CD28+ CD45RA− CD8br AC mediated the effects of Interleukin- 6 on Alzheimer's disease: A Mendelian Randomization Study

Background
IL-6 has garnered significant attention as a potential factor in AD pathogenesis. The association between peripheral immune cells and IL-6 is evident, yet how peripheral immune cells mediate IL-6’s effects on AD remains enigmatic regarding the precise pathophysiological processes. To address these uncertainties, we employed genetic evidence to investigate their impact. Our current study explores further the intricate relationship between IL-6, peripheral immune cells, and AD by using extensive publicly available genetic data, aiming to provide novel insights into this critical area of medical research.

Methods
The relevant data regarding IL-6, 731 peripheral immune cells, and AD were screened and retrieved from the GWAS database. Subsequently, we predominantly utilized the IVW approach to carry out bi-directional MR analyses between IL-6, 731 peripheral immune cells, and AD. We utilized two-step, two-sample MR analyses to determine three key factors: (i) IL-6 exhibits associations with both AD and specific peripheral immune cells, respectively, and there is an absence of inverse causality. (ii) Specific peripheral immune cells exhibit associations with AD, and there is an absence of inverse causality. (iii) to identify which peripheral immune cells mediate the effects of IL-6 on AD. Then we employed the MVMR approach to verify whether the mediating relationships obtained from the two-step, two-sample MR analyses remained valid. Furthermore, we calculated their respective mediating effects, the combined mediating effects, and the proportions of their mediating effect shares. All of the aforementioned steps were utilized to verify the reliability of causality employing sensitivity analysis, heterogeneity analysis, and horizontal pleiotropy analysis.

Results
Our findings indicate a significant correlation between increased IL-6 levels and a reduced risk of AD (P = 0.009, OR = 0.941, 95%CI = 0.899- 0.985), along with elevated levels of CD28+ CD45RA− CD8br AC (P = 0.007, OR = 1.159, 95%CI = 1.007- 1.333). Also indicates a significant correlation between increased CD28+ CD45RA− CD8br AC (P = 0.005, OR = 0.983, 95%CI = 0.971- 0.995) levels and a reduced risk of AD. Therefore, through MVMR analysis, the effect of IL-6 on AD increased from -0.061 to -0.046 (95% CI: -0.090, -0.002) after genetic adjustment for CD28+ CD45RA− CD8br AC.

Conclusions
Increased CD28+ CD45RA− CD8br AC levels appear to partially mediate the effect of IL-6 on reducing AD risk.