Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging

Abstract

The ε4 allele of the polymorphic apolipoprotein E gene is associated with increased risk of Alzheimer's disease (AD), deposition of β-amyloid (Aβ), and reduction in cerebral glucose metabolism in asymptomatic people. Although ApoE4 may exert an effect on AD risk through amyloidogenic pathways, whether its effect on glucose metabolism is related to Aβ is unknown. To answer this question, we examined data from 175 cognitively normal older people (mean age, 77; 87 men, 88 women) in the Alzheimer's disease neuroimaging initiative studied concurrently with [(18)F]flurodeoxyglucose (FDG) positron emission tomography measures of glucose metabolism and the radiotracer [(18)F]florbetapir, an imaging agent which labels fibrillar Aβ in vivo. Based on a threshold value of florbetapir uptake determined in separate samples, subjects were categorized as florbetapir+ or florbetapir-. Glucose metabolism was measured as a continuous variable in a group of regions of interest (ROIs) selected a priori based on their involvement in AD, and also by using a whole-brain voxelwise approach. Among this sample, 29% of subjects were florbetapir+ and 23% were ApoE4 carriers. As expected, there was a significant association between ApoE4 genotype and florbetapir positivity. Florbetapir status, however, was not significantly associated with glucose metabolism, but the ApoE4 genotype was associated with lower metabolism in both voxelwise and ROI approaches. These results show that ApoE genotype, and not aggregated fibrillar forms of Aβ, contributes to reduced glucose metabolism in aging and adds to a growing list of neural consequences of ApoE that do not appear to be related to Aβ.

Figure 1.

Relationships between florbetapir positivity, ApoE carrier status, and glucose metabolism (FDG-PET). Analysis indicates a significant effect of ApoE, but no effect of florbetapir.

Figure 2.

Results of whole brain voxelwise analysis showing three contrasts as indicated in the label. Lower threshold for all images is t = 1.70, p = 0.05 uncorrected, with brighter shades indicating higher t and p values as indicated. No significant voxels were found for the contrast ApoE4+ > ApoE4−. The blue set of ROIs represents the composite, pre-specified ROI as defined in the text. The peak voxels of clusters meeting the p < 0.001 clusterwise criterion (see Materials and Methods) for the ApoE4− > ApoE4+ contrast (top row) are listed in Table 2.