The human APOE4 genotype has been identified as a crucial risk factor for developing neurodegenerative diseases, such as Alzheimer, in elderly. However, no clear directions to generate a prevention plan for APOEε4 carriers exist nowadays. In this sense, current knowledge states that chronic neuroinflammation is a convergent point to neural diseases, contributing to neurodegeneration. Interestingly, APOE is an immunomodulatory agent, establishing a nexus between those premises. However, mechanisms underlying this association are yet to be clarified.We aimed to identify in aged transgenic mice the most vulnerable APOE genotype and sex after a chronic inflammatory challenge. Behaviour (anxiety and sociability) as well as biochemical parameters on serum and hippocampus were evaluated. Therefore, 15 to 16 month-old humanized apoE3 and apoE4 homozygous male and female mice, were treated with an intraperitoneal dose of 0 or 0,25mg/kg of lipopolysaccharide three times a week on alternate days until 17 doses (6 weeks). Behavioural tests started on the 5th injection, and at the end of the experimental procedures, serum and tissues were collected for biochemical assays.Our results showed differences associated with treatment in the cytokine profile and behaviour assessed, demonstrating that peripheral chronic inflammation has an effect on neuroinflammation, potentially altering brain functions. These involve APOE genotype, with a characteristic E3 and E4 response influenced in a sex-dependent manner. The final outlook generates a multifactorial scheme of vulnerability highlighting those risk factors, APOE genotype and sex, with new perspectives to consider, which encourages future interventions with them in mind.