Lower cerebral oxygen utilization is associated with Alzheimer’s disease‐related neurodegeneration on MRI and poorer cognitive performances among apolipoprotein E ε4 carriers

Abstract

AbstractBackgroundOxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are markers of oxygen utilization and neuronal energy demands that may offer insights into normal and abnormal changes in aging. This study cross‐sectionally related OEF and CMRO2 to cognitive and structural neuroimaging variables among older adults. Because apolipoprotein E (APOE)‐ε4 status is an Alzheimer’s disease (AD) genetic risk factor and a molecular mediator of vascular damage, we tested whether APOE‐ε4 status modified associations.MethodVanderbilt Memory and Aging Project participants free of stroke and dementia (n=237, 75±7 years, 37% female) underwent neuropsychological testing and multimodal 3T brain MRI, including T 1‐weighted imaging (grey matter volumes/thickness), fluid attenuated inversion recovery (white matter hyperintensities (WMHs)), T2‐relaxation‐under‐spin‐tagging (venous oxygenation (Yv)), and pseudo‐continuous arterial spin‐labeling (cerebral blow flow (CBF)). Participant‐specific Yv, arterial oxygenation, and hematocrit were used to calculate OEF, which multiplied by CBF yielded CMRO2. Linear regressions related OEF and CMRO2 individually to cognition, grey matter volumes, an AD imaging signature (Schwarz et al., 2016), and WMHs adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, Clinical Dementia Rating, APOE‐ε4 status, and (as appropriate) intracranial volume. Follow‐up models tested predictor x APOE‐ε4 status interactions on outcomes followed by APOE‐ε4 status stratification.ResultMain effects were mostly null (p‐values>0.04). APOE‐ε4 status interacted with both OEF and CMRO2 on language (p‐values<0.04), episodic memory (p<0.04), hippocampal volume (p‐values<0.03), and Schwarz AD signature (p‐values<0.05). APOE‐ε4 status also interacted with CMRO2 on total grey matter volume (p=0.04), inferior lateral ventricle volume (p=0.01), executive function (p=0.05), and visuospatial skills (p=0.01). For all interactions, lower OEF and CMRO2 related to worse cognitive performances and smaller regional grey matter structures in APOE‐ε4 carriers only.Conclusion APOE‐ε4 status modifies associations linking cerebral oxygen metabolism markers (CMRO2, OEF) to worse episodic memory performance and smaller neuroimaging variables in regions susceptible to AD‐related neurodegeneration. Consistently, results are present in APOE‐ε4 carriers only. Congruence between cognitive and neuroimaging findings suggests that oxygen metabolism and APOE‐ε4 may interact early in the pathogenesis of AD and related neurodegeneration with important clinical consequences.