Do deficits in mitochondrial spare respiratory capacity contribute to neuropsychological changes seen in Alzheimer’s disease?

Abstract

Background In clinical settings, AD is defined by characteristic deficits in neuropsychological testing supported by amyloid and tau biomarkers and neuroimaging abnormalities. The biological cause of neuropsychological changes is not established. Tau deposition correlates with, but does not fully account for all observed neuropsychological impairments. We have shown mitochondrial spare respiratory capacity (MRSC) is lowered in AD patient fibroblasts. This study investigates if fibroblast mitochondrial functional abnormalities correlate with neuropsychological/neuroimaging changes in AD. Method 10 AD patient and 10 control fibroblast samples were taken via skin biopsy. Adenosine Triphosphate (ATP) and extracellular lactate were measured using luminescent and fluorescent protocols respectively. Mitochondrial membrane potential (MMP) was measured using tetramethylrhodamine dye. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. In‐depth Neuropsychological profiling, and brain structural MRIs were undertaken on all participants. Correlations were performed between MMP, MRSC and neuropsychological/MRI AD markers. Result Reductions in delayed (p<0.0001) and immediate recall (p<0.0001), semantic fluency (p<0.0001), phonemic fluency (p=0.0033) and MMSE (p=0.0009) scores were seen in AD patients. After controlling for age, education and brain reserve; left hippocampal (p=0.001), left parietal (p=0.002), right parietal (p=0.001) and anterior medial prefrontal cortical (p=0.017) gray matter volumes were reduced in AD patients. Fibroblast metabolic markers showed a reduction in MMP (p=0.001), MRSC (p<0.0001), glycolytic reserve(p=0.05), and extracellular lactate (p<0.05) in AD patients. MRSC and MMP correlated significantly with immediate recall ([MRSC, p=0.0041],[MMP, p=0.0115]), delayed recall ([MRSC, p=0.0013],[MMP, p=0.0138]) and semantic memory ([MRSC, p=0.0039],[MMP, p=0.009]) tests. The correlations between MRSC and neuropsychological measures remained after controlling for age, education and brain reserve. No correlations were seen between grey matter volumes and fibroblast metabolism. Conclusion This study highlights how in‐depth metabolic analysis of sporadic AD fibroblasts identifies functional abnormalities that correlate with neuropsychological features distinctive to AD. This work may also explain how some of the fundamental biological processes that are affected in Alzheimer’s disease may contribute to the neuropsychological profiles that define the condition.