equation models to explicitly distinguish functional status and therefore "dementia-relevant" variance in cognitive task performance (i.e., "δ" for dementia). Our approach is modular and can be directed to other targets. In this analysis, we construct a δ ortholog representing the "cognitive correlates of age" (cAGE). cAGE largely mediates age's effects on dementia severity, as rated by the Clinical Dementia Rating Scale Sum of boxes and has an area under the receiver operating curve = 0.96 for the diagnosis of Alzheimer's Disease versus controls. We then test cAGE's association with serum insulin-like growth factor binding protein 2 (IGF-BP2), which has previously been associated with age-related cognitive changes in animals, and with cortical atrophy in older humans. IGF-BP2's adverse effects on cognition are largely mediated through cAGE, independent of education, ethnicity, gender, depression ratings, serum homocysteine levels, hemoglobin A1c, and apolipoprotein e4 status. This suggests that age-specific cognitive decline may be moderated by IGF-BP2 and that modulation of that protein's function(s) might ameliorate age-specific cognitive impairments.