Association of APOE alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease neuroimaging markers

Abstract

Introduction: TOMM40 and APOC1 variants can modulate the APOE-ε4-related Alzheimer's disease (AD) risk by up to fourfold. We aim to investigate whether the genetic modulation of ε4-related AD risk is reflected in brain morphology.

Methods: We tested whether 27 magnetic resonance imaging-derived neuroimaging markers of neurodegeneration (volume and thickness in temporo-limbic regions) are associated with APOE-TOMM40-APOC1 polygenic profiles using the National Alzheimer's Coordinating Center Uniform Data Set linked to the AD Genetic Consortium data.

Results: All brain regions studied using structural phenotypes were smaller in individuals with AD. The ε4 allele was associated with smaller limbic (entorhinal, hippocampus, parahippocampus) brain volume and cortical thickness in AD cases than controls. There were significant differences in the associations for the higher-risk and lower-risk ε4-bearing APOE-TOMM40-APOC1 profiles with temporo-limbic region markers.

Discussion: The APOE-AD heterogeneity may be partly attributed to the modulating role of the TOMM40 and APOC1 genes in the APOE cluster.

Highlights: The ε4 allele is associated with smaller values of neuroimaging markers in AD cases. Larger values of neuroimaging markers may protect against AD in the ε4 carriers. TOMM40 and APOC1 variants differentiate AD risk in the ε4 carriers. The same variants can differentiate the links between ε4 and neuroimaging markers.

Keywords: APOE locus; Alzheimer's disease; neuroimaging markers; polygenic profiles.

FIGURE 1

Brain imaging regions comprising the AD signature volume (ADSV) composite.

FIGURE 2

Correlation matrix between 29 brain imaging measurements. ADSV, Alzheimer's disease signature volume; GrayVol, total gray matter volume; HippoVol, total hippocampus volume; HOSA, hippocampal occupancy score averaged; LEnt, left entorhinal volume; LEnt_m, left entorhinal thickness; LHippo, left hippocampus volume; LHOS, left hippocampal occupancy score; LMidTemp, left middle temporal gray matter volume; LMidTemp_m, left middle temporal gray matter thickness; LParHip, left parahippocampal gray matter volume; LParHip_m, left parahippocampal gray matter thickness; LPrecun, left precuneus gray matter volume; LPrecun_m, left precuneus gray matter thickness; LSupTem, left superior temporal gray matter volume; LSupTem_m, left superior temporal gray matter thickness; REnt, right entorhinal volume; REnt_m, right entorhinal thickness; RHippo, right hippocampus volume; RHOS, right hippocampal occupancy score; RMidTemp, right middle temporal gray matter volume; RMidTemp_m, right middle temporal gray matter thickness; RParHip, right parahippocampal gray matter volume; RParHip_m, right parahippocampal gray matter thickness; RPrecun, right precuneus gray matter volume; RPrecun_m, right precuneus gray matter thickness; RSupTem, right superior temporal gray matter volume; RSupTem_m, right superior temporal gray matter thickness; WhiteVol, total white matter volume.

FIGURE 3

Definition of compound genotypes (CompGs) used in the analyses. Group 1 (neutral) included carriers of the apolipoprotein E (APOE) ε3ε3 genotype and any allele of rs2075650 and rs12721046. Group 2 represents the lower‐risk CompG (LR‐CompG) comprising one or two copies of the ε4 allele and major allele homozygotes of rs2075650 and rs12721046 SNPs. Group 3, representing the higher‐risk CompG (HR‐CompG), also included one or two copies of the ε4 allele, in addition to at least one minor allele of rs2075650 or rs12721046. Upper and lower case (for AA, Ag, etc) denotes here major and minor allele, respectively.

FIGURE 4

Patterns of the associations of genetic variants with 27 brain imaging measurements. Genetic variants are represented by the apolipoprotein E (APOE) ε4 allele, the lower‐risk compound genotype (LR‐CompG), and the higher‐risk compound genotype (HR‐CompG). For APOE ε4, LR‐CompG, and HR‐CompG, the reference was the APOE ε3ε3 genotype. For HR versus LR (HR vs. LR), the reference was the LR‐CompG. The x‐axis shows abbreviations for the 27 brain imaging measurements. Thickness indicated by the suffix “_m” is measured in millimeters. Color indicates associations with β < 0 (red) and β > 0 (green). Color shades indicate the significance provided in the figure legend. Alzheimer's disease (AD) unadj, AD adj, Interactions, AD cases, and Controls denote the results from models for AD unadjusted, adjusted, interaction, and AD stratification analyses, respectively. Detailed numerical estimates are provided in Tables S1‐S6. ADSV, Alzheimer's disease signature volume; GrayVol, total gray matter volume; LEnt, left entorhinal volume; LEnt_m, left entorhinal thickness; LHippo, left hippocampus volume; LHOS, left hippocampal occupancy score; LMidTemp, left middle temporal gray matter volume; LMidTemp_m, left middle temporal gray matter thickness; LParHip, left parahippocampal gray matter volume; LParHip_m, left parahippocampal gray matter thickness; LPrecun, left precuneus gray matter volume; LPrecun_m, left precuneus gray matter thickness; LSupTem, left superior temporal gray matter volume; LSupTem_m, left superior temporal gray matter thickness; REnt, right entorhinal volume; REnt_m, right entorhinal thickness; RHippo, right hippocampus volume; RHOS, right hippocampal occupancy score; RMidTemp, right middle temporal gray matter volume; RMidTemp_m, right middle temporal gray matter thickness; RParHip, right parahippocampal gray matter volume; RParHip_m, right parahippocampal gray matter thickness; RPrecun, right precuneus gray matter volume; RPrecun_m, right precuneus gray matter thickness; RSupTem, right superior temporal gray matter volume; RSupTem_m, right superior temporal gray matter thickness; WhiteVol, total white matter volume.

FIGURE 5

Figural representation of the focused brain regions. The regions shown have significantly smaller values of the brain imaging measurements in carriers of the lower‐risk compound genotype (LR‐CompG) than in carriers of the higher‐risk compound genotype (HR‐CompG) in the AD adjusted model. They include the left superior temporal cortex thickness (LSupTem_m; red), right middle temporal gray matter volume (RMidTemp; yellow) and right entorhinal thickness (REnt_m; yellow, upper medial view). Detailed numerical estimates from this analysis represented here are provided in Table S4.