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Brain Advance Access originally published online on March 14, 2006
Brain 2006 129(5):1240-1248; doi:10.1093/brain/awl054
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Reduced functional brain activity response in cognitively intact apolipoprotein E {varepsilon}4 carriers

Johanna Lind1, Jonas Persson4, Martin Ingvar1, Anne Larsson5, Marc Cruts7, Christine Van Broeckhoven7, Rolf Adolfsson6, Lars Bäckman2, Lars-Göran Nilsson3, Karl Magnus Petersson1 and Lars Nyberg4

1 Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital N-8, 2 Stockholm Aging Research Center, 3 Department of Psychology, Stockholm University, Stockholm, 4 Department of Psychology, 5 Department of Radiation Sciences, 6 Clinical Sciences and Psychiatry, Umeå University, Umeå, Sweden and 7 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium

Correspondence to: Johanna Lind, Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital N-8, 171 76 Stockholm, Sweden E-mail: Johanna.Lind{at}cns.ki.se

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) is the main known genetic risk factor for Alzheimer's disease. Genetic assessments in combination with other diagnostic tools, such as neuroimaging, have the potential to facilitate early diagnosis. In this large-scale functional MRI (fMRI) study, we have contrasted 30 APOE {varepsilon}4 carriers (age range: 49–74 years; 19 females), of which 10 were homozygous for the {varepsilon}4 allele, and 30 non-carriers with regard to brain activity during a semantic categorization task. Test groups were closely matched for sex, age and education. Critically, both groups were cognitively intact and thus symptom-free of Alzheimer's disease. APOE {varepsilon}4 carriers showed reduced task-related responses in the left inferior parietal cortex, and bilaterally in the anterior cingulate region. A dose-related response was observed in the parietal area such that diminution was most pronounced in homozygous compared with heterozygous carriers. In addition, contrasts of processing novel versus familiar items revealed an abnormal response in the right hippocampus in the APOE {varepsilon}4 group, mainly expressed as diminished sensitivity to the relative novelty of stimuli. Collectively, these findings indicate that genetic risk translates into reduced functional brain activity, in regions pertinent to Alzheimer's disease, well before alterations can be detected at the behavioural level.

Key Words: Alzheimer's disease; apolipoprotein E; memory; fMRI

Abbreviations: APOE = apolipoprotein E; BA = Brodmann area; fMRI = functional MRI; MTL = medial temporal lobe; SPMs = statistical parametric maps

Received November 15, 2005. Revised January 17, 2006. Accepted February 8, 2006.


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