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The focus on amyloid plaques and neurofibrillary tangles has yielded no Alzheimer's disease (AD) modifying treatments in the past several decades, despite successful studies in preclinical mouse models. This inconsistency has caused a renewed focus on improving the fidelity and reliability of AD mouse models, with disparate views on how this improvement can be accomplished. However, the interactive effects of the universal biological variables of AD, which include age, APOE genotype, and sex, are often overlooked. Age is the greatest risk factor for AD, while the ε4 allele of the human APOE gene, encoding apolipoprotein E, is the greatest genetic risk factor. Sex is the final universal biological variable of AD, as females develop AD at almost twice the rate of males and, importantly, female sex exacerbates the effects of APOE4 on AD risk and rate of cognitive decline. Therefore, this review evaluates the importance of context for understanding the role of APOE in preclinical mouse models. Specifically, we detail how human AD pathology is mirrored in current transgenic mouse models ("What") and describe the critical need for introducing human APOE into these mouse models ("Who"). We next outline different methods for introducing human APOE into mice ("How") and highlight efforts to develop temporally defined and location-specific human apoE expression models ("When" and "Where"). We conclude with the importance of choosing the human APOE mouse model relevant to the question being addressed, using the selection of transgenic models for testing apoE-targeted therapeutics as an example ("Why"). Unlabelled Image • What: AD is uniquely human, but molecular mechanisms can be measured in Tg mice. • Who: A universal biological variable of AD, APOE is critical for preclinical models. • How: There are several strategies for developing APOE -Tg mice. • When/Where: Developmental and region-specific models probe apoE expression patterns. • Why: Therapeutic strategies targeting apoE can exploit the relevant mouse model(s). [ABSTRACT FROM AUTHOR]

• APOE transgenic mouse models of Alzheimer's disease have evolved overtime to include various methods to knock-down or express apolipoprotein E. • Limitations of current APOE transgenic models include comparing FAD/m- APOE with FAD/ APOE-/- mice to determine the effect of APOE on AD pathology. • Few recent models are phenotypically characterized by APOE isoform with genetic (sex, age) and modifiable (e.g., inflammation, obesity) Alzheimer's disease risk factors. • New data presented further characterizes the EFAD mice and supports the interactive effects of APOE genotype with sex on FAD-induced pathology. Identified in 1993, APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to the common variant APOE3. Since the mid 1990's, transgenic (Tg) mice have been developed to model AD pathology and progression, primarily via expression of the familial AD (FAD) mutations in the presence of mouse- APOE (m- APOE). APOE4 , associated with enhanced amyloid-β (Aβ) accumulation, has rarely been the focus in designing FAD-Tg mouse models. Initially, FAD-Tg mice were crossed with human (h)- APOE driven by heterologous promoters to identify an APOE genotype-specific AD phenotype. These models were later supplemented with FAD-Tg mice crossed with APOE- knockouts (APOE-/- or APOE -KO) and h- APOE -targeted replacement (h- APOE -TR) mice, originally generated to study the role of APOE genotype in peripheral lipid metabolism and atherosclerotic lesion development. Herein, we compare the m- and h- APOE multi-gene clusters, and then critically review the relevant history and approaches to developing a Tg mouse model to characterize APOE -dependent AD pathology, in combination with genetic (sex, age) and modifiable (e.g., inflammation, obesity) risk factors. Finally, we present recent data from the EFAD mice, which express 5xFAD mutations with the expression of the human apoE isoforms (E2FAD, E3FAD and E4FAD). This includes a study of 6- and 18-month-old male and female E3FAD and E4FAD, a comparison that enables examination of the interaction among the main AD risk factors: age, APOE genotype and sex. While no single transgenic mouse can capture the effects of all modifiable and genetic risk factors, going forward, a conscious effort needs to be made to include the factors that most significantly modulate AD pathology. [ABSTRACT FROM AUTHOR]