Synergistic interaction between APOE and family history of Alzheimer's disease on cerebral amyloid deposition and glucose metabolism

Abstract

Background: Recently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer's disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks-the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)-on AD-related brain changes in cognitively normal (CN) middle-aged and older adults.

Methods: [¹¹C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [¹⁸F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses.

Results: A significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aβ) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions.

Conclusions: Strong synergistic effects of APOE4 and FH on Aβ deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aβ. Other unspecified risk factors-genes and/or environmental-that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.

Keywords: APOE; Amyloid beta deposition; Cerebral glucose metabolism; Cognitively normal adults; Family history of Alzheimer’s disease.

Fig. 1

Mean PiB retention and FDG uptake SUVRs. a AD_PiB-ROI between FH^– and FH⁺. b AD_PiB-ROI between APOE4^– and APOE4⁺. c AD_FDG-ROI between FH^– and FH⁺. d AD_FDG-ROI between APOE^– and APOE⁺. e Interaction effect of FH and APOE on PiB retention. f Interaction effect of FH and APOE on FDG uptake. The green shaded area in e denotes below the PiB SUVR threshold of 1.4. Error bars indicate standard error. *P < 0.05; **significant difference in the post-hoc analyses adjusted for multiple comparisons using Dunn-Sidak correction (P_B < 0.0085). Aβ amyloid beta, APOE4 apolipoprotein ε4 allele, APOE4⁺ APOE4 carriers, APOE4^– APOE4 noncarriers, FDG [¹⁸F] fluoro-2-deoxyglucose, FH family history of Alzheimer’s disease, FH⁺ individuals with FH, FH^– individuals without FH, L left hemisphere, PiB [¹¹C] Pittsburg compound B, R right hemisphere, SUVR standardized uptake value ratio

Fig. 2

Regions showing significant differences in Aβ deposition from voxel-wise analyses. a FH⁺APOE4⁺ compared with FH⁺APOE4^–. b FH⁺APOE4⁺ compared with FH^–APOE4⁺. c FH⁺APOE4⁺ compared with FH^–APOE4^–. A anterior, APOE4 apolipoprotein ε4 allele, APOE4⁺ APOE4 carriers, APOE4^– APOE4 noncarriers, FH family history of Alzheimer’s disease, FH⁺ individuals with FH, FH^– individuals without FH, L left hemisphere, P posterior, R right hemisphere

Fig. 3

Regions showing significant difference in cerebral glucose metabolism from voxel-wise analyses. a FH⁺APOE4⁺ compared with FH⁺APOE4^–. b FH⁺APOE4⁺ compared with FH^–APOE4⁺. c FH⁺APOE4⁺ compared with FH^–APOE4^–. APOE4 apolipoprotein ε4 allele, APOE4⁺ APOE4 carriers, APOE4^– APOE4 noncarriers, FH family history of Alzheimer’s disease, FH⁺ individuals with FH, FH^– individuals without FH, L left hemisphere, R right hemisphere