Significance The absence of disease-modifying therapeutics for Alzheimer’s disease (AD) continues, and an understanding of early, easily accessible biomarkers to inform treatment strategies remains elusive. This study uses knowledge of blood metabolites previously associated with midlife cognition—a preclinical predictor of AD—to systematically investigate causal associations with later AD status. Given that the pathological changes underlying AD are thought to develop years before clinical manifestations of the disease, developing these findings further could hold special utility in informing early treatment intervention.