Single lifestyle factors affect brain biomarkers and cognition. Here in this work, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based ?-amyloid (A?), hippocampal volume, and cognitive function in aged controls. Lower A? burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ?4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, A? load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive function and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Finally, our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.