Alzheimer's disease (AD) is the most common form of dementia in individuals over 
the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 
allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are 
being considered. One unresolved question in ApoE biology is whether ApoE is 
necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic 
loss and cognitive dysfunction; however, these findings are complicated by the 
fact that ApoE knock-out mice have highly elevated plasma lipid levels, which 
may independently affect brain function. To bypass the effect of ApoE loss on 
plasma lipids, we generated a novel mouse model that expresses ApoE normally in 
peripheral tissues, but has severely reduced ApoE in the brain, allowing us to 
study brain ApoE loss in the context of a normal plasma lipid profile. We found 
that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction 
similar to that of ApoE KO mice; however, the bEKO mice did not have the 
learning and memory impairment observed in ApoE KO mice. Moreover, we found that 
the memory deficit in the ApoE KO mice was specific to female mice and was fully 
rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced 
in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These 
findings suggest that plasma lipid levels can influence cognition and synaptic 
function independent of ApoE expression in the brain.
SIGNIFICANCE STATEMENT: One proposed treatment strategy for Alzheimer's disease 
(AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk 
factor for the disease. A major concern of this strategy is that an animal model 
of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and 
cognitive impairment; however, these mice also develop dyslipidemia and severe 
atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to 
wild-type levels normalizes plasma lipids in ApoE KO mice. While this does not 
rescue synaptic loss, it does completely restore learning and memory in the 
mice, suggesting that both CNS and plasma ApoE are independent parameters that 
affect brain health.