APOE Genotype Modulates Proton Magnetic Resonance Spectroscopy Metabolites in the Aging Brain

Background: Proton magnetic resonance spectroscopy (H-1-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer's disease. Additionally, we examined these measures in relation to cognition. Methods: We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of H-1-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained. Results: General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myoinositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE x age interaction and APOE status each had a significant effect on H-1-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE x age variable modulation of cognition was mediated by H-1-MRS metabolites. Conclusions: In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers.