Circulating Metabolite Signatures Associated With Amyloid Positivity, Cognitive Performance and Plasma P-tau181 Levels in Cognitively Unimpaired Older Adults.

Emerging evidence suggests altered circulating metabolite levels in individuals with Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) compared to healthy controls; how these metabolites alter with early cortical amyloidosis-before symptom onset-remains unclear. This cross-sectional study aimed to investigate plasma metabolites obtained through targeted profiling using the Biocrates AbsoluteIDQ® p400 HR kit. The study cohort comprises 100 cognitively unimpaired (CU) older adults, stratified into CU Aβ- (negative positron emission tomography [PET]-amyloid-beta [Aβ]) and CU Aβ+ (positive PET-Aβ) groups. Significantly altered metabolites were further analysed for associations across amyloid plaque deposition, cognitive performance and plasma tau phosphorylated at threonine 181 (P-tau181) levels and for their ability to differentiate cortical PET-Aβ status in CU older adults. Significant between-group differences were observed in eighteen metabolites from phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and ceramide (Cer) classes, wherein significantly lower levels of PC species and higher levels of LPC(17:1) and Cer(43:1) were detected in CU Aβ+ individuals compared to CU Aβ-. Notably, the differences became more pronounced when PC-to-LPC ratios were analysed. Across the spectrum, lower PC-to-LPC ratios were associated with greater cortical amyloid deposition, poorer cognitive performance and higher plasma P-tau181 levels. Elevated Cer(43:1) levels were also associated with higher cortical amyloid deposition. Upon receiver operating characteristic (ROC) analyses, these metabolite panels significantly distinguished CU Aβ  individuals from CU Aβ-, demonstrating good to excellent diagnostic performance. Given their association with membrane damage, synaptic dysfunction, oxidative stress, neuroinflammation and apoptosis, these metabolites may represent potential biomarkers reflecting early AD-related biochemical changes in CU older adults.