It is increasingly recognized that the declines in brain structure and function in persons with no clinical brain disease that we call brain aging and the 2 brain diseases that most frequently affect older adults (dementia and stroke) are the theoretically predictable consequences of a lifetime of injury that overcomes genetically and environmentally determined reserve and resilience, a concept encapsulated in the shorthand phrase life-course illness. Despite this insight, details of the various factors that adversely affect the brain health of older adults (and clarity on which times during life have the greatest effect and hence provide the best opportunities for intervention) remain unclear. One reason for this is the need for decades of follow-up to ascertain the delayed outcomes of putative risk factors. It is only in this century that the earliest epidemiological studies completed 50 years of follow-up on their participants.1 Another challenge is the need to understand not just which risk factors are important and when they act but also how they act and the biological pathways altered. The tools of genetics, molecular biology, and brain imaging now permit researchers to explore these questions in an epidemiological setting. In this issue of JAMA Neurology, Lane and colleagues2 leverage recently acquired brain-imaging data that permit them to dissect the outcomes of conventional vascular risk factors on markers of vascular brain injury and neurodegeneration, including brain amyloid burden on positron emission tomographic (PET) imaging, in 463 adults followed up for more than 3 decades.