Healthy lifestyles, plasma proteomic profile and long-term risk of dementia

Abstract

Considering the irreversible nature of dementia, lifestyle modification has been recognized as potentially effective preventive strategies. However, whether proteomic signatures of individuals mediate or modifiy the associations between healthy lifestyles and cognitive health remain unclear. Herein, we conducted proteome-wide association analyses and identified 12 plasma proteomic markers that were associated with both overall healthy lifestyle score and incident dementia (Bonferroni corrected P-values <0.05) among 53,014 individuals aged 55 years and older in the UK Biobank.Aggregately, they mediated 17.6% (95% CI, 10.0%, 29.6%) of the lifestyle-dementia association. The associations between overall healthy lifestyle score and two key proteinomic markers (GDF15 and IGFBP3) were further replicated in the Framingham Heart Study Offspring cohort. In the proteome-wide interaction analysis, the lifestyle-dementia association significanly differed by certain proteomic features. Using a machine-learning approach, we developed and tested 8 lifestyle protein stratification scores (LPSSs) to identify pariticipants showing stronger associations between overall or individual healthy lifestyles and dementia. In particular, the LPSS for overall healthy lifestyle (consisting of 25 proteins) identified a population with a substantially stronger lifestyle-dementia association (Harzard Ratio: 0.38, 95%CI: 0.32-0.45) compared with overall population (0.67, 0.60-0.75). Individuals with higher LPSS thus may exibit stronger responses to healthy lifestyle interventions, leading to substantially improved proportions of potentially preventable dementia cases. For example, the population attributable fraction of unhealthy diet increased from 1.63% in the overall population to 29.15% in the targeted population with higher LPSS for healthy diet. Our findings highlighted the key proteomic biomarkers that may serve as intervention intermediate outcomes and inform targeted lifestyle interventions for primary prevention of dementia.