The potential utility of genetic susceptibility to life course modifiable factors for dementia prevention

Abstract

AbstractBackgroundPotentially modifiable risk factors for dementia prevention, intervention, and care based on efforts to curb the increasing prevalence of dementia have been presented by the dementia committees. These risk factors for developing dementia need to be managed throughout the life cycle. However, the criteria for prioritizing risk management in subtype dementias caused by various factors are still uncertain in clinical practice. In this study, using a polygenic risk score (PRS) approach, we investigated the association of genetic susceptibility to life‐course modifiable factors in each subtype of dementia, including all‐cause dementia, and evaluated the utility of using it for predicting dementia.MethodWe utilized 5,974 all‐cause dementia cases and propensity‐matched healthy control data from UK Biobank. We generated APOE isoforms and Alzheimer’s disease (AD)‐PRS (excluding APOE regions) derived from the IGAP 2019 genome‐wide association study (GWAS) using genotyped data. Then, we performed a regression analysis to confirm the associations between AD‐PRS, APOE status, and each type of dementia. In addition, to investigate the genetic susceptibility of life‐course modifiable factors, we generated PRSs related to 18 life‐course factors for dementia prevention using independent GWAS summary statistics. Then, using each life‐course factor PRS, multivariate regression analysis was conducted to evaluate whether PRS is associated with each type of dementia independent of age, sex, genetic principal components, APOE status, and AD‐PRS.ResultThe APOE status and AD‐PRS showed significant associations with all‐cause dementia as well as AD dementia (ADD), vascular dementia (VD), and frontotemporal dementia (FTD) (Figure 1). In the multivariate regression analysis, hypertension, and body mass index PRSs showed significant associations with ADD and VD. In addition, vascular risk factors such as type 2 diabetes, high‐density lipoprotein, and systolic blood pressure PRSs showed significant associations with VD. In particular, in FTD, unlike other subtype dementias, only depression genetic susceptibility and relationship were found.ConclusionWe observed that genetically predicted life‐course modifiable factors were associated with risks of several types of dementia independently of the well‐known non‐modifiable risk factors (APOE status and AD‐PRS). Our findings suggest the potential utility of prioritizing candidate modifiable factors that should be primarily managed for dementia prevention in personalized medicine.