Immune, blood-brain barrier, and metabolic biomarkers mediate gut-brain axis crosstalk in alzheimer’s disease

Abstract

Background: Gut microbiota may influence Alzheimer’s disease (AD) pathogenesis by modulating host homeostasis. However, population-based causal evidence linking gut dysbiosis to Alzheimer’s disease pathogenesis, especially via immune, vascular, and metabolic pathways, remains insufficient. Methods: We performed Mendelian randomization (MR) and colocalization analysis on 629 gut microbiota features and 2,103 immune, blood-brain barrier (BBB), and metabolic biomarkers regarding the risk of AD and cerebrospinal fluid (CSF) pathological biomarkers. Results: We identified that mucin-degraders, short-chain fatty acid (SCFA) producers, and Programmed Cell Death Protein 1/Programmed Death-Ligand 1 (PD-1/PD-L1)-related biomarkers were associated with lower AD risk, while cardiovascular microbes, Amyloid-beta (Aβ)-related proteins, and lipoproteins were linked to higher risk. Increased AD risk was associated with decreased SCFA producers, branched-chain amino acids (BCAAs), and lactate, but with increased liver-disease microbes, fatty acids, and glycoprotein acetyls. Notably, Desulfovibrionaceae and Methanobrevibacter emerged as critical contributors to AD. Erysipelotrichaceae abundance inversely modulates CSF phosphorylated tau (p-tau) pathology while being increased by Aβ42 pathology, suggesting a microbiota-mediated feedback circuit in AD. Mediation analysis highlighted the role of CD28−CD8+ T cells, CD19 on IgD+ CD24+ B cells, glycoproteins, and low-density lipoprotein (LDL) in microbiota-gut-brain axis bidirectional communication. Colocalization analyses confirmed causal links between AD and LDL metabolism through shared variant rs7412 (posterior probability, PP = 1.0), while revealing colocalized architecture for amyloid-tau copathology at rs71352238 (PP = 1.0). Conclusions: Our study reveals a bidirectional gut–brain feedback loop in AD, in which gut microbiota promote neuroinflammation and immune aging, while AD exacerbates gut dysbiosis via lipid metabolic dysregulation. This self-reinforcing mechanism involving immune signaling, BBB disruption, and SCFA imbalance offers potential targets for integrated microbiota-based interventions in AD prevention.