Patterns of brain activation in people at risk for Alzheimer's disease

Abstract

Background: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition.

Methods: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later.

Results: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory.

Conclusions: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory.

Figure 1. Statistical Parametric Maps of the Brain Used to Assess Subjects’ Performance on Memory-Activation Tests in Carriers of the APOE ε4 Allele and Carriers of the APOE ε3 Allele

Three-dimensional renditions of the surface of the brain are shown in gray, and colored areas indicate regions of significantly increased MRI signal intensity during learning or recall periods as compared with resting periods. The signal intensity increased significantly in the left inferior frontal region, the right prefrontal cortex, the transverse temporal gyri bilaterally, and the left posterior temporal and inferior parietal regions in both groups. However, both the extent and the intensity of activation were greater among the carriers of the APOE ε4 allele. The carriers of the APOE ε4 allele also had significant increases in the left parahippocampal region (Talairach and Tournoux atlas co-ordinates, −12, −38, and −10), the left dorsal prefrontal cortex (−56, 0, and 34; −50, −5, and 44), and in the inferior and superior parietal lobes (−48, −52, and 44 and −20, −80, and 26, respectively) and the anterior cingulate gyrus (12, 20, and 32). Direct comparisons of the carriers of the APOE ε4 allele and the carriers of the APOE ε3 allele (bottom panel, which shows the difference between the carriers) further demonstrated the greater extent and magnitude of activity in the left prefrontal region (atlas coordinates −60, 2, and 14 and −54, −18, and 32) and bilateral orbitofrontal, superior temporal, and inferior and superior parietal regions in the carriers of the APOE ε4 allele.

Figure 2. Examples of Activation Maps on Single MRI Planes

Two carriers of the APOE ε3 allele (Panel A) had fewer and less extensive areas of statistically significant activation (indicated in red) than did two carriers of the APOE ε4 allele (Panel B). The white lines indicate examples of regions of interest used for the analyses of data within subjects.

Figure 3. MRI Signal Intensity in the Hippocampus

Panel A shows the percent increases in signal intensity during learning or recall periods as compared with periods of rest, for the hippocampus and parahippocampal gyrus, averaged among subjects in each group. These increases are plotted for the nine minutes of the experiment; the peaks indicate periods of learning or recalling the word pairs, whereas the valleys indicate periods when the subjects were at rest. In both groups the signal intensity increased during the learning or recall periods as compared with the interspersed periods of rest, though these increases were larger in the carriers of the APOE ε4 allele. Panel B shows the mean (±SD) percent change in the MRI signal intensity in the hippocampus and parahippocampal gyrus during each of the six periods of recall. The response among the carriers of the APOE ε4 allele was consistently larger than the response among the carriers of the APOE ε3 allele.