Epidemiological studies show that individuals who carry the relatively uncommon
APOE ε2 allele rarely develop
Alzheimer disease, and if they do they have a later age of onset, milder
clinical course, and less severe neuropathological findings than others with
Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for
Alzheimer disease,
APOE ε4, which has an age of onset several decades earlier, as well as a more aggressive
clinical course and notably more severe neuropathological findings, especially in terms of the amount of
amyloid deposition. Even one
APOE ε2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by
APOE ε2, or if
APOE ε2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to
APOE2 via a gene
therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human
APOE4. This result suggests a promising protective effect of exogenous
APOE2, revealing a cell non-autonomous effect of the
protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit
APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an
APOE2 therapeutic could be effective in
Alzheimer disease even in individuals born with the risk ε4 allele.
One Sentence Summary: Introduction of
ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in
amyloid load and plaque associated synapse loss, and reduces
neuroinflammation by modulating microglial responsiveness to plaques.