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

Abstract

BackgroundRecently, 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.ResultsA 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.ConclusionsStrong 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.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0411-x) contains supplementary material, which is available to authorized users.

Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial

“…Challenges to dementia prevention studies include identifying a population at risk of progressing to dementia before the onset of irreversible neurodegeneration. Aging, APOE4 , positive family history of dementia [13] , and sedentary lifestyles [14] increase the risk of developing dementia. Carbon-13 tracer studies suggest that both aging and carrying the APOE4 allele accelerate DHA oxidation and loss [ 15 , 16 ].…”

Family history of Alzheimer’s disease alters cognition and is modified by medical and genetic factors

“…The two major risk factors for the more common late-onset form of AD are increasing age and a first-degree family history of dementia (FH) (Braak et al, 2011; Green et al, 2002). FH is known to encompass both heritable and nonheritable risk factors for AD (Chang et al, 2012; Yi et al, 2018). FH has been associated with changes in multiple cognitive domains previously in children (13 years old) and young adults (35 years old); however, fewer cognitive domain changes were reported in middle-age (53 years old) and older (65–78 years old) FH adults (Aschenbrenner et al, 2016; Bloss et al, 2008; Honea et al, 2009; La Rue et al, 2008; Miller et al, 2005; Parra et al, 2015; Zeng et al, 2013).…”

Genetic risk of dementia modifies the impact of obesity on limbic white matter and spatial navigation behavior in cognitively healthy adults

“…Together this pattern of results suggests that genetic-related risk factors (APOE and family history) affect medial temporal lobe input (PHC) but not output (fornix) structures, whilst age, sex and obesity affect output (fornix) but not input (PHC) structures. As APOE and family history are associated with earlier and larger amyloid and tau burden 33,106 , and LOAD pathology is known to spread from the entorhinal cortices, that are adjacent to the parahippocampal gyrus, into the medial temporal lobes 107,108 , this pattern may reflect tissue vulnerabilities that may precede the development of LOAD pathology.…”

“…It is wellestablished that APOE-e4 is associated with an earlier onset of LOAD 24,27 and a larger burden of amyloid-β plaques [28][29][30][31][32] . This is particularly the case in those individuals with a FH of LOAD 33,34 . In cognitively healthy individuals, APOE-e4 has been linked to vulnerabilities in spatial navigation 35 , executive function 36,37 and processing speed 38 and both APOE-e4 and FH to impairments in episodic memory 36,[39][40][41][42] .…”