Dysfunctional Cellular Energy Metabolism is a Premorbid Characteristic of Late-Onset Alzheimer’s disease

Age is the main risk factor for late-onset Alzheimer’s disease (LOAD) and all processes in normal aging also occur in LOAD pathology. While some factors appear to be more specific to LOAD and may be genetically determined, others are acquired through the aging process. Because bioenergetic metabolism is among the most fundamental features of cell functions, changes thereof have profound effects on every aspect of aging. In both fibroblasts and induced pluripotent stem cell (iPSC)-derived immature and mature brain cells of subjects with LOAD, we observed bioenergetic substrate deficiencies, including reductions in the redox agent nicotinamide adenine dinucleotide (NAD) or glucose uptake and metabolism, and alterations of associated bioenergetic-dependent cell functions. These data suggest that dysfunctional bioenergetics is an inherent cell-specific and cell-autonomous risk factor in LOAD. Together with findings from the brains of normally aging individuals or patients with LOAD, our data support the view that in LOAD, inherent cell-metabolic dysfunctions may occur in development and early life, altering the trajectory of the normal aging process in youth and middle-age, and predisposing neuropathological events that lead to symptomatic features of LOAD later in life. Our studies seek to further identify and characterize the cellular mechanisms underlying LOAD-associated bioenergetic abnormalities. The results of these studies may reveal targets and methods for treating individuals at risk for LOAD before illness develops or delaying disease onset and progression later in life.