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Blood-based mitochondrial bioenergetic profiling is a feasible, economical, and minimally invasive approach that can be used to examine mitochondrial function and energy metabolism in human subjects. In this study, we use 2 complementary respirometric techniques to evaluate mitochondrial bioenergetics in both intact and permeabilized peripheral blood mononuclear cells (PBMCs) and platelets to examine sex dimorphism in mitochondrial function among older adults. Employing equal numbers of PBMCs and platelets to assess mitochondrial bioenergetics, we observe significantly higher respiration rates in female compared to male participants. Mitochondrial bioenergetic differences remain significant after controlling for independent parameters including demographic parameters (age, years of education), and cognitive parameters (mPACC5, COGDX). Our study illustrates that circulating blood cells, immune cells in particular, have distinctly different mitochondrial bioenergetic profiles between females and males. These differences should be taken into account as blood-based bioenergetic profiling is now commonly used to understand the role of mitochondrial bioenergetics in human health and aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Introduction: Despite evidence for systemic mitochondrial dysfunction early in Alzheimer's disease (AD) pathogenesis, reliable approaches monitoring these key bioenergetic alterations are lacking. We used peripheral blood mononuclear cells (PBMCs) and platelets as reporters of mitochondrial function in the context of cognitive impairment and AD., Methods: Mitochondrial function was analyzed using complementary respirometric approaches in intact and permeabilized cells from older adults with normal cognition, mild cognitive impairment (MCI), and dementia due to probable AD. Clinical outcomes included measures of cognitive function and brain morphology., Results: PBMC and platelet bioenergetic parameters were lowest in dementia participants. MCI platelets exhibited higher maximal respiration than normocognitives. PBMC and platelet respiration positively associated with cognitive ability and hippocampal volume, and negatively associated with white matter hyperintensities., Discussion: Our findings indicate blood-based bioenergetic profiling can be used as a minimally invasive approach for measuring systemic bioenergetic differences associated with dementia, and may be used to monitor bioenergetic changes associated with AD risk and progression., Highlights: Peripheral cell bioenergetic alterations accompanied cognitive decline in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD) and related dementia (DEM). Peripheral blood mononuclear cells (PBMC) and platelet glucose-mediated respiration decreased in participants with dementia compared to normocognitive controls (NC). PBMC fatty-acid oxidation (FAO)-mediated respiration progressively declined in MCI and AD compared to NC participants, while platelet FAO-mediated respiration exhibited an inverse-Warburg effect in MCI compared to NC participants. Positive associations were observed between bioenergetics and Modified Preclinical Alzheimer's Cognitive Composite, and bioenergetics and hippocampal volume %, while a negative association was observed between bioenergetics and white matter hyperintensities. Systemic mitochondrial dysfunction is associated with cognitive decline., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)