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 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.