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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Goodman, Richard A; Lochner, Kimberly A; Thambisetty, Madhav et al. (2017) Prevalence of dementia subtypes in United States Medicare fee-for-service beneficiaries, 2011-2013. Alzheimers Dement 13:28-37
Wong, Matthew W; Braidy, Nady; Poljak, Anne et al. (2017) Dysregulation of lipids in Alzheimer's disease and their role as potential biomarkers. Alzheimers Dement 13:810-827
Thambisetty, Madhav; Casanova, Ramon; Varma, Sudhir et al. (2017) Peril beyond the winner's curse: A small sample size is the bane of biomarker discovery. Alzheimers Dement 13:606-607
Thambisetty, Madhav (2017) Understanding mechanisms and seeking cures for Alzheimer's disease: Why we must be ""extraordinarily diverse"". Am J Physiol Cell Physiol :ajpcell.00111.2017
Seyfried, Nicholas T; Dammer, Eric B; Swarup, Vivek et al. (2017) A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease. Cell Syst 4:60-72.e4
Varma, V R; Varma, S; An, Y et al. (2017) Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry 22:13-23
Snowden, Stuart G; Ebshiana, Amera A; Hye, Abdul et al. (2017) Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study. PLoS Med 14:e1002266
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
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
Kueider, Alexandra M; Tanaka, Toshiko; An, Yang et al. (2016) State- and trait-dependent associations of vitamin-D with brain function during aging. Neurobiol Aging 39:38-45

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