Over the reporting period for the last year, we have published on the relationships between recently identified novel AD risk genes and measures of brain function, pathology and the age-at-onset (AAO) of AD. While we previously reported on the association between plasma concentration of clusterin (or apolipoprotein-J;apoJ) and measures of AD pathology, we recently examined the relationship between the AD risk variant clusterin gene (CLU) and longitudinal changes in brain function during aging. This analysis was performed in the neuroimaging substudy of the BLSA (BLSA-NI) and used resting state cerebral blood flow (rCBF) to measure longitudinal changes in brain function. We showed that even non-demented older individuals who carry one or more of the AD-related risk alleles of CLU show significantly greater increments in rCBF within memory circuits of the brain in comparison to risk allele non-carriers. Similarly, while we have previously reported on the association between plasma concentrations of several complement-related proteins and AD pathology, we recently studied the effect of the AD risk variant, Complement Receptor-1 (CR1) gene on brain amyloid deposition in non-demented older individuals within the BLSA-NI. We showed, somewhat unexpectedly, that risk allele carriers of CR1 actually show lower brain amyloid burden relative to non-carriers. Equally importantly, we reported that an interaction between the CR1 and APOE genes modulates brain amyloid burden. These findings are important in drawing attention to alternate, non-amyloid pathways underlying risk for AD, such as neuroinflammation as well as the need to study gene x gene interactions to gain a better understanding of such mechanisms. Using data collected by the National Alzheimers Disease Coordinating Center and available through NIAGADS, we examined whether any of the novel AD risk genes influence the AAO of AD. This phenotype is believed to have a heritability that is distinct from disease risk. It is also important to study in the context of strategies to delay the onset of AD. We showed that the novel AD risk variant PICALM exerts a small effect on the AAO, with risk allele carriers showing a lower age at onset of AD. In other studies, we showed that insulin resistance (IR) is not related to the extent of AD pathology in non-demented individuals and that midlife IR is associated with longitudinal changes in brain function during aging. In our biomarker studies, we have applied novel technology such as human protein microarrays and Antibody Array Interaction Mapping (AAIM) to identify novel protein biomarkers and protein x protein interactions associated with AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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National Institute on Aging
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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
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
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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