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

The APOE ɛ4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE3, with APOE2 providing a protective effect. APOE4 is associated with accelerated amyloid‐β (Aβ) accumulation, both as amyloid plaque and soluble oligomeric forms of Aβ (oAβ), the latter considered a proximal neurotoxin. Using EFAD mice, a novel, tractable human‐APOE/familial AD‐transgenic (FAD‐Tg) preclinical mouse model, we have developed the mechanistic hypothesis that APOE4 causes a reduction in apoE lipidation, resulting in inefficient clearance of soluble Aβ, synaptic loss, and memory deficits. By 6‐months (M), E4FAD mice have greater cognitive impairment, AD pathology and soluble Aβ levels, with lower apoE lipidation levels compared to E3FAD. However, the effect of aging on EFAD mice has not been analyzed beyond 6M. In this study, at 8M, 10M, 14M and 18M, we measured amyloid deposition, neuroinflammation and tau pathology, as well apoE lipidation, and soluble levels of Aβ42, oAβ and apoE/Aβ complex. AD pathology continues with age (E4FAD > E3FAD) spreading from the subiculum and deep layers of the frontal cortex to the entire length of the cortex and particularly the thalamus. Comparison of Aβ deposition identified with an Aβ mAb vs. Thio‐S staining revealed both regional and age‐dependent changes in plaque morphology. Importantly, while the levels of soluble Aβ42 plateaued at 10M in E4FAD and 14M in E3FAD mice, oAβ levels continued to increase, from 6–18M with E4FAD > E3FAD. The predictive validity of preclinical FAD‐Tg mouse models that lack h‐APOE, the major genetic risk factor for AD, remains unclear. As the greatest risk factor for AD is age, aged EFAD mice address both these critical risk factors.