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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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An, Yang; Varma, Vijay R; Varma, Sudhir et al. (2018) Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimers Dement 14:318-329
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Hohman, Timothy J; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol 75:989-998
Varma, Vijay R; Oommen, Anup M; Varma, Sudhir et al. (2018) Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study. PLoS Med 15:e1002482
Seddighi, Sahba; Varma, Vijay R; An, Yang et al. (2018) SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. J Alzheimers Dis 61:401-414
Shi, Liu; Baird, Alison L; Westwood, Sarah et al. (2018) A Decade of Blood Biomarkers for Alzheimer's Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. J Alzheimers Dis 62:1181-1198
Wong, Dean F; Comley, Robert A; Kuwabara, Hiroto et al. (2018) Characterization of 3 Novel Tau Radiopharmaceuticals, 11C-RO-963, 11C-RO-643, and 18F-RO-948, in Healthy Controls and in Alzheimer Subjects. J Nucl Med 59:1869-1876
Seddighi, Sahba; Varma, Vijay; Thambisetty, Madhav (2018) ?2-macroglobulin in Alzheimer's disease: new roles for an old chaperone. Biomark Med 12:311-314
Kueider, Alexandra M; An, Yang; Tanaka, Toshiko et al. (2017) Sex-Dependent Associations of Serum Uric Acid with Brain Function During Aging. J Alzheimers Dis 60:699-706
Toledo, Jon B; Arnold, Matthias; Kastenmüller, Gabi et al. (2017) Metabolic network failures in Alzheimer's disease: A biochemical road map. Alzheimers Dement 13:965-984

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