The effect of sex on APOE‐modulated AD pathology in EFAD mice

Abstract

APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) and is associated with accelerated accumulation of both amyloid plaques and and soluble oligomeric forms of the amyloid‐β peptide (oAβ), likely a proximal neurotoxin. Importantly, female APOE4 carriers have a greater lifetime risk for developing AD, an increased rate of cognitive decline and accelerated accumulation of Aβ compared to male APOE4 carriers. In vivo progress has been limited by the lack of a tractable familial AD‐transgenic (FAD‐Tg) mouse model expressing human (h)‐ rather than mouse (m)‐APOE. To study the interactions among sex, h‐APOE and AD pathology, we developed the EFAD‐Tg mice by introducing the h‐APOE genotypes into the 5×FAD‐Tg mice. We previously demonstrated that in the EFAD mice, confirmed in human control and AD samples of CSF and brain, that apoE lipidation is lower and soluble Aβ levels are higher with APOE4 vs. APOE3. Thus, we have developed the mechanistic hypothesis that AD pathology and APOE4 cause a reduction in apoE lipidation, resulting in inefficient clearance of soluble A β synaptic loss, memory/cognitive deficits, and dementia. Novel preliminary data demonstrate that the differences in female vs. male E4FAD mice mimic these established APOE4 vs. APOE3 differences in Aβ aggregation/accumulation, and apoE levels/lipidation. In addition, amyloid deposition, neuroinflammation and tau pathology is significantly greater in the EFAD females compared to males. These data suggest that sex profoundly influences APOE genotype‐specific effects on AD pathology, with apoE lipidation and oAβ levels possibly at the intersection between these two AD risk factors. Together, these data will help to address the critical need for treatment options for women at high risk for AD from the APOE4 allele.Support or Funding InformationCurrent LaDu lab funding includes NIH (NIA) P01AG044682, R21AG030128, R21AG048498, R21AG051233, CCTS (UL1RR029879)