Peripheral Mitochondrial Energetics are Associated with Cortical Neurophysiological Alterations in Alzheimer’s Disease

Abstract Alzheimer’s disease is associated with both mitochondrial dysfunction and altered neurophysiological signalling. Peripheral measures of mitochondrial respiration have been established as effective predictors of mitochondrial function in the healthy brain, and more recently, of altered brain signalling in clinical groups. Here, we sought to assess whether peripheral mitochondrial energetics are associated with altered neural signalling in Alzheimer’s disease. We collected task-free magnetoencephalography (MEG) from individuals on the Alzheimer’s disease continuum (69.21 6.91 years; n = 38) and cognitively normal older adults (72.20 4.73 years; n = 20). Each participant also provided a blood sample for analysis of mitochondrial respiration using the Seahorse XF96 Analyzer. We used region-wise linear models to test the relationship between ATP-linked mitochondrial respiration and Alzheimer’s disease-associated neurophysiological changes. We found that mitochondrial respiration linked to ATP production is associated with altered alpha and theta band cortical rhythms in Alzheimer’s disease (α: p FDR < 0.05, r = -0.7; θ: p FDR < 0.05, r = -0.6). We then tested colocalization of mitochondria-neurophysiological relationships with a human brain atlas of respiratory capacity and found that brain regions with lower mitochondrial respiratory capacity exhibit a stronger relationship between aperiodic signalling and peripheral ATP-linked respiration ( p FDR = 0.003, r = 0.35). Our findings suggest that peripheral blood measures of mitochondrial function can offer insight into the neurophysiological alterations associated with energetic changes in Alzheimer’s disease and warrant further investigation into the translational potential of joint neuronal-mitochondrial markers of neurological diseases of aging.