Understanding mechanisms and seeking novel biomarkers in Alzheimer's disease

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Over the reporting period for the last year, we have published on the relationships between genetic risk for obesity associated with a common variant in the FTO gene and several intermediate phenotypes such as impulsivity, dietary patterns and brain function during aging. Understanding the pleiotropic effects of genetic risk underlying obesity is critical if we are to develop behavioral interventions targeting life-style related risk factors such as obesity. We have examined the relationships between midlife obesity and the age-at-onset of AD as well as its relationship with AD pathology. We report, for the first time that midlife obesity accelerates the onset of AD and worsens AD neuropathology in the brain. We have studied both state (i.e. serum vitamin-D concentrations) and trait (i.e. genetic variations in the gene encoding vitamin-D binding protein, DBP) as modulators of brain function and structure during aging. In our biomarker studies, we have reported on the depletion of three phosphatidylcholine (PC) molecules in the plasma of patients with Alzheimer's disease (AD). We have subsequently extended these findings to test their association with cognitive performance in non-demented older individuals as well as with brain function (measured by resting state cerebral blood flow; rCBF). We have shown that a decrease in plasma concentrations of these PCs is also associated with lower cognitive performance during aging as well as with reduction in rCBF/brain function in several brain regions associated with higher order cognitive processing. Our findings suggest that perturbations in peripheral PC metabolism may be a common feature of both AD as well as age-associated cognitive performance. We have completed one of the largest blood biomarker studies of preclinical AD using metabolomics analyses of serum. Here, we analyzed nearly 800 serial serum samples collected through the Baltimore Longitudinal Study of Aging (BLSA) and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). We also used a multi-platform metabolomics approach using mass spectrometry and nuclear magnetic resonance to discover cerebrospinal fluid biomarkers in AD. Using high-density human protein arrays, we are investigating changes in serum autoimmune signatures as biomarkers of preclinical AD. Both targeted and global metabolomics as well as tandem mass tagging (TMT)-proteomics methods are currently being used to investigate the molecular bases of cognitive resilience to AD pathology in autopsy-derived brain tissue samples.