Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study

The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40–70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7–8% of total POHP effect on FAmean. SEM yielded significant total effects for FAmean, MDmean and ISOVFmean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FAmean) and 19% (ISOVFmean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.

show abstract

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

Shen,

Wu,

Huang

et al. 2024

Preprint

View full text Add to dashboard Cite

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.

show abstract

Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study

Cited by 6 publications

References 60 publications

Life's essential 8 and cardiovascular diseases progression among adults in the United Kingdom

Life's essential 8 and cardiovascular diseases progression among adults in the United Kingdom

Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and brain white matter microstructural integrity: the UK Biobank study

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

Contact Info

Product

Resources

About