We found that among older people who had the APOE ε4 allele and a normal memory for their age, both the magnitude and the extent of brain activation during verbal memory challenge were greater than those among similar subjects who had the APOE ε3 allele. These differences in patterns of brain activation in the left hemisphere correlated with the degree of decline in memory among subjects who were retested two years later. These functional MRI results extend established findings in PET studies of Alzheimer’s disease and aging to persons at genetic risk for Alzheimer’s disease.
Our findings are consistent with those of other neuroimaging studies that reported increased brain activity during cognitive challenge in subjects with normal cognitive function. More complex stimuli or more demanding cognitive processing results in a greater magnitude and area of signal intensity in regions critical to the task; likewise, as performance improves, through either innate ability or practice, the increase in signal intensity becomes smaller and more focal.19,20
The greater increase in signal intensity in brain regions necessary for tasks requiring memory among the carriers of the APOE ε4 allele suggests that they performed additional cognitive work to accomplish the task. Expanding the territory of neural tissue dedicated to such tasks, as well as increasing the number of neurons recruited or the firing rate within a given functional area, may augment the brain’s processing capacity, operating dynamically in response to cognitive demands. In persons at risk for Alzheimer’s disease, such increased brain activity may effectively serve a compensatory role, wherein subjects use additional cognitive resources to bring memory-related performance to a normal level.
In support of this compensatory hypothesis were the greater differences between groups during periods of recall, when subjects had to apply cognitive effort to retrieve the correct response. By contrast, differences between the groups were less pronounced during periods of learning, when subjects listened to but did not actively try to recall experimental stimuli. Furthermore, among the carriers of the APOE ε4
allele the MRI signal intensity was increased in the anterior cingulate gyrus and dorsal prefrontal cortex, regions that show greater activation as cognitive effort increases.32
The most plausible explanation for this pattern of response is that subjects at genetic risk for Alzheimer’s disease use greater cognitive effort to achieve the same level of performance as subjects who are not at genetic risk.
Although both groups of subjects had normal results on the logical-memory measure of the Wechsler Memory Scale, the results among carriers of the APOE ε4
allele were poorer.23
Such measures of delayed recall are particularly sensitive to the decline in memory associated with this allele.33
The scores themselves were within the normal range and, when interpreted concomitantly with the results of a battery of memory tests, were not low enough to arouse clinical concern. Nonetheless, slight declines in the results of such tests may have greater importance when they are interpreted in combination with functional imaging and genetic data.
For signal intensity to be increased in association with compensatory processing, there must be enough healthy neural tissue to accommodate such a change. A substantial neural loss, by contrast, would most likely be associated with attenuated brain activity. Indeed, activation-imaging studies of patients with Alzheimer’s disease revealed decreased brain activity in the parietal and hippocampal regions and relatively higher activity in regions of the cortex that were not affected by the disease.13,21
In those studies, tasks requiring memory made fewer demands on the subjects than in our study and apparently resulted in a passive approach to the task. By contrast, in our study, subjects closely attended to and actively retrieved stimuli. Such demanding paradigms may present a challenging behavioral probe that causes the observed increase in the patterns of signal intensity. Hence, we refer to our approach as a cognitive stress test.12
In the subgroup of subjects whom we studied two years later, the level of brain activation at base line correlated with the degree of longitudinal memory decline. The pattern of these results suggests the potential usefulness of combining studies of brain activation and assessments of genetic risk in predicting future cognitive decline.
Several methodologic issues deserve comment. Changes in magnetic susceptibility arising from increased cerebrospinal fluid as a result of atrophy may affect medial temporal structures. Atrophy alone, however, could not explain the different results in the two groups of subjects, since the effects were largely unilateral and were present primarily during the recall periods. Because the functional MRI measure is a relative one, reduced base-line blood flow could provide an alternative explanation for the results.11
Many factors influence the functional MRI signal, including the sensitivity of the scanner, the homogeneity of the field, the subject’s head motion, and the dependent signal measure.30,34
Our results indicate that, as a group, older persons with a genetic risk for Alzheimer’s disease have alterations in brain function without obvious morphologic or behavioral indications of impending disease. Initial longitudinal follow-up indicates that the baseline level of brain activation can be used to predict subsequent decline in memory.