Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

Background: The presence of the apolipoprotein E ( APOE) epsilon 4 allele is a major risk factor for the development of Alzheimer's disease ( AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI ( fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the epsilon 4 allele on hippocampal activation has not been firmly established. Methods: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe ( MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged ( mean = 54 years) individuals who had at least one parent with AD. Results: We found that epsilon 3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to epsilon 3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in epsilon 3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the epsilon 3/3 homozygotes, but not in the epsilon 3/4 heterozygotes. Conclusion: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE epsilon 4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline.