AbstractIntroductionModifiable health and lifestyle factors increase risk of dementia, but whether modifiable factors, when measured in late‐midlife, impact the emergence or progression of Alzheimer's disease (AD) pathophysiologic or cognitive changes remains unresolved.MethodsIn initially cognitively unimpaired, late middle‐aged participants (N = 1215; baseline age, M [standard deviation] = 59.3 [6.7] years) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), we investigated the influence of the Lifestyle for Brain Health (LIBRA) index, a lifestyle‐based dementia risk score, on AD‐related cognitive trajectories and amyloid beta (Aβ) plaque accumulation.ResultsOverall, lower baseline LIBRA, denoting healthier lifestyle and lower dementia risk, was related to better overall cognitive performance, but did not moderate apolipoprotein E ε4 or Aβ‐related longitudinal cognitive trajectories. LIBRA was not significantly associated with Aβ accumulation or estimated age of Aβ onset.DiscussionIn WRAP, late‐midlife LIBRA scores were related to overall cognitive performance, but not AD‐related cognitive decline or Aβ accumulation in the preclinical timeframe.Highlights The Lifestyle for Brain Health (LIBRA) index was associated with cognitive performance in late‐midlife. LIBRA did not moderate apolipoprotein E ε4 or amyloid‐related cognitive decline. LIBRA was not associated with the onset or accumulation of amyloid plaques.