AbstractBackgroundAlzheimer’s Disease (AD) drives the global rising incidence of neurodegenerative dementia. Disease progression includes cerebral aggregation of amyloid‐beta plaques and immune activation. Many AD animal models carry mutations that cause an early onset of these phenotypes, but the mutations are rare in human populations; most cases are idiopathic and late‐onset AD (LOAD). Another approach utilizing a transgenic APOE animal model may better model clinical populations. APOE4 is the predominant genetic risk factor for LOAD and confers increasing risk for LOAD in allelic fashion, relative to normative APOE3. This study investigates the JAX humanized APOE knock‐in mouse model of LOAD’s translational potential for peripheral biomarkers of pathology in aged, male and female mice.MethodAged mice of both sexes (23‐25 months old; 39M/37F) with APOE3/3,APOE3/4, andAPOE4/4 genotypes underwent blood plasma amyloid‐beta (Aß) measurement. A subset of these animals (30M/28F) additionally received peripheral immunophenotyping of whole blood via flow cytometry. Two‐way ANOVA and post‐hoc t‐tests were conducted to determine data significance.ResultsFemale mice had lower Aß42 plasma levels as well as a decreased Aß42/40 ratio, suggesting higher levels of the aggregate‐prone Aß42 protein in the brain, but there were no observed APOE genotype effects. Blood plasma Aß40 levels did not differ by genotype or sex. Whole blood flow cytometry showed an elevation in CD8+ memory T cells in APOE4/4 mice relative to APOE3/3 andAPOE3/4 mice. Aged female mice had a peripheral immune cell profile consistent with a more reactive and dysfunctional immune system than genotype‐matched aged males: higher levels of CD11b+ B cells, CD4+ helper T cells, and CD8+ cytotoxic T cells along with a lower percentage of naïve CD4+ and CD8+ T cells.ConclusionIn mice aged to resemble a ∼70‐year‐old human population, these results suggest increased brain levels of the aggregate‐prone Aß42 isoform and a reactive peripheral immune system in female APOE mice. This sex difference is consistent with the increased prevalence of LOAD in women. However, the specificity of APOE4 genotype effects may define the translational potential of this humanized APOE mouse model of late‐onset Alzheimer’s Disease.Research supported by T32AG061897, R01AG057931, and RF1AG059093 to RDB.