The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory

Abstract

First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.

Fig. 1

(A) An omnibus F-test of the PV > NV contrast revealed significant activation in bilateral PCC, medial and lateral parietal cortices, prefrontal and left parahippocampal gyrus (P_FDR < 0.05, cluster size > 0.8 cm³). With the PV > NV contrast (shown in blue bar), the −APOE4 group showed greater signals compared to the +APOE4 group in a region spanning the left precuneus and PCC (B and C) and the −FH group showed greater signals in the left dorsal precuneus than the +FH group (D and E).

Fig. 2

In a 2 × 2 ANCOVA analysis, the APOE4, FH and their interaction effects showed similar clusters with both PV and NV responses [P < 0.05 (corrected for cluster size)]. (A and D) A larger response was observed in the −APOE4 group compared to the +APOE4 in the left anterior cingulate cortex to PV (A) or NV faces (D). (B and E) A larger response was observed in the −FH group compared to the +FH group in the left medial superior frontal gyrus (signal shown in the plot) and left cuneus. There is a clear declining trend in PV or NV response amplitude with the accumulation of Alzheimer's disease risk factors (+FH and +APOE4). (C and F) The interaction between FH and APOE4 showed significance in the bilateral fusiform–parahippocampal gyrus with both PV (C) and NV faces (F).

Fig. 3

(A) A voxel-wise whole brain regression analysis revealed a significant correlation (P < 0.05, cluster-size corrected) between d′ and the PV > NV contrast in the left posterior hippocampus, parahippocampal–retrosplenial gyrus and left superior frontal cortex. (B) d′ scores are plotted according to risk factors. There was no significant difference due to either APOE4 or FH effect with the ANOVA analysis. (C) Scatter plot showing the positive linear correlation (R² = 0.326) between d′ scores and the left retrosplenial PV > NV BOLD signal difference. The adjusted BOLD signals were relatively evenly distributed across subjects from each subgroups according to risk factors.