Updated LIfestyle for BRAin health (LIBRA2) Score, Genetics, and Risk of Alzheimer Disease, Vascular Dementia, and Stroke in Older Adults

Background and ObjectivesDementia and stroke are major global causes of disability, with modifiable lifestyle factors playing a significant role in their development. The updated LIfestyle for BRAin health (LIBRA2) score integrates 15 modifiable risk and protective factors to quantify lifestyle-based dementia risk, but its relationship with stroke and dementia subtypes remains unexplored. We investigated LIBRA2's association with stroke and dementia subtypes while also assessing potential interactions with genetic susceptibility.MethodsProspective data were used from the French multicenter Three-City (3C) Study, with participants aged 65 years and older followed for up to 17 years. Weighted LIBRA2 scores at baseline were constructed based on the presence of 15 modifiable risk and protective factors, with higher scores representing higher lifestyle-based dementia risk. Cox proportional hazards models were used to study the association of LIBRA2 with incident dementia (and subtypes) and stroke, adjudicated by expert neurologist panels. Genetic susceptibility to dementia and stroke was assessed using APOE epsilon 4 carriership and disease-specific genetic risk scores.ResultsAnalyses included 4,731 participants for stroke (mean age 73.8 years, 60.1% female) and 4,737 participants for dementia (mean age 73.8 years, 59.9% female). One-point increases in LIBRA2 scores (theoretical range -6.1 to +25.7) were associated with increased dementia risk (hazard ratio [HR] 1.08; 1.06-1.11), with a stronger association for vascular and mixed dementia (HR 1.13; 1.08-1.18) compared with Alzheimer disease (AD) dementia (HR 1.06; 1.03-1.09). LIBRA2 was not significantly associated with incident stroke risk (HR 1.03; 0.99-1.07). No significant interaction was found between LIBRA2 and APOE epsilon 4 carriership or disease-specific genetic risk scores in relation to dementia subtypes or stroke.DiscussionLIBRA2 serves as a valuable tool for assessing lifestyle-related dementia risk and its subtypes but showed no association with stroke, highlighting the potential for a stroke-specific risk reduction model. These associations were independent of genetic disease susceptibility, reinforcing the universal benefits of lifestyle modifications on dementia risk reduction. The stronger association between LIBRA2 (and some individual components) and vascular or mixed dementia, compared with AD dementia, highlights the pivotal role of vascular mechanisms in the relationship between lifestyle and brain health.