The effect of apolipoprotein E on regional brain function during cognition

Apolipoprotein E (APOE) is a transporter of cholesterol and lipids. In brain, it is involved in lipid homeostasis and neuronal repair. The APOE epsilon4 allele is the only identified genetic risk factor for late-onset Alzheimer's disease, and it is further associated with poorer functional outcome and increased mortality following traumatic brain injury and intracranial hemorrhage, suggesting that pathophysiological effects may not be limited to particular brain regions or functions. Neuroimaging studies in cognitively healthy carriers of the epsilon4 allele have found decreased brain metabolism, increased atrophy, and differences in the degree of regional brain function during task performance. Most imaging investigations of brain activity during cognition have utilized memory tasks, which access the hippocampal formation. The majority, which have been conducted in older individuals, report increased activation in epsilon4 carriers. However, an examination of young individuals found reduced activation in carriers. Most such studies have been limited by small sample size. In a large cohort of healthy individuals, we examined the effects of the APOE epsilon4 allele on regional brain function in multiple brain areas/circuits to test whether alterations in neural recruitment in carriers would be limited to memory-related neural circuitry. We further investigated the interactions of age and APOE genotype, through the inclusion of an older cohort, on cognitive performance and on medial temporal lobe activation during a declarative memory task. A large sample (n = 245) of cognitively healthy, right-handed, Caucasian adults, ages18-50 years, participated in fMRI tasks of attention, emotion, and working and declarative memory, and completed neuropsychological measures. An older cohort (n = 26) aged 51-68 was included in analyses of the fMRI declarative memory task and the neuropsychological measures. Compared to APOE epsilon3 carriers, matched young epsilon4 carriers evidenced reduced BOLD response in task-relevant areas during performance of working memory and declarative memory tasks, but not during tasks of attention and emotion. These areas included the dorsolateral prefrontal cortex, medial frontal gyrus, precuneus, and iPL during the working memory task, and the hippocampus and parahippocampus during the declarative memory task. Genotype-related findings in the hippocampal formation during encoding and retrieval varied depending upon age; young epsilon4 carriers demonstrated decreased activation when compared with epsilon3 carriers, but, in contrast, showed increased activation with increasing age. Alterations in brain activation in carriers were not associated with alterations in cognitive performance: there were no between-genotype differences in neuroimaging task performance, and on behavioral testing outside the scanner, young epsilon4 carriers actually outperformed epsilon3 homozygotes on a logical memory test. These findings suggest that the neurofunctional effect of the epsilon4 allele, while particularly relevant to memory related circuitry, is not limited to the medial temporal lobe and may reflect greater neural efficiency in young carriers and impaired function in response to age-associated neural changes in older carriers.