Sex Differences in the Relationship Between APOE and AD: Role of Sexual Phenotype

Alzheimer’s disease (AD) is an adult-onset progressive neurodegenerative disorder that preferentially affects brain regions critical to learning, memory, and executive function. There is no cure and few palliative treatments that modify disease progression. AD is characterized by an age-induced increased in -amyloid (A) peptides, which can aggregate to form amyloid plaques, a pathological hallmark of the disease, as well as soluble oligomers of the A42 peptide (oA), thought to be a cellular neurotoxin. Although 94-99% of AD is sporadic, the majority of risk can be accounted for by three biological risk factors, or the universal biological variables of AD (UBVs), specifically age, APOE and sex. Although age is the greatest risk factor for AD, the greatest genetic risk factor is APOE4, which encodes apolipoprotein E4 (apoE4) and increases risk up to 15-fold compared to common genotype APOE3. Importantly, females have a 2-fold increased risk for AD compared to males and female APOE4 carriers have the greatest risk for AD. The mechanism(s) underlying the synergistic increase in risk with APOE4 and female sex remains unknown. To address this gap in knowledge, we utilized the EFAD-transgenic (Tg) mouse model, an AD-Tg line that overexpresses human A42 and either human APOE4 (E4FAD) or APOE3 (E3FAD). EFAD-Tg mouse pathology mirrors the human risk imparted by the human UBVs, such that disease progression occurs: ♂E3FAD < ♀E3FAD < ♂E4FAD < ♀E4FAD. The goal of this study is to evaluate the role of maleness and femaleness in the APOE4-induced AD risk/pathology, to accomplish this, we developed a continuum of sexual phenotypes by steroid manipulation of prenatal sexual differentiation in E3FAD and E4FAD mice to create feminized males (♀/♂) and masculinized females (♂/♀) for comparison with the male (♂/♂) and female (♀/♀) E3FAD and E4FAD mice. Our hypothesis is that the level of feminization will correspond to the development of pathology, with ♂/♂ EFAD mice < ♂/♀ EFAD mice < ♀/♂ EFAD mice < ♀/♀EFAD mice, and these effects will be exacerbated in the presence of APOE4. Specifically, the increased AD pathology predicted in ♀/♂ compared to ♂/♀ suggests that the process of masculinization/defeminization induced by testosterone during organizational phase will actively protect against the AD-promoting effects of female sex. Decreased pathology in ♂/♀E4FAD is demonstrated by a decrease in A deposition, insoluble apoE, and total apoE to similar levels to ♂/♂E4FAD suggesting a protective effect. ♂/♀E4FAD also demonstrated increased proportion of lipoprotein associated apoE consistent with the protective effect observed in A deposition. Synaptic viability produced the following results for the level of pathology consistent with our hypothesis above: ♂/♂E4FAD < ♂/♀E4FAD < ♀/♂E4FAD. The results support the central role of masculinization and testosterone in actively protecting against the AD-promoting effects of female sex with APOE4 genotype.