Evidence of altered posteromedial cortical FMRI activity in subjects at risk for Alzheimer disease

Abstract

The posteromedial cortices and other regions of the "default network" are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed functional magnetic resonance imaging (fMRI) to investigate whether the presence of apolipoprotein E (APOE) epsilon allele and degree of memory impairment were associated with the dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into epsilon carriers and noncarriers, underwent fMRI during a memory-encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the epsilon carriers relative to noncarriers. Even among cognitively normal subjects, epsilon carriers demonstrated reduced posteromedial deactivation compared with the noncarriers in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE epsilon and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD.

FIGURE 1

Functional MRI statistical maps of APOE ε4 carriers (e4+) compared to non-carriers (e4-) across all subjects, ranging from healthy elderly with Clinical Dementia Rating (CDR) of 0.0 to patients with Alzheimer disease (AD; CDR = 1.0), demonstrated differential fMRI activity (p < 0.05, cluster-corrected) in: (A) left (L) precuneus, (B) right (R) ventral anterior cingulum, (C) R middle frontal gyrus, (D) R inferior frontal gyrus, and (E) L dorsal anterior cingulum (MNI coordinates of the crosshairs are reported in the figure). In each of these regions, magnitude of fMRI signal was greater in the ε4 carriers than in non-carriers (unpaired t-test, two-tailed uncorrected p-values are indicated in the figure). Difference in BOLD signal magnitude across the CDR groups was tested using one-way ANOVA (p-values reported in the figure). Scatter plots demonstrate the relationship between regional BOLD signal and Rey Auditory Verbal Learning (RAVLT) delayed recall scores (Pearson's correlation, r- and p-values are indicated in the figure). The statistical map presenting significantly different activation areas in ε4 carriers versus non-carriers (red–yellow) is overlaid on the statistical map demonstrating significantly different activation areas in AD patients versus healthy elderly (dark green–light green).

FIGURE 2

Within the group of healthy elderly with Clinical Dementia Rating (CDR) of 0.0, fMRI activity (p < 0.05, cluster-corrected) in the APOE ε4 carriers (e4+) differed significantly from that of non-carriers (e4-) in the left (L) precuneus. Region-of-interest analysis revealed greater BOLD fMRI signal magnitude in the ε4 carriers than in non-carriers (p = 0.001, unpaired t-test). Greater positive BOLD signal (i.e., reduced fMRI task-induced deactivation) was related to poorer Rey Auditory Verbal Learning (RAVLT) delayed recall performance (p = 0.03, Pearsson's correlation). The statistical map presenting significantly different activation areas in ε4 carriers versus non-carriers (red–yellow) is overlaid on the statistical map demonstrating significantly different activation areas in AD patients versus healthy elderly (dark green–light green).