Abstract
Late onset Alzheimer’s disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.
Highlights
APOE genotype and female chromosomal sex are two known risk modulators for late onset Alzheimer’s disease (LOAD), where APOE4 carriers [1,2,3,4,5,6,7,8] and females [9,10,11,12,13,14] exhibit a higher life-time risk of Alzheimer’s disease
APOE4 carriers had an earlier onset of brain glucose hypometabolism in multiple brain regions, including posterior cingulate, parietal lobe, temporal lobe, prefrontal cortex, parahippocampal gyrus, and thalamus [24, 30], which was paralleled by a greater reduction in glucose metabolism in longitudinal analyses [23, 30]
To investigate the systemic modulation of sex and APOE genotype, we performed a comprehensive analysis of both peripheral and brain metabolites, RNA transcripts in 16 months old human APOE3 (hAPOE3) and hAPOE4 male and female mice. Results of these analyses indicate that lipid metabolism was upregulated in hAPOE4 mice, especially in females
Summary
APOE genotype and female chromosomal sex are two known risk modulators for late onset Alzheimer’s disease (LOAD), where APOE4 carriers [1,2,3,4,5,6,7,8] and females [9,10,11,12,13,14] exhibit a higher life-time risk of Alzheimer’s disease. APOE4 carriers had an earlier onset of brain glucose hypometabolism in multiple brain regions, including posterior cingulate, parietal lobe, temporal lobe, prefrontal cortex, parahippocampal gyrus, and thalamus [24, 30], which was paralleled by a greater reduction in glucose metabolism in longitudinal analyses [23, 30]. In both MCI and AD populations, APOE4 carriers display more widespread brain glucose hypometabolism [26] and a more severe phenotype in regions vulnerable to AD pathology, including parietal lobe, temporal lobe, and cingulate areas [27, 28, 35]
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