Peripheral versus Central Index ofMetabolic Dysfunction and Associations with Clinical and Pathological Outcomes inAlzheimer's Disease.

Abstract

Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimer's disease (AD) diagnosis. IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional grey matter and glucose metabolism associations. Each point increase in IGFBP-2 corresponded to a three times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex. IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers.