fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease

Abstract

Objective: To determine whether APOE genotype influences brain response and whether nonverbal stimuli generate findings comparable with those of previous studies that used verbal stimuli. The relationship between APOE genotype and blood oxygenation level dependent (BOLD) brain response was examined during a picture-encoding task in nondemented older adults.

Methods: Twenty nondemented participants with normal episodic memory function were divided into two groups based on the presence (n = 10) or absence (n = 10) of the APOE epsilon4 allele. Picture learning was completed during functional MRI in a blocked design alternating between experimental (novel pictures) and control (repeated picture) conditions.

Results: Nondemented older adults with an APOE epsilon4 allele showed greater magnitude and extent of BOLD brain response during learning of new pictures relative to their matched epsilon3 counterparts. Different patterns and directions of association between hippocampal activity and learning and memory performance were also demonstrated.

Conclusions: The results suggest that brain response differences are not due to poorer general memory abilities, differential atrophy, or brain response during control conditions, but instead appear to be directly influenced by APOE genotype. Results are consistent with a compensatory hypothesis wherein older adults at genetic risk for Alzheimer disease by virtue of the APOE epsilon4 allele appear to require additional cognitive effort to achieve comparable performance levels on tests of episodic memory encoding.

Figure 1

Magnitude and direction of brain response to the task overlaid onto axial slices of a representative anatomic image in Talairach space (slices span from 12 inferior to 54 superior in 6 mm increments). Activations shown include voxels significant at p < 0.025 that are contained within a cluster of 13 or more voxels. Color scale represents effect sizes for the within-subjects difference between conditions (ENCODE vs REPEAT) as measured by eta² (red voxels: 0.50 < η² ≤ 0.75; yellow voxels: 0.76 < η² & 1.0 [η² indexes the effect size for the magnitude of the difference between the observed response and 0]). See also table 2 for areas of significant activation. (A) APOE ε4 participants. (B) APOE ε3 participants.

Figure 2

Clusters of significant difference between APOE ε4 and ε3 participants for encoding-related brain response overlaid on a representative anatomic image in Talairach (1988) space (slices span from 12 inferior to 54 superior in 6 mm increments). Activations shown include voxels significant at p < 0.025 that are contained within a cluster of 13 or more voxels. Color scale represents effect sizes for the ε4 – ε3 difference in fit coefficient as measured by eta² (signed to reflect the direction of the contrast) (red voxels: 0.50 < η² ≤ 0.75; yellow voxels: 0.76 < η² < 1.0).