Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers.
The apolipoprotein E epsilon4 (APOE epsilon4) 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 epsilon4 carriers (age range: 49-74 years; 19 females), of which 10 were homozygous for the epsilon4 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 epsilon4 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 epsilon4 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.
Department of Clinical Neuroscience, MR Research Center, Karolinska Hospital N-8, Stockholm, Sweden. Johanna.Lind@cns.ki.se
Johanna
J
Lind
Jonas
J
Persson
Martin
M
Ingvar
Anne
A
Larsson
Marc
M
Cruts
Christine
C
Van Broeckhoven
Rolf
R
Adolfsson
Lars
L
Bäckman
Lars-Göran
LG
Nilsson
Karl Magnus
KM
Petersson
Lars
L
Nyberg
D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping / Q000379:methods; D002353:Carrier State; D042241:Early Diagnosis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008568:Memory; D008875:Middle Aged; D009483:Neuropsychological Tests; D011446:Prospective Studies; D012660:Semantics
D053327:Apolipoprotein E4; D001057:Apolipoproteins E