Using APOE Genotype to Identify New Biomarkers of Alzheimer's Disease Risk
Dumanis, Sonya Benjamina E.
Rebeck, G. William
Alzheimer's disease (AD), unlike the other leading causes of death, does not have a cure or an effective intervention strategy. The largest genetic risk factor for AD is APOE, with the ε4 allele increasing and the ε2 allele decreasing one's risk for the disease. It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g. amyloid plaques, synaptic and neuron loss). Here, we characterize the differences between the at risk group for AD (the ε4 carriers) and the not-at risk group (non-ε4-carriers), to determine what underlies APOE-related risk to AD.To do this, we utilized APOE Targeted Replacement (TR) mice. These animals express the human APOE alleles(APOE-ε2, APOE-ε3, or APOE-ε4) under the mouse APOE promoter, and do not develop the plaques and tangles diagnostic of AD. We found that despite the lack of AD pathology, APOE-ε4 TR mice had alterations at the synapse. Specifically, APOE-ε4 TR mice have fewer dendritic spines at the post-synaptic terminal and simpler neuronal morphology compared to the other APOE genotypes. Pre-synaptically, we found that APOE-ε4 TR mice have reduced levels of glutaminase, increased levels of VGLUT1 and increased levels of glutamine (GLN). Taken together, these data suggest that the APOE-ε4 allele affects brain function well before AD pathogenesis occurs.To begin addressing the mechanism by which APOE can impact dendritic spine morphology, we examined the role of the apoE receptor, ApoEr2. We found that increased surface levels of ApoEr2 promoted dendritic spine formation and that the ligand binding domain is necessary for us to observe these effects, suggesting that ApoEr2 may be involved in APOE related changes at the synapse.To test whether there are CSF biomarkers of APOE-associated risk that could be followed in preventative therapeutic AD approaches, we examined levels of GLN in ante-mortem CSF samples from healthy controls. Consistent with our mouse studies, we found that APOE-ε4 carriers had higher levels of GLN compared to the other genotypes. These studies suggest that GLN may be a novel biomarker used to assess AD patients in their pre-clinical phases and as a therapeutic measure in preventative AD trials.
Showing items related by title, author, creator and subject.
Human APOE4 Affects Microglial Reactivity and Spatial Cognition in a Mouse Model of Alzheimer's Disease Risk Rodriguez, Gustavo Armando (Georgetown University, 2015)Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder that results in declarative memory deficits. Apolipoprotein e4 (APOE-ε4) is the strongest genetic risk factor for developing AD, and influences ...
DiBattista, Amanda Marie (Georgetown University, 2016)Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer’s disease (AD), the E4 allele for apolipoprotein E (APOE4), but have few strategies to reduce their risk. To identify markers associated ...
Recall of disclosed Apolipoprotein E genotype and lifetime risk estimate for Alzheimer's disease: the REVEAL Study Eckert, Susan LaRusse; Katzen, Heather; Roberts, J. Scott; Barber, Melissa; Ravdin, Lisa D.; Relkin, Norman R.; Whitehouse, Peter J.; Green, Robert C. (2006-12)