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Systems Genomics to Dissect the Metabolic Components of Alzheimer’s Disease


Alzheimer’s disease (AD) is a chronic neurodegenerative disease that accounts for most cases of dementia. Progressive neuronal atrophy and the decline of cognitive function observed in AD results from the accumulation of extracellular amyloid-β (Aβ) and intraneuronal aggregates of hyperphosphorylated tau. Emerging evidence supports the importance of metabolic dysregulation in AD, but the underlying mechanisms and connections between metabolism and Aβ accumulation remain elusive. We conducted a two-part study to dissect the metabolic components of AD. In a human study, we investigated the shared genetically perturbed pathways between AD and type 2 diabetes (T2D) via the integration of human genome-wide association studies, tissue-specific regulation of gene expression, and network modeling. We found shared gene networks between AD and T2D involved in lipid metabolism, insulin receptor signaling, adaptive immunity, complement cascade, cell cycle, PPAR signaling, and extracellular matrix. We further pinpointed key regulators of the shared networks such as SLC15A3, NCKAP1L, FERMT3, FN1, and EMR1. In a mouse study, we investigated the cell type-specific transcriptome changes of the hippocampus and hypothalamus in the 5XFAD model under metabolic modulation via dietary challenges, namely fructose, docosahexaenoic acid (DHA), and nicotinamide riboside (NR). We identified robust cell type-specific responses to disease state in the 5XFAD model including increased expression of proteolytic and lipid transport genes which act to compensate for amyloidosis. Fructose was found to reverse these transcriptional signatures, likely impairing amyloid clearance mechanisms, which was rescued by DHA and NR. Lastly, based on the genetically informed disease subnetworks, we predict PPARγ agonists and androgen receptor agonists to be possible drugs in the prevention of AD, and based on transcriptional profiles in 5XFAD, we predict phensuximde and tankyrase inhibitors to neutralize the deleterious effects of amyloidosis.

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