Effect of Alzheimer disease risk on brain function during self-appraisal in healthy middle-aged adults

Abstract

Context: Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks.

Objective: To determine whether parental family history of AD (hereafter referred to as FH) or presence of the epsilon4 allele of the apolipoprotein E gene (APOE4) exerts independent effects on brain function during SA.

Design: Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words.

Setting: An academic medical center with a research-dedicated 3.0-T MR imaging facility.

Participants: Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH.

Main outcome measure: Blood oxygen-dependent contrast measured using T2*-weighted echo-planar imaging.

Results: Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype.

Conclusions: Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors.

Figure 1

Main effect of task across all 110 cognitively normal participants. Orthographic coronal, sagittal and axial views are shown as well as lateral and transverse maximum intensity projections of the result. Left is on left. The map is thresholded at p_FDR <.05 corresponding to t>2.57. The main effect of task in this comparison was used to restrict inference on subsequent comparisons of risk status. See Table 2 for cluster locations and statistical details.

Figure 2

The interaction between FH and APOE4 status. The three clusters that reached statistical significance are shown in sagittal and axial views. The corresponding plots depict the mean for the four groups (error bars 95% confidence interval), derived from the first eigenvariate of each subject across the entire cluster. A * indicates the mean differed significantly from the −FH,+e4 group (p<.005).

Figure 3

Statistical parametric map of the main effect of first-degree family history. The figure shows regions where the −FH groups activate more on average than the +FH groups. Select brain slices are shown (left is on left) depicting the result in the posterior cingulate and subiculum with corresponding plots of the mean signal change, derived from the first eigenvariate across the cluster (error bars 95% confidence interval).