The role of lifestyle and health-related factors in dementia risk has been established. However, how a combination of modifiable risk factors, as reflected by the LIBRA (LIfestyle for BRAin health) index, contributes to cognitive resilience to genetic susceptibility to dementia (CRgen) remains unclear. We selected 6,774 Three-City study participants without dementia at baseline (mean age=74 years) and with ≥2 cognitive measures over time. Genetic risk was defined through ApoE-ε4 carriage alone (ε4-carriers) or combined with high AD-specific genetic risk scores beyond ApoE (ε4-carriers/GRS-high). To define CRgen, we modeled and compared the cognitive slopes of at-risk individuals to their demographically similar peers without genetic risk; at-risk individuals with the most preserved cognition were defined as resilient (ε4-carriers [n=237]; ε4-carrier/GRS-high [n=319]), and the least preserved as non-resilient (ε4-carriers [n=866]; ε4-carrier/GRS-high [n=1,249]). Lower LIBRA risk scores at baseline, denoting healthier lifestyle and reduced dementia risk, were linearly associated with greater odds of CRgen, both in ε4-carriers (odds ratio [OR]=1.11;95%CI=1.05-1.18) and ε4-carriers/GRS-high (OR=1.16;95%CI=1.11-1.22). When examining the LIBRA components, cognitive activity and coronary heart diseases history showed the strongest independent associations with CRgen (all P≤.01). Genetically susceptible older adults can develop cognitive resilience, which may be promoted by lifestyle modifications and health management simultaneously.< Réduire