28 Aug 2000

The ε4 variant of the apolipoprotein-E (ApoE) gene has been shown to confer increased risk for Alzheimer's disease. Gary Small, Susan Bookheimer, and colleagues report in the New England Journal of Medicine that carriers of the ε4 allele need to exert their brains more to perform memory tests.

In a functional MRI study of 16 neurologically normal carriers of the ε4 allele (mean age 62 years) and 14 controls, the researchers found that ε4 carriers had the same level of brain activation at rest (both in terms of number of areas activated and levels of activation in specific areas) as did controls. They also achieved the same memory test results as noncarriers of the gene, but once they applied themselves to the memory tasks, MRI scans suggested that they were consuming more energy in the process. This was particularly true in areas affected by Alzheimer's disease (e.g., left hippocampal, parietal, and prefrontal regions), but also in terms of the total number of areas activated throughout the brain. In a subgroup of subjects reassessed two years later, the degree of brain activation at baseline correlated with the degree of decline in verbal memory.

Can this sort of test predict who will eventually develop Alzheimer's disease? In an accompanying editorial, Ingmar Skoog of Sahlgrenska University Hospital in Goteborg, Sweden, points out that not all people with the ApoE ε4 allele get Alzheimer's disease. He thinks it likely that these data reflect early pathogenesis related to Alzheimer's, but cautions that they could also reflect the presence of the allele without necessarily reflecting the disease's pathology. He concludes, "The most important implications of the findings ... may concern the selection of patients for future clinical trials and a new outcome measure for the evaluation of treatment efficacy and the characteristics of those who are likely to have a response."—Hakon Heimer