Immune cells: Mediators in the metabolites and Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly individuals across the globe. While genetic, environmental, and lifestyle factors are known to influence the onset of AD, the underlying mechanisms remain unclear.

Objective: To elucidate the intricate interplay between metabolites and immune cell activation in the ethology of AD, and to determine their collective impact on AD risk.

Methods: We conducted a comprehensive analysis of genome-wide association studies data to examine the relationships between metabolites, immune cell phenotypes, and the risk of AD. Our study encompassed a comprehensive examination involving 731 distinct immune cell types, 1400 metabolites, and a large cohort comprising10,520 AD cases with 401,661 controls. We employed univariate Mendelian randomization to assess bidirectional relationships between metabolites and AD, metabolites and immune cells, as well as immune cells and AD. Subsequently, multivariate Mendelian randomization was then applied to evaluate the potential mediating role of immune cells on the relationship between metabolites and AD.

Results: Specific metabolites, the histidine/pyruvate ratio and homoarginine, were positively associated with the risk of AD, mediated by immune cells. Conversely, 4-hydroxycoumarin and glycolithocholate sulfate showed protective associations against AD. Immune cell markers, CD64 on monocytes and HLA DR on CD14 CD16 monocytes were linked to higher AD risk, while CD33 HLA DR CD11b myeloid cells and HLA DR on CD8 T cells were protective.

Conclusions: This study highlights the critical role of immune cells in the pathogenesis of AD, demonstrating how their interaction with specific metabolites influences disease risk.