Understanding mechanisms and seeking novel biomarkers in Alzheimer's disease

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1. We have expanded on our studies testing metabolic perturbations in Alzheimer's disease (AD) to identify distinct abnormalities in brain glucose utilization, phospholipid/fatty acid metabolism, cholesterol/oxysterol biosynthesis as well as polyamine metabolism and transmethylation reactions. 2. We have initiated analyses of real-world prescription datasets to test the hypothesis that drugs targeting abnormal metabolism may alter the risk of incident AD. Our hypothesis is that exposure to one or more of these drugs will protect against AD. This will provide a strong rationale for further confirmation in randomized clinical trials (RCTs). We have secured support from the NIA IRP through special-AD funds for the 'Drug Repurposing for Effective Alzheimers Medicines (DREAM)' study. It aligns well with one of the milestones in the National Alzheimer's Project Act (NAPA) i.e. Initiate research programs for translational bioinformatics and network pharmacology to support rational drug repositioning and combination therapy from discovery through clinical development. 3. While cardiovascular risk factors such as obesity, diabetes and hypercholesterolemia increase the risk of AD, the biological mechanisms underlying metabolic syndrome (MetS) are unclear. Whether these risk factors operate through shared mechanisms in older individuals from diverse environmental, cultural and genetic backgrounds, is also unknown. We have compared associations between serum metabolite profiles and MetS in older individuals from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS) to address this question. Our results suggest that there are both shared and unique blood metabolite signatures associated with MetS in North American and Japanese older individuals. These studies hold promise for the development of personalized treatments targeting abnormal metabolism in diseases such as AD.