Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain network

Abstract

Purpose: To determine the effect of the apolipoprotein E (APOE) genotype on atrophy rates of specific brain gray matter regions hypothesized to be key components of cognitive networks disrupted in Alzheimer disease.

Materials and methods: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All subjects and their legal representatives gave written informed consent prior to data collection. The authors analyzed data from 237 subjects (mean age, 79.9 years; 40% female) with mild cognitive impairment (MCI) in the ADNI database and assessed the effect of the APOE ε4 and ε2 alleles on regional brain atrophy rates over a 12-48-month period. Brain regions were selected a priori: 15 experimental and five control regions were included. Regional atrophy rates were derived by using a fully automated algorithm applied to T1-weighted magnetic resonance (MR) imaging data. Analysis consisted of mixed-effects linear regression with repeated measures; results were adjusted for multiple testing with Bonferroni correction.

Results: Thirteen of 15 experimental regions showed a significant effect of ε4 for higher atrophy rates (P < .001 for all). Cohen d values ranged from 0.26 to 0.42, with the largest effects seen in the amygdalae and hippocampi. The transverse temporal cortex showed a trend (P = .02, but did not survive Bonferroni correction) for a protective effect (Cohen d value = 0.15) of ε2. No control region showed an APOE effect.

Conclusion: The APOE ε4 allele is associated with accelerated rates of atrophy in 13 distinct brain regions in limbic and neocortical areas. This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially contribute to cognitive decline. Online supplemental material is available for this article.

RSNA, 2013

Figures

Figure 1:

Medial, inferior, superior, and lateral images of a three-dimensional FreeSurfer reference brain model show regions of accelerated atrophy in the presence of APOE ε4 in subjects with MCI. Effect size of the APOE ε4 acceleration of cortical atrophy is depicted by color: Blue signifies a magnitude of Cohen d value of less than 0.25; yellow, 0.25–0.35; and red, more than 0.35. Gray areas were not examined.

Figure 2:

Whisker box plots of regionwise atrophy rates according to APOE genotype in subjects with MCI. Top row: Control regions. Bottom three rows: Experimental regions. For the x-axis, “2” denotes ε2 carrier, “3” denotes ε3/ε3 homozygote, and “4” denotes ε4 carrier. The y-axis values represent log volume per month: A value of 1.00 (approximately) represents a 1% increase in volume annually. Negative values indicate atrophy. * = regions that showed significantly higher atrophy rates in ε4 carriers than in ε3/ε3 homozygotes. WM = white matter.