Aging shapes baseline immunity in sterile-housed female hAPOE mouse genotypes

The Apolipoprotein E ε4 allele (APOE4) is a major risk factor in the development of late-onset Alzheimer's Disease (LOAD; AD) and has been associated with altered immunological responses, particularly under inflammatory challenge. Whether APOE genotype shapes baseline peripheral immunity across aging remains unclear. Because experimental context can influence immune phenotypes, we focus here on baseline profiles under specific-pathogen-free barrier housing (sterile housing) and discuss their implications. To this end, we highlight the peripheral immune profile in female humanized APOE mice (APOE3/3, APOE3/4, APOE4/4) maintained under sterile housing at 6, 9, and 15 months of age. Immunophenotyping of blood and spleen revealed significant age-related changes in B and T cell subpopulations and cytokine levels. Significant increases in activated and effector CD4⁺ and CD8⁺ T cells, as well as plasma cells, were observed at 15 months of age, particularly in the spleen. These shifts were primarily driven by ageing rather than APOE genotype. The only genotype-related differences detected were an increase in plasma TNF-α and IL-1β levels at 15 months and 9 months, respectively, in APOE4 compared with APOE3. Overall, aging exerts a stronger influence than APOE genotype on baseline peripheral immunity in female hAPOE mice under sterile housing, establishing an age-stratified baseline and providing a context-dependent rationale for future challenge-based studies to define genotype-by-inflammation interactions relevant to LOAD.