Associations of varicose veins with cerebrospinal fluid biomarkers of Alzheimer's disease pathologies in adults without dementia: the CABLE study

Abstract

Background: Previous studies have found a correlation between varicose veins (VVs) and cognitive decline, and individuals with VVs have a higher prevalence of Alzheimer's disease (AD). However, the associations between VVs and the core pathologies of AD have not yet been investigated. The research was designed to analyze the relationships between VVs and cerebrospinal fluid (CSF) biomarkers of AD pathologies.

Methods: We included 1,298 participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database without dementia. Multiple linear regression (MLR) model was applied to assess the relationships between the VVs and CSF AD biomarkers. Then, we conducted subgroup analyses according to age, gender, education levels and apolipoprotein E genotype ε4 (APOE-ε4) carrier status. Additionally, mediation effects were assessed using causal mediation analyses with 10,000 bootstrapped iterations.

Results: In total subjects, VVs had negative correlations with CSF Aβ₄₂ (β = -0.157, p = 0.038) and CSF Aβ₄₂/Aβ₄₀ ratio (β = -0.272, p < 0.001), as well as positive correlations with CSF Aβ₄₀ (β = 0.170, p = 0.024), CSF p-tau (β = 0.192, p = 0.008), CSF t-tau/Aβ₄₂ ratio (β = 0.190, p = 0.011), and CSF p-tau/Aβ₄₂ ratio (β = 0.248, p = 0.001), after adjusting for age, sex, education levels and APOE-ε4 carrier status. Subgroup analyses demonstrated that the relations between VVs and CSF AD biomarkers were more significant in female, mid-life adults (40-65 years), less-educated individuals and APOE-ε4 non-carriers. Moreover, CSF Aβ₄₂/Aβ₄₀ ratio might be a partial mediator of the association between VVs and p-tau pathology.

Conclusion: Our study found correlations between VVs and CSF AD biomarkers, suggesting that VVs may be a potential risk factor for the development of AD.

Keywords: Alzheimer’s disease; biomarkers; dementia; inflammation; varicose veins.

FIGURE 1

Differences of CSF AD biomarkers in VVs and non-VVs groups. Participants with VVs had lower CSF Aβ₄₂ level (A), as well as lower CSF Aβ₄₂/Aβ₄₀ ratio (E) compared to these without VVs. Participants with VVs had higher CSF p-tau/Aβ₄₂ ratio (G) compared to these without VVs. And there were no significant differences in CSF Aβ₄₀ (B), t-tau (C), p-tau (D), t-tau/Aβ₄₂ ratio (F) between the VVs and non-VVs groups. VVs, Varicose veins; CSF, cerebrospinal fluid; Aβ, amyloid-β; t-tau, total tau; p-tau, phosphorylated tau; NS, Not Significant. *p < 0.05, **p < 0.01, ***p < 0.001.

FIGURE 2

Heatmap for subgroup analyses of the association between VVs and CSF AD biomarkers. Multiple linear regression models were employed with adjustment for age, gender, education levels, APOE-ε4 carrier status. In the subgroup analyses, the association between VVs and CSF AD biomarkers was stronger correlated in mid-life individuals, female, individuals with less education and individuals without APOE-ε4 gene. Colors represented beta-estimates, asterisks indicated statistical significance (*p < 0.05, **p < 0.01, ***p < 0.001). VVs, Varicose veins; APOE-ε4, apolipoprotein E genotype ε4; CSF, cerebrospinal fluid; AD, Alzheimer’s disease; Aβ, amyloid-β; t-tau, total tau; p-tau, phosphorylated tau.

FIGURE 3

CSF Aβ₄₂/Aβ₄₀ ratio mediated association between VVs and p-tau. Causal mediation analyses with 10,000 bootstrapped iterations were used to examine the mediation effects of Aβ₄₂/Aβ₄₀ on p-tau. Each model path was adjusted for age, gender, education levels, and APOE-ε4 carrier status. In this model, a represents the effect of VVs on CSF Aβ₄₂/Aβ₄₀ ratio, while b represents the effect of CSF Aβ₄₂/Aβ₄₀ ratio on p-tau pathology. c denotes the total effect of VVs on p-tau pathology before accounting for the mediator, whereas c’ indicates the direct effect of VVs on p-tau pathology after adjusting for CSF Aβ₄₂/Aβ₄₀ ratio. The IE, calculated as a × b, quantifies the mediation effect, reflecting the extent to which CSF Aβ₄₂/Aβ₄₀ ratio mediates the association between VVs and p-tau pathology. VVs, Varicose veins; IE, indirect effect; APOE-ε4, apolipoprotein E genotype ε4; CSF, cerebrospinal fluid; Aβ, amyloid-β; p-tau, phosphorylated tau; MCP, monocyte chemoattractant protein; IL, interleukin; TNF, tumor necrosis factor; VCAM, vascular cell adhesion protein.