Complexes of beta-amyloid peptides and of intracellular proteins in cerebrospinal fluid: New biomarkers of Alzheimer's disease?

Abstract

Background: Insulin resistance, as seen in type 2 diabetes, has been shown to increase the risk of late onset Alzheimer’s Disease (AD) by as much as two-fold. In AD patients, characteristic findings are seen with structural magnetic resonance imaging (MRI) including global atrophy as well as regional reductions in gray matter volume (GMV) in the hippocampus, precuneus, posterior cingulate gyrus, parietotemporal, prefrontal, and orbitofrontal cortices. Additionally, negative correlations between peripheral insulin levels and regional GMV are seen in insulin resistant subjects in the middle temporal gyrus.The current study investigated whether elevated fasting glucose (FSG) levels were associated with lower GMV in brain areas that have been preferentially affected by AD. This association difference was further investigated between carrier and non-carrier (NC) groups of the apolipoprotein E (APOE) e4 allele, a genetic risk factor for late onset AD. Methods: Statistical Parametric Mapping (SPM), an automated brain imaging analysis computer package, was used to spatially normalize individual brains to a standard brain template, to obtain GMV maps from structural MRI, and to examine the correlations between higher FSG levels and lower structural MRI GMV measurements in 118 cognitively normal, non-diabetic individuals 6466 years of age (59e4 carriers and 59 NCs). A significance threshold of p 1⁄4 .005 was set for all imaging related analyses. Results: As predicted, significant correlations were seen between higher levels of FSG and lower GMV in AD-affected regions including the left inferior orbitofrontal cortex, parietal, and occipital lobes and the left and right frontal and temporal lobes. Negative correlations between FSG and regional GMV in the middle temporal gyri confirmed findings seen in insulin resistant subjects. Additionally, these associations in AD-related areas are seen in both carriers and NC. Conclusions: Higher FSG levels in cognitively normal, non-diabetic, older adults are associated with lower GMV in AD related brain areas, confirming that elevated FSG may be associated with AD risk, independent of APOEe4 status. Lastly, this study encourages the consideration of elevated FSG and other indicators of glucose control as targets for AD prevention trials, complementing the findings previously established with fluorodeoxyglucose positron emission tomography neuroimaging.