Meta-analysis identifies 311 serum metabolite associations in Alzheimer's disease trajectory

Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), yet the temporal nature of metabolite-phenotype associations remains poorly understood. We systematically evaluated 506 serum metabolites across 4,063 longitudinal samples from 1,430 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), applying cross-sectional, multi-timepoint meta-analysis and time-interaction analysis. Across 15 AD-related phenotypes, we identified 311 significant metabolite associations, of which 243 emerged from cross-sectional analyses, 281 from the multi-timepoint meta-analysis and 17 metabolites that showed a significant change in their association with AD over time. In total, 128 metabolites, such as cortisol, creatinine, lysophosphatidylcholines, and polyunsaturated triglycerides, showed persistent associations over time, providing evidence for chronic and systemic metabolic dysregulation in the disease. Association analyses together highlight impaired energy metabolism, branched-chain amino acid depletion, disrupted neurotransmitter levels and oxidative stress as key metabolic features of AD. We demonstrate broad replication of the reported metabolite associations in prior studies and independent lipidomics dataset in ADNI. In summary, this work expands previous metabolomics studies in AD and provides novel leads regarding timing and persistence of metabolic alterations across the disease trajectory.