The world population is getting older, and this age group faces important health challenges, among which age-related cognitive decline stands out. Therefore, it is important to identify vulnerability and protective health factors in order to understand ways to prevent cognitive decline. This thesis aimed to address the relationship between the Hypothalamic–Pituitary–Adrenal (HPA) axis and cognitive functioning during aging, taking into account genetic (Apolipoprotein E, ApoE, polymorphism), situational (loneliness), and individual factors (personality traits). To do this, a group of healthy older people over 55 years of age, men and women, were evaluated. A neuropsychological battery was administered to assess global cognition, attention, executive function, working and declarative verbal memory. Participants also provided saliva samples to measure the HPA-axis functioning (cortisol levels) and the ApoE genotype. In addition, participants completed the revised UCLA loneliness scale, the NEO-Five Factor Inventory to measure the big five personality traits, the Cognitive Reserve Questionnaire, and the Short Form Health Survey (SF-36) to assess subjective physical and mental health. Furthermore, different objective health measures were also obtained: Body Mass Index (BMI), Waist-Hip Ratio (WHR), Glycated Hemoglobin (HbA1c), Low-Density Lipoprotein (LDL) and High-Density Lipoprotein (HDL) Cholesterol, and Pulse Pressure. The main results/conclusions of this thesis are, first, that the ApoE-ε2 allele has been shown to be a protective factor for learning ability. The ApoE-ε3 allele was related to a more adaptive HPA-axis response, with beneficial effects on cognitive performance, whereas the ApoE-ε4 allele could be a vulnerability factor in the adverse effects of HPA-axis dysregulation on cognition. In addition, loneliness was associated with a dysregulation of the HPA-axis. Furthermore, loneliness was not associated directly with cognitive function in healthy older adults, but it was indirectly related to worse cognitive performance via higher bedtime cortisol levels. Therefore, the dysregulation of the HPA-axis appears to be one of the mechanisms underlying the relationship between loneliness and cognitive impairment. Concerning personality dimensions, our results confirm that neuroticism is an important health risk factor in aging because it is associated with a dysregulation of the HPA-axis, decline in attention via a dysregulation of the HPA-axis, and worse objective and subjective health. In contrast, conscientiousness appears as a robust protective factor for health in older people because it is associated with healthier HPA-axis functioning and better objective and subjective health; however, it is not a predictor of cognitive change in healthy older adults. Regarding extraversion, it could protect against decline in executive function and delayed memory recall, but favor decline in immediate memory recall, which could be explained by cognitive reserve. Openness and agreeableness did not seem important predictors of health outcomes in older people, but they are protective factors against decline in immediate recall via cognitive reserve, and delayed recall, respectively. Finally, it is worth noting that regarding to the sex/gender, our results suggest that neuroticism is a greater risk factor for decline in working memory in men, and for health in women, whereas extraversion is a protective factor for health in women, but a risk factor in men.