Body-wide changes in bioenergetics, i.e., energy metabolism, occur in normal aging and disturbed bioenergetics may be an important contributing mechanism underlying late-onset Alzheimer's disease (LOAD). We investigated the bioenergetic profiles of fibroblasts from LOAD patients and healthy controls, as a function of age and disease. LOAD cells exhibited an impaired mitochondrial metabolic potential and an abnormal redox potential, associated with reduced nicotinamide adenine dinucleotide metabolism and altered citric acid cycle activity, but not with disease-specific changes in mitochondrial mass, production of reactive oxygen species, transmembrane instability, or DNA deletions. LOAD fibroblasts demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to IGF-1. The increase of glycolysis and the abnormal mitochondrial metabolic potential in LOAD appeared to be inherent, as they were disease-and not age-specific. Our findings support the hypothesis that impairment in multiple interacting components of bioenergetic metabolism may be a key mechanism contributing to the risk and pathophysiology of LOAD.Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by slow progressive deterioration and death of neurons. A number of interacting factors determine the risk of AD and among the better-studied pathophysiologic pathways, the "amyloid cascade hypothesis" proposes that AD is precipitated by an accumulation of Aβ-containing plaques and tangles of hyperphosphorylated tau (p-tau) 1-3 . This hypothesis is best supported for familial/early-onset forms of AD (EOAD), while less so for the more common sporadic/ late-onset forms (LOAD) 4,5 . In LOAD, accumulation of toxic Aβ and p-tau may not be the initial cause of neural degeneration and may instead be consequences of other causative factors 5,6 . Changes in bioenergetics, i.e., energy metabolism, are part of the normal aging process and disturbed bioenergetics may be a contributing mechanism underlying LOAD 7-10 . These anomalies are body-wide, but affect the brain most substantially because of its exceptionally high-energy requirements. Thus, changes of bioenergetics and metabolism could be at the core of determining the survival capacities of brain cells with age and under stress, with these processes influenced, in turn, by genetic predisposition, epigenetics, environment, and lifestyle.Bioenergetics is the metabolism of various fuel molecules to produce and utilize energy through glycolysis, mitochondrial respiration, that is, oxidative phosphorylation (OxPhos), or the pentose phosphate pathway (PPP). Healthy eukaryotic cells produce ATP about 12% through glycolysis and 88% through OxPhos, on average. In the 1920s, German physician-chemist Otto Warburg discovered that mammalian cancer cells can switch from OxPhos to glycolysis when exposed to low oxygen, called the "Warburg effect" 11 . Unlike proliferating cells, post-mitotic neurons have very little ability to use glycolysis, a...

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer’s disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a “multi-hit” disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

Sporadic or late-onset Alzheimer’s disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.