Abstract
Polymorphic alleles in the apolipoprotein E (APOE) gene are the main genetic determinants of late-onset Alzheimer's disease (AD) risk. Individuals carrying the APOE E4 allele are at increased risk to develop AD compared to those carrying the more common E3 allele, whereas those carrying the E2 allele are at decreased risk for developing AD. How ApoE isoforms influence risk for AD remains unclear. To help fill this gap in knowledge, we performed a comparative unbiased mass spectrometry-based proteomic analysis of post-mortem brain cortical tissues from pathologically-defined AD or control cases of different APOE genotypes. Control cases (n = 10) were homozygous for the common E3 allele, whereas AD cases (n = 24) were equally distributed among E2/3, E3/3, and E4/4 genotypes. We used differential protein expression and co-expression analytical approaches to assess how changes in the brain proteome are related to APOE genotype. We observed similar levels of amyloid-β, but reduced levels of neurofibrillary tau, in E2/3 brains compared to E3/3 and E4/4 AD brains. Weighted co-expression network analysis revealed 33 modules of co-expressed proteins, 12 of which were significantly different by APOE genotype in AD. The modules that were significantly different by APOE genotype were associated with synaptic transmission and inflammation, among other biological processes. Deconvolution and analysis of brain cell type changes revealed that the E2 allele suppressed homeostatic and disease-associated cell type changes in astrocytes, microglia, oligodendroglia, and endothelia. The E2 allele-specific effect on brain cell type changes was validated in a separate cohort of 130 brains. Our systems-level proteomic analyses of AD brain reveal alterations in the brain proteome and brain cell types associated with allelic variants in APOE, and suggest further areas for investigation into the upstream mechanisms that drive ApoE-associated risk for AD.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia and affects millions of people worldwide (Prince et al, 2015), yet the biological basis of the disease remains poorly understood
We did not observe a difference in the levels of amyloid-β by ApoE genotype in AD, a few ApoE 2/3 carriers had lower amyloid-β levels compared to E3/3 and E4/4 (Figure 1A)
In patients who died with AD dementia, we observed similar levels of amyloid-β across ApoE 2/3, 3/3, and 4/4 genotypes in dorsolateral prefrontal cortex (DLPFC), and lower levels of tau in E2/3 carriers compared to E4/4 carriers, with no difference in tau levels between E3/3 and E4/4 carriers
Summary
Alzheimer’s disease (AD) is the most common cause of dementia and affects millions of people worldwide (Prince et al, 2015), yet the biological basis of the disease remains poorly understood. APOE is present in three common alleles within humans: ε2 (E2), ε3 (E3), and ε4 (E4). The presence of an E2 allele lowers the odds to develop AD to 0.6 (Corder et al, 1994; Farrer et al, 1997). A number of hypotheses have been proposed to explain how the ApoE protein influences risk for AD, including effects on lipid metabolism, amyloid-β metabolism, mitochondrial function, cerebrovascular integrity, and inflammation (Huang, 2010; Verghese et al, 2011; Tai et al, 2016; Zhao et al, 2018). The mechanism(s) by which allelic variation in the APOE gene influences AD risk remains unclear
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