Correlations between apolipoprotein E ε4 gene dose and brain-imaging measurements of regional hypometabolism

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) epsilon 4 gene dose (i.e., the number of epsilon 4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE epsilon 4 carriers have abnormally low CMRgI in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 epsilon 4 homozygotes, 46 heterozygotes, and 78 epsilon 4 noncarriers who were individually matched for their gender, age, and educational level, we now find that epsilon 4 gene dose is correlated with lower CMRgI in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.