Identification and modification of amyloid-independent phenotypes of APOE4 mice

Background: Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (APOE4), but have no course for reducing their risk. The association of non-steroidal anti-inflammatory drug (NSAID) use with reduced risk of AD for APOE4-carriers suggests that NSAIDs may be useful in AD prevention. Methods: We identified phenotypes associated with APOE4 in APOE knock-in mice in order to define modifiable measures that correlate with risk of AD. Results: APOE4 mouse brains showed altered post-translational modifications and biochemical distribution of APOE compared to APOE3 mice; these differences were also observed in brains of human APOE4 carriers. Two-month treatment with ibuprofen significantly altered the expression pattern of APOE in APOE4 mice to that of APOE3 mice; PPAR-γ agonist pioglitazone also had a significant effect. APOE4 mice also show deficits in dendritic spine density, and ibuprofen and pioglitazone significantly increased dendritic spine density. Conclusions: We report new phenotypes associated with APOE4 in human and APOE knock-in mice and their mitigation with NSAID treatment, through COX-2 inhibition and PPAR-γ activation.