Project Summary
The presence of the 4 allele of APOE (APOE4) is the greatest genetic risk factor for late onset
Alzheimer’s disease (AD), increasing the risk approximately 12-fold when homozygous for APOE4
compared to the most common APOE3/APOE3 genotype. However, the mechanisms by which different
APOE alleles mediate Alzheimer’s risk are unclear. The overall goals for this study are to 1) Investigate
neutrophil activation and lifespan as therapeutic targets to reduce AD risk or progression in the context of
different APOE genotypes and 2) Identify microbial interactions that represent promising targets to reduce
neutrophilic inflammation in the context of different APOE genotypes. A multitude of data demonstrate that
individuals with different APOE genotypes vary in their responses to inflammatory stimuli, and ApoE-
modulated neuroinflammation is emerging as a potential new mediator of APOE genotype-specific
cognitive decline. We propose that the gastrointestinal (GI) and peripheral immune systems represent a
likely bridge between infection or microbial dysbiosis and neuroinflammation, and that neutrophils, as the
most abundant leukocyte with great potential for inflammatory damage, mediate altered responses in
individuals with different APOE alleles to drive neuroinflammation and cognitive decline. Our hypothesis is
that APOE4 increases neutrophil activation and lifespan in the GI, periphery, and brain, thus contributing to
neuroinflammation and cognitive decline. This hypothesis is based on compelling evidence from published
work and our preliminary data. Studies have demonstrated that neutrophils infiltrate the brain vasculature
and parenchyma during AD and neutrophil activation in the periphery corresponds with disease
progression in AD. Our preliminary data suggests that APOE alters neutrophil activation in a genotype-
specific manner, as has been observed previously in glial cells. We will address our hypothesis and achieve
our study goals by pursuing the following three aims: 1) Investigate neutrophil lifespan, activation, and
functionality in the GI tract, periphery, and brain based on APOE genotype and age in mice expressing
human APOE2, APOE3, and APOE4 under the endogenous promotor (APOE-TR); 2) Investigate
microbiome changes longitudinally in APOE-TR mice and ApoE modulation of neutrophil responses to APOE
genotype-specific commensal bacteria and A; and 3) Investigate neutrophils as mechanistic drivers of
neuroinflammation and cognitive impairment in response to inflammatory stimuli in the context of different
APOE genotypes. This project is significant because no studies have investigated APOE-specific neutrophil
responses despite a proposed role for neutrophils in AD. This project is translationally innovative and
actionable because the information gained will inform the testing of neutrophil-targeted or microbial-targeted
therapeutic approaches in AD mouse models and humans and determine if they should be tailored based on
APOE genotype.
