Background There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. Methods and findings We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's

Objectives To assess the prevalence and changes over time of ideal Life’s Simple Seven (LSS) in African-Americans. Methods Prospective cohort of 5301 African-Americans from the Jackson Heart Study (JHS) from 2000 to 2013. Each of the LSS metrics was categorized as poor, intermediate, or ideal. Results Among men, the prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal LSS was 3.3%, 23.0%, 33.5%, 24.7%, 11.6%, 3.6%, 0.3%, and 0%, respectively. Corresponding values for women were 1.7%, 26.3%, 33.1%, 22.8%, 11.9%, 3.7%, 0.6%, and 0%. Prevalence of ideal diet was 0.9%. The proportions of those meeting LSS ideal recommendations for cholesterol and fasting glucose declined from the first through third JHS visits across all age groups, whereas prevalence of ideal BMI declined only in participants <40 years at a given visit. Prevalence of ideal blood pressure did not change over time and being ideal on physical activity improved from the first [18.3% (95% CI: 17.3% to 19.3%)] to third visit [24.8% (95% CI: 23.3% to 26.3%)]. Conclusions Our data show a low prevalence of ideal LSS (especially diet, physical activity, and obesity) in the JHS and a slight improvement in adherence to physical activity recommendations over time.

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The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.