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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000200-01
Application #
8736492
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2013
Total Cost
$507,529
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Gupta, Veer Bala; Doecke, James D; Hone, Eugene et al. (2016) Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging. Alzheimers Dement (Amst) 3:18-26
Goodman, Richard A; Lochner, Kimberly A; Thambisetty, Madhav et al. (2016) Prevalence of dementia subtypes in U.S. Medicare fee-for-service beneficiaries, 2011-2013. Alzheimers Dement :
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Wennberg, Alexandra M V; Spira, Adam P; Pettigrew, Corinne et al. (2016) Blood glucose levels and cortical thinning in cognitively normal, middle-aged adults. J Neurol Sci 365:89-95
Casanova, Ramon; Varma, Sudhir; Simpson, Brittany et al. (2016) Blood metabolite markers of preclinical Alzheimer's disease in two longitudinally followed cohorts of older individuals. Alzheimers Dement 12:815-22
Henderson, Benjamin W; Gentry, Erik G; Rush, Travis et al. (2016) Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid-β levels in brain. J Neurochem 138:525-31
Westwood, Sarah; Leoni, Emanuela; Hye, Abdul et al. (2016) Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly. J Alzheimers Dis 52:561-72
Chuang, Y-F; Tanaka, T; Beason-Held, L L et al. (2015) FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet. Mol Psychiatry 20:133-39
Ebshiana, Amera A; Snowden, Stuart G; Thambisetty, Madhav et al. (2015) Metabolomic method: UPLC-q-ToF polar and non-polar metabolites in the healthy rat cerebellum using an in-vial dual extraction. PLoS One 10:e0122883

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