Alzheimer's Disease (AD) is the most common neurodegenerative disorder, characterized by memory loss and cognitive impairment [1]. The hallmark pathological features of AD are β-amyloid (Aβ) accumulation and tau hyperphosphorylation [2]. Despite extensive research, the pathogenesis of AD remains incompletely understood, and effective treatments are limited [3]. Increasing evidence suggests that inflammation and immune dysregulation play critical roles in the development and progression of AD [4]. Colony-stimulating factors (CSFs), which are key regulators of hematopoiesis and immune responses, have been implicated in the pathophysiology of AD [[5], [6], [7]].

CSFs, including granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF), are essential for the proliferation, differentiation, and activation of myeloid cells [8]. These factors and their receptors are involved in various physiological processes, including immune response modulation, inflammation, and tissue repair [9,10]. Previous observational studies have suggested a potential link between CSF levels and the incidence of AD [11,12]. However, due to confounding factors and the potential for reverse causation, the results have been inconsistent [12], leaving the causal relationship between CSFs and AD unclear.

The Mendelian Randomization (MR) approach provides a powerful tool to investigate causal relationships between exposures and diseases using genetic variants as instrumental variables (IVs) [13]. Since genetic variants are randomly distributed to offspring, MR can significantly reduce the impact of confounding factors and reverse causation. In this study, we employed both univariable MR (UVMR) and multivariable MR (MVMR) approaches to elucidate the causal impact of blood CSFs and their receptors on the risk of AD and its biomarkers, such as Aβ and phosphorylated tau (p-Tau) levels in cerebrospinal fluid, and to assess the role of hematological traits and inflammation.