Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• The apolipoprotein E epsilon4 (APOE ε4) allele is the primary genetic risk factor for Alzheimer's disease (AD).
• Early detection of AD pathogenesis is crucial for timely intervention.
• Functional neuroimaging offers potential for identifying preclinical AD markers.

Purpose of the Study:

• To investigate functional brain activity differences in cognitively intact APOE ε4 carriers compared to non-carriers.
• To explore whether genetic risk for AD is associated with altered brain function before clinical symptoms manifest.

Main Methods:

• A large-scale functional MRI (fMRI) study comparing 30 APOE ε4 carriers (including 10 homozygotes) with 30 non-carriers.
• Participants performed a semantic categorization task while undergoing fMRI.
• Groups were matched for age, sex, and education; all participants were cognitively normal.

Main Results:

• APOE ε4 carriers exhibited reduced task-related brain activity in the left inferior parietal cortex and bilateral anterior cingulate cortex.
• A dose-dependent effect was observed, with homozygous carriers showing the most pronounced parietal hypoactivity.
• The APOE ε4 group displayed abnormal right hippocampal responses during novelty processing, indicating reduced sensitivity to stimulus novelty.

Conclusions:

• Genetic risk for Alzheimer's disease, indicated by the APOE ε4 allele, is associated with reduced functional brain activity in key regions.
• These functional alterations occur in cognitively intact individuals, suggesting they are preclinical markers of AD risk.
• fMRI can detect brain changes related to AD genetic risk prior to behavioral or cognitive impairment.