Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele)

Abstract

Objective: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects.

Methods: Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable.

Results: Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition.

Conclusion: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

FIGURE 1. Non-verbal Memory Task

Note: List length varied for the titrated demand (TD) condition, so that each subject’s performance was approximately 75% accurate. For presentation purposes, a list length of three shapes during the TD condition is illustrated here.

FIGURE 2. Areas of Lower TD–SD Activation Differences in ε4 Carriers

Note: TD: titrated demand condition; SD: simple demand condition. A. Two-dimensional projections (glass brain) of statistical parametric map, depicting areas where significantly (p <0.05, Bonferroni-corrected) lower TD–SD activation differences were noted for ε4 carriers. B. Two-dimensional brain sections indicating the exact localization of the areas where significantly (p<0.05, Bonferroni-corrected) lower TD–SD activation differences were noted for ε4 carriers. Each row corresponds to one single location (indicated by the point where the two axes cut), presented from three different sections (sagittal, coronal, and axial). The order of presentation follows that of Table 2: left superior temporal, right superior frontal, left postcentral, left precuneus, and posterior cingulate gyri.

FIGURE 3. Plot of TD–SD Activation Differences for Subjects With and Without an ε4 allele in All the Areas Where Significant Interactions Were Noted

Note: TD: titrated demand condition; SD: simple demand condition. Subjects carrying the ε4 allele manifest significantly smaller TD–SD activation differences in all these regions. Talaraich coordinates in parentheses.