Identification of an Inherent Bioenergetic and Metabolic Phenotype in Late-Onset Alzheimer’s Disease ^†

Abstract

The pathology of late-onset Alzheimer’s disease (LOAD) is still poorly understood, but it is multifactorial and closely related to changes with aging. We developed a cellular platform for collecting skin fibroblasts or blood cells from LOAD patients and non-demented control individuals, which are then used in an induced pluripotent stem cell (iPSC) paradigm to produce brain cells for determining LOAD pathogenic processes in the context of age, disease, genetic background, cell development, and cell type. This model has provided evidence for an innate inefficient cellular energy management in LOAD that is associated with alterations of cellular transcriptomes and lipid compositions, and interconnected cause-and-effect linkages, such as impaired insulin/IGF-1 signaling, bioenergetic substrate deficiencies, diminished glucose metabolism, and disruption of autophagic flux, among others. In addition, a testing of compounds revealed some restoration of these altered bioenergetic and metabolic processes in LOAD cells. Altogether, our studies have identified an inherent LOAD-associated cellular metabolic phenotype as a potential risk factor for developing neurodegenerative diseases with aging. We propose that our cellular model allows for patient-oriented examination of numerous mechanisms and interactions in LOAD pathogenesis, which can be used as a basis for a personalized medicine approach to predict altered aging and risk of developing dementia, and to test or implement (customized) therapeutic or disease-preventive intervention strategies.