Blood‐based bioenergetic profiling reveals differences in mitochondrial function associated with cognitive performance and Alzheimer's disease

Abstract

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.

Effects of 30 days bed rest and exercise countermeasures on PBMC bioenergetics

“…Changes in mitochondrial function in PBMCs occur in various infectious, neurological, cardiopulmonary, vascular, and metabolic diseases as well as in cancer. 8 In individuals with Alzheimer's 13 and in geriatric patients with fatigue, mitochondrial respiration of PBMCs is decreased. 34 A study by Karabatsiakis et al proposed a notable impairment in mitochondrial function among individuals with major depression.…”

“…11 Nevertheless, PBMC mitochondrial function appears responsive to various pathologies, including major depression and Alzheimer's and is influenced by physical exercise. [12][13][14][15] Per volume of blood, PBMC mitochondrial respiratory function increased following acute exercise in collegiate swimmers 16 and healthy adults. 14 Other studies demonstrate improved bioenergetics in PBMCs after lowintensity exercise, 15 and its modulation by fitness status in females.…”

“…Although appealing, the usability of mitochondrial function of PBMCs as a surrogate and systemic marker may be limited due to the heterogeneity and marked differences in the metabolic properties of different immune cell subtypes 11 . Nevertheless, PBMC mitochondrial function appears responsive to various pathologies, including major depression and Alzheimer's and is influenced by physical exercise 12–15 . Per volume of blood, PBMC mitochondrial respiratory function increased following acute exercise in collegiate swimmers 16 and healthy adults 14 .…”

Plasma glycocholic acid and linoleic acid identified as potential mediators of mitochondrial bioenergetics in Alzheimer’s dementia

“…Samples that had an increase in respiration by more than 10% following cytochrome c addition were not used. Additionally, a cell viability with protocol described in our recently accepted publication added further validation to confirm mitochondrial integrity (Mahapatra et al, 2022). For additional information on the terms and abbreviations adopted to describe the highresolution respirometry parameters in this manuscript refer to Gnaiger (2014).…”

Bisdemethoxycurcumin (BDC)-Loaded H-Ferritin-Nanocages Mediate the Regulation of Inflammation in Alzheimer’s Disease Patients

“…In fact, it has been shown that PBMCs from AD patients share alterations that have been found in other tissues, including neurons [ 8 , 9 , 10 ]. PBMCs have been often used as a model to investigate neurodegenerative diseases, because, even if they are peripheral cells, they offer the possibility to study and regulate pathways associated with neurodegenerative disorders as mitochondrial disfunctions, oxidative stress [ 11 , 12 , 13 ], and epigenetic [ 14 ].…”