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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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
Whiley, Luke; Sen, Arundhuti; Heaton, James et al. (2014) Evidence of altered phosphatidylcholine metabolism in Alzheimer's disease. Neurobiol Aging 35:271-8
Hales, Chadwick M; Seyfried, Nicholas T; Dammer, Eric B et al. (2014) U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21. Mol Neurodegener 9:15
Thambisetty, Madhav; Ferrucci, Luigi (2014) Soluble interleukin-6 receptor levels and risk of dementia: one more signpost on a long road ahead. J Am Geriatr Soc 62:772-4
Thambisetty, Madhav; Beason-Held, Lori L; An, Yang et al. (2013) Alzheimer risk variant CLU and brain function during aging. Biol Psychiatry 73:399-405
Thambisetty, Madhav; Beason-Held, Lori L; An, Yang et al. (2013) Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging. Neurobiol Aging 34:2271-6
Thambisetty, Madhav; An, Yang; Tanaka, Toshiko (2013) Alzheimer's disease risk genes and the age-at-onset phenotype. Neurobiol Aging 34:2696.e1-5
Thambisetty, Madhav; Jeffrey Metter, E; Yang, An et al. (2013) Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol 70:1167-72