Abstract Body: Late-onset Alzheimer's Disease (LOAD) mouse models are characterized by two human LOAD-associated mutations APOE4 and TREM2[R47H]. APOE4 alters the transport and metabolism of amyloid-beta by binding heparin sulfate proteoglycans in the vascular extracellular matrix promoting amyloid-beta retention and increasing collagen accumulation. In parallel, altered TREM2 expression impacts macrophage function by promoting amyloid-beta phagocytosis. Overtime both genes promote chronic inflammation and vessel wall thickening, reducing arterial compliance and increasing vascular stiffness, which is associated with disease progression and elevated cardiovascular risk.
In this study, we sought to identify which genetic factor(s) in human transgenic mice replicating LOAD will predispose to increased pulse wave velocity (PWV), which is associated with arterial stiffness.
This study utilized B6 (control), TREM2[R47H], APOE4, and LOAD1 transgenic mice which were enrolled at 8 weeks of age. Mice were maintained in groups of no more than five per cage under standard housing conditions with a 12-hour light/dark cycle at the New York Institute of Technology College of Osteopathic Medicine animal facility. At 52 weeks of age, carotid-femoral PWV was collected using doppler ultrasound and analyzed using Vevo LAB ultrasound analysis software. All procedures were conducted in accordance with institutional and federal guidelines and were approved by the Institutional Animal Care and Use Committee. Statistical analysis was performed using GraphPad Prism 10 software (GraphPad, San Diego, CA, USA). The effects of TREM2[R47H] and APOE4 variants were assessed using a logistic regression analysis with genotypes and sex as binary predictors and increased stiffness (top quartile in PWV) as an outcome. A p-value of less than 0.05 was considered statistically significant.
The preliminary data show that both mutations were independently associated with increased arterial stiffness (TREM2[R47H] Odds Ratio [OR] = 3.98[95%CI: 1.30 – 14.03], p = 0.0152; APOE4 OR = 3.20[1.03-11.34], p = 0.0443). Sex was not a significant predictor of increased PWV in this study.
TREM2[R47H] and APOE4 variants are associated with increased arterial stiffness on mouse models of LOAD consuming a high-fat, high-sugar diet. Limitations of this study include the relatively small sample size used to obtain the data. Additional studies may implement multiple measurements of stiffness taken over a greater longitudinal period.