Open Access Highly Accessed Research article

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

Mehul A Trivedi12, Taylor W Schmitz12, Michele L Ries12, Britta M Torgerson12, Mark A Sager2, Bruce P Hermann3, Sanjay Asthana12 and Sterling C Johnson12*

Author Affiliations

1 Geriatric Research Education and Clinical Center, William S. Middleton Veteran's Affairs Hospital, Madison, WI, USA

2 Department of Medicine, University of Wisconsin Medical School, Madison, WI, USA

3 Department of Neurology, University of Wisconsin Medical School, Madison, WI, USA

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BMC Medicine 2006, 4:1  doi:10.1186/1741-7015-4-1

Published: 13 January 2006



The presence of the apolipoprotein E (APOE) ε4 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 ε4 allele on hippocampal activation has not been firmly established.


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.


We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 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 ε3/3 homozygotes, but not in the ε3/4 heterozygotes.


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 ε4 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.