Abstract. Obesity and overweight, well known risk factors for cardiovascular disease and type 2 diabetes, are now associated with Alzheimer's disease (AD). It remains to be determined if obesity and overweight contribute to the risk of developing AD through modulating levels of amyloid-beta (Aβ), a key molecule in AD pathogenesis. Thus, we investigated whether there were any associations between plasma Aβ levels and body mass index (BMI) or fat mass (FM) in a group of 18 healthy adults. A statistically significant correlation was found between BMI, FM, and plasma levels of Aβ42 (BMI r = 0.602, P = 0.008; FM r = 0.547, P = 0.019), the longer, more pathogenic form of Aβ, but not with plasma levels of the shorter, less pathogenic Aβ40. Although not significant, positive correlations between plasma levels of Aβ42 and levels of insulin and the inflammatory marker C-reactive protein (CRP), along with an inverse trend between plasma Aβ42 levels and levels of high density lipoprotein (HDL) were answered. These results suggest that proteins implicated in inflammation, cardiovascular disease and type 2 diabetes, which in turn are risk factors for AD, may contribute to the associations between BMI/FM and plasma Aβ42 levels. Longitudinal studies involving larger cohorts are required to determine if elevated body fat may predispose individuals to AD through increasing Aβ42 levels throughout early to late adulthood.

BackgroundInflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases.MethodsGenotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE ε4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases.ResultsAPOE ε4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE ε4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases.ConclusionThese findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.