Genetic predisposition, modifiable risk factor profile and long-term dementia risk in the general population

Abstract

The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led to the discovery of genetic factors that play a role in the pathogenesis of dementia, including the apolipoprotein E ( APOE) genotype and a large and still growing number of genetic variants. ^{1, 2} Beyond the genetic architecture, several modifiable risk factors have been implicated in the development of dementia. ³ Prevention trials to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset this increased genetic risk. Here, we leverage long-term data on both genetic and modifiable factors from 6352 individuals aged 55 years and older within the population-based Rotterdam Study. In this study, we demonstrate that among individuals at low- and intermediate genetic risk, favorable modifiable risk profiles are related to a lower risk of dementia compared to those with an unfavorable profile. In contrast, these protective associations were not found among those at high genetic risk.