Flavin-Containing Monooxygenase 3 and Trimethylamine N-Oxide in Neurodegeneration: Evidence, Limitations, and Translational Considerations

Flavin-containing monooxygenase 3 (FMO3) oxidizes gut microbiota-derived trimethylamine (TMA) to trimethylaminuria N-oxide (TMAO), a metabolite associated with vascular, inflammatory, and neurodegenerative processes. Primary trimethylaminuria (TMAU), caused by reduced FMO3 function, provides a rare example of altered TMA/TMAO handling, but it should be used as a conceptual model rather than as a clinical analogue of common dementias. This review examines evidence connecting FMO3-mediated metabolism and TMAO biology with cognitive decline and neurodegeneration. Current evidence is more extensive for Alzheimer’s disease and vascular or chronic kidney disease-related cognitive dysfunction, where TMAO has been associated with inflammation, endothelial dysfunction, blood-brain barrier disruption, and amyloid-beta/ tau-related pathways. Evidence directly linking FMO3 to Parkinson’s disease or amyotrophic lateral sclerosis remains limited, and the proposed FMO3-monoamine oxidase interaction in human brain metabolism remains inferential. TMAO should also be interpreted in context, as its associations may differ by disease stage, medication status, renal function, diet, and gut microbiota composition. Clinical use of FMO3 genotyping or TMAO measurement is not established. Future studies should combine FMO3 genotype, plasma and urinary TMA/TMAO phenotyping, renal function, dietary exposure, medication use, microbiota-related factors, and cognitive outcomes to define subgroups and assess the safety of TMAO-lowering or FMO3-targeted strategies.