APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42

Abstract

Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-β (Aβ) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aβ plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.

Figure 1.

Altered functional connectivity of the precuneus in cognitively normal PIB− APOE4+ versus APOE4− participants. a–d, Medial and lateral sagittal sections identifying statistically significant regional differences in functional connectivity of the precuneus between APOE4+ and APOE4− cognitively normal individuals previously determined by PIB PET studies to be PIB−. L, Left; R, right; Hip, hippocampus; Parahip, parahippocampus; Temp, temporal cortex; GR, gyrus rectus; Sup Temp/F-P O, superior temporal gyrus/frontoparietal operculum.

Figure 2.

Altered functional connectivity of the precuneus in cognitively normal PIB− APOE4+ versus APOE4− participants. The graph compares regional correlation magnitudes for APOE4+ and APOE4− individuals for regions shown in Figure 1. L, Left; R, right; Sup Temp/F-P O, superior temporal gyrus/frontoparietal operculum.