The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation

Abstract

First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E epsilon4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD [family history (+FH)] and 64 age- and education-matched controls without a first-degree family history of any dementia [no family history (-FH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 x 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the -FH +epsilon4 group exhibited the greatest signal change, and the +FH +epsilon4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function.

Figure 1.

Statistical parametric maps of the signal change to novel versus previously learned items, and the reverse, in the negative family history (−FH) group (top) (n = 64), and the positive family history (+FH) (middle) group (n = 68) collapsed across APOE status. The bottom row contains the results of the SPM{t} contrast of the difference (Diff) between FH groups indicating greater activity in the mesial and ventral temporal lobe in the −FH group (there were no significant voxels in the reverse direction). The statistical maps are overlaid on the same atlas brain in Montreal Neurological Institute (MNI) space. All maps are constrained to voxels in which the global F statistic was significant (p_FWE < 0.05). Left is on the left of the image. The single-group contrasts (top two rows are thresholded at p_FWE < 0.05; t = 4.11); the between-group contrast (on which inferences are based) is thresholded at p_FDR < 0.005; t = 3.10. The positive (hot colors) and negative (blue) t-maps are shown for the single-group maps. See Table 2 for a summary of the statistical results and voxel coordinates of maxima. L, Left; R, right.

Figure 2.

Notched box plot of signal change in the right hippocampal region (at MNI location 34–22-18) for each of the four groups. The plot contains the mean of each group, the 95% confidence interval about the mean represented by the notch in each box, and the 5th, 25th, 75th, and 95th percentiles, representing the range of variability in fMRI signal change at this location.

Figure 3.

The influence of FH on ε4 carriers only. Statistical parametric map coronal montage of the contrast −FH, +ε4 > +FH, + ε4. The map is thresholded at p_FDR < 0.005. The right (R) and left (L) hippocampi as well as the ventral temporal lobes are significantly different between groups. There were no differences in the reverse direction. Left is on the left side of the image. See Table 3 for a summary of the statistics and voxel coordinates of maxima.