Preventing or delaying late life cognitive impairment and dementia through lifestyle interventions is one of the greatest global challenges of the 21st century. The long preclinical phase of dementia offers an ideal time window for prevention measures, but the best timing and target group is not known. In this regard, it will become essential to understand why some elderly at-risk individuals are resistant to developing significant brain pathology and why in those with manifested brain pathology, some individuals are resilient against cognitive decline. In DIVERT-AD, I aim to unravel how modifiable lifestyle factors contribute to resistance and resilience to dementia by exploiting longitudinal population brain imaging. The key objectives are to determine whether a favourable lifestyle profile in mid- and late-life can attenuate (1) higher early-life risk of developing neuropathology, and/or (2) the adverse effect of neuropathology on cognition and then (3) to apply this knowledge to one of the first population-based positron emission tomography investigations of amyloid pathology, the key hallmark of Alzheimer’s disease. To achieve these goals, I will combine genetics, lifestyle, neuropsychology and brain imaging data from three large population-based cohorts, the Rotterdam Study, Framingham Heart Study and UK Biobank, including a total of ~47,000 participants. Neuropathology will be first determined by magnetic resonance imaging techniques measuring neurodegenerative and vascular pathologies and will be later refined by molecular imaging of amyloid plaques (~700 participants). Advanced epidemiological methods will be used to account for time-varying effects of lifestyle measures and confounders. Results from DIVERT-AD will provide unique insights into the impact of lifestyle factors on the brain and cognition in the preclinical phase of dementia. In turn, these insights are of major importance for developing targeted prevention strategies.