BACKGROUND: Education and cognition demonstrate consistent inverse associations with Alzheimer's Disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites can reflect the endpoint of biological processes and are accessible and malleable. Identifying metabolites with aetiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms. METHODS: Using data from the largest metabolomics genome-wide association study (N≈24,925) and three independent AD cohorts (N=4,725), cross-trait polygenic scores were generated and meta-analyzed. Metabolites genetically associated with AD were taken forward for causal analyses. Bidirectional two-sample Mendelian randomization (MR) interrogated univariable causal relationships between (i) metabolites and AD, (ii) metabolites, education and cognition (iii) education, cognition and AD, and (iv) education and cognition. Mediating relationships were computed using multivariable MR. RESULTS: Thirty-four metabolites were genetically associated with AD at p<0.05. Of these, glutamine and free cholesterol in extra-large high-density lipoproteins (XL.HDL.FC) demonstrated a protective causal effect (Glutamine: 95% CI=0.70-0.92; XL.HDL.FC: 95% CI=0.75-0.92). An AD-protective effect was also observed for education (95% CI=0.61-0.85) and cognition (95% CI=0.60-0.89), with bidirectional mediation evident. Cognition as a mediator of the education-AD relationship was stronger than vice-versa, however. No evidence of mediation via any metabolite was found. CONCLUSIONS: Glutamine and XL.HDL.FC show protective causal effects on AD. Education and cognition also demonstrate protection, though education's effect is almost entirely mediated by cognition. These insights provide key pieces of the AD causal puzzle, important for informing future multi-modal work and progressing towards effective intervention strategies.