Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load

Abstract

Objective: To comprehensively assess neurobiological effects of the protective APOE2 allele in the aged brain using a cross-sectional multimodal neuroimaging approach.

Methods: Multimodal neuroimaging data were obtained from a total of 572 older individuals without dementia (cognitively normal and mild cognitive impairment) enrolled in the Alzheimer's Disease Neuroimaging Initiative and included assessments of regional amyloid load with AV45-PET, glucose metabolism with fluorodeoxyglucose-PET, and gray matter volume with structural MRI. Imaging indexes of APOE2 carriers were contrasted to risk-neutral APOE3 homozygotes, and analyses were controlled for age, sex, education, and clinical diagnosis. Additional models examined genotype-specific effects of age on the imaging markers.

Results: In region-of-interest-based analyses, APOE2 carriers had significantly less precuneal amyloid pathology and did not show the typical age-related increase in amyloid load, although the age × genotype interaction was only trend-level significant. In contrast, parietal metabolism and hippocampal volume did not differ between APOE2 and APOE3 genotypes, and both groups showed comparable negative effects of age on these markers. The amyloid specificity of APOE2-related brain changes was corroborated in 2 complementary analyses: spatially unbiased voxel-wise analyses showing widespread reductions in amyloid deposition but no differences in gray matter volume or metabolism and an analysis of CSF-based biomarkers showing a significant effect on amyloid but not on tau pathology.

Conclusions: Regarding the range of Alzheimer disease biomarkers considered in the present study, the APOE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology in the aged brain.

Figure 1. Illustration of the modality-specific ROIs

Anatomical locations of the modality-specific regions of interest (ROIs) are depicted in representative views of the study template. More detailed information on ROI definition is provided in appendix e-1. FDG = fluorodeoxyglucose; GM = gray matter.

Figure 2. Effects of age and APOE genotype on multimodal imaging markers

Precuneal AV45 standard uptake value ratios (SUVRs) (A), parietal fluorodeoxyglucose (FDG) SUVR (B), and hippocampal volumes (C) are plotted against age for APOE3 (black) and APOE2 (red) genotypic groups. Separate linear regression lines are fitted for each group. Cognitively normal individuals are represented by diamonds; those with mild cognitive impairment, by circles.

Figure 3. Voxel-wise analysis of reduced amyloid load in older APOE2 carriers without dementia

Figure shows results of a voxel-wise 2-sample t test assessing reduced AV45 standard uptake value ratios (SUVRs) in APOE2 carriers compared to the APOE3 control group across the entire brain while controlling for age, sex, education, and clinical diagnosis (cognitively normal or mild cognitive impairment). Statistical map was thresholded at p < 0.05, corrected for multiple voxel-wise comparisons with the false discovery rate. Analogous analyses for fluorodeoxyglucose SUVR or gray matter volume did not reveal any significant effects.