Evidence for effect modification by serum clusterin on dendritic cells in association with dementia
Sithara Vivek- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Alzheimer’s disease (AD) and AD related dementias (ADRD) are complex heterogeneous diseases with multiple pathogenic mechanisms. Previous experimental studies showed that serum clusterin has a significant role in the maturation of dendritic cells (DCs). Studies showed that myeloid DCs (mDCs) in blood were dysregulated in AD and higher levels of serum clusterin related to higher incidence of dementia. We evaluated the association of DCs in peripheral blood and serum clusterin and their interaction with AD/ADRD.
Method
We used data from 3072 participants in the Health and Retirement Study (HRS) who participated in the 2016 Venous Blood Study (VBS), and had flow cytometry, clusterin and cognition assessed. We used generalized survey logit models to evaluate the association between the DCs, clusterin, and dementia after adjusting for age, sex, race, education, comorbidity, body mass index (BMI) and Cytomegalovirus (CMV) seroprevalence. Utilizing the RNAseq data, we performed differential gene expression (DGE) analysis on DCs, clusterin and dementia to identify overlapping genes in the biological process.
Result
We found that after covariate adjustment, a higher percentage of dendritic cells was associated with lower odds of having dementia (OR = 0.61, 95% CI: [0.44, 0.86]; p = 0.005). We found that higher levels of serum clusterin was associated with higher odds of having dementia. This relationship was somewhat attenuated after covariate adjustment (OR = 1.07, 95% CI [0.99, 1.16], p = 0.09). We found a significant interaction between serum clusterin and DCs in the association with dementia (p = 0.02) with those having low DCs and high clusterin being at increased ADRD risk (OR = 1.25) and those with high DCs and low clusterin being at lower ADRD risk (OR = 0.48) as compared to those who have both low DCs and low clusterin. We identified three genes (TUBB4A, WASHC5 and GSTA4) that were dysregulated in the pathways of DCs and clusterin in association with dementia.
Conclusion
This study has shown, for the first time, an interaction between serum clusterin and DCs in peripheral blood that is associated with increased risk of dementia in a large sample of older adults that needs to be validated in future studies.