Observational studies have shown associations between immune cells, lipids, and Alzheimer’s disease (AD), but their specific causal relationships and the mediating role of lipids remain unclear.

Within a network Mendelian randomization (MR) framework, we first applied two-sample univariable MR to assess the causal effects of immune cells and lipids on AD. Then, multivariable MR was used in mediation analyses to determine whether lipids mediate the effects of immune cells on AD. Finally, reverse MR analyses were performed to minimize potential bias from reverse causation. The inverse variance weighted method was used as the primary estimator.

The analysis revealed that elevated levels of CD33 on CD33dim HLA DR+ CD11b+ and CD33 on CD33dim HLA DR+ CD11b- were associated with an increased risk of AD. Mediation analysis further indicated that polyunsaturated fatty acids are protective lipid metabolites for AD and partially mediate the effects of the aforementioned immune cells on AD, with mediation proportions of 3.70% and 3.67%, respectively.

This study provides new insights into how immune cells may influence AD pathogenesis through lipid metabolism. It also offers a theoretical basis and potential direction for developing immune–lipid-based strategies for AD prevention and intervention.