Beta-Amyloid Associated Differential Effects of APOE ε4 on Brain Metabolism in Cognitively Normal Elderly

Abstract

Although apolipoprotein (APOE) ε4 allele is a well-established risk factor for late-onset Alzheimer disease (AD), the mechanism of its effects on AD pathogenesis is not fully understood. We aimed to investigate the effects of APOE genotype on regional cerebral glucose metabolism in cognitively normal (CN) elderly. We further tried to elucidate whether or not such effects are associated with beta-amyloid protein (Aβ) deposition. 31 CN elderly participants underwent clinical examination, a range of neuropsychological tests, APOE genotyping, and Pittsburgh compound-B- and fluorodeoxyglucose-PET scans. 17 APOE ε4 carriers and 15 non-carriers were included. Both hypometabolic and hypermetabolic regions were observed in ε4 carriers compared with noncarriers when age, education, and sex were controlled. When the degree of global cerebral Aβ deposition was adjusted, the hypometabolic regions in the temporo-parietal area (i.e., BA 22 and 39) largely disappeared, whereas the hypermetabolic regions persisted in medial frontal and anterior temporal areas (i.e., BA 38, 11, and 39). Behaviorally, verbal episodic memory scores of APOE ε4 carriers were slightly lower than those of noncarriers, though still within normal range. Our findings indicate that decreased cerebral glucose metabolism in the temporoparietal junction associated with APOE ε4 in CN elderly appears to be mediated by Aβ deposition, and the effect of APOE ε4 on hypermetabolism in the frontal and anterior temporal regions is independent of Aβ and may be associated with presence of compensatory mechanism in CN elderly with the ε4 allele.