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The Journal of Neuroscience, May 31, 2006, 26(22):6069-6076; doi:10.1523/JNEUROSCI.0959-06.2006

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Neurobiology of Disease
The Influence of Alzheimer Disease Family History and Apolipoprotein E 4 on Mesial Temporal Lobe Activation

Sterling C. Johnson,^1,2 Taylor W. Schmitz,^1,2 Mehul A. Trivedi,^1,2 Michele L. Ries,^1,2 Britta M. Torgerson,^1,2 Cynthia M. Carlsson,^1,2 Sanjay Asthana,^1,2 Bruce P. Hermann,¹ and Mark A. Sager¹

¹University of Wisconsin–Madison, Madison, Wisconsin 53705, and ²Veterans Administration Hospital, Madison, Wisconsin 53705

Correspondence should be addressed to Sterling C. Johnson, Geriatric Research Education and Clinical Center, Veterans Administration Hospital, 2500 Overlook Terrace (11G), Madison, WI 53705. Email: scj{at}medicine.wisc.edu

First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E 4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD [family history (+FH)] and 64 age- and education-matched controls without a first-degree family history of any dementia [no family history (–FH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 x 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the –FH +4 group exhibited the greatest signal change, and the +FH +4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function.

Key words: Alzheimer disease; fMRI; memory formation; hippocampal function; imaging; dementia

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Received Dec. 28, 2005; revised April 7, 2006; accepted April 28, 2006.

Correspondence should be addressed to Sterling C. Johnson, Geriatric Research Education and Clinical Center, Veterans Administration Hospital, 2500 Overlook Terrace (11G), Madison, WI 53705. Email: scj{at}medicine.wisc.edu

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