Abstract
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.
Keywords
amyloid pathology, blood-based biomarkers, circulating metabolites, cognitive performance, plasma P-tau181, preclinical Alzheimer’s disease
Document Type
Journal Article
Date of Publication
1-1-2026
Article Number
892
E-ISSN
15591182
ISSN
08937648
Volume
63
Issue
1
PubMed ID
42733048
Publication Title
Molecular Neurobiology
Publisher
Springer
School
School of Medical and Health Sciences
Funding Information
MQ Research Seeding Grant, Macquarie University, Grant/Award Number: 2018-02532, 681712, 201809-2016862, 2017-00915, FO2017-0243 and JPND2019-466-236; Macquarie University HDR Grant. European Union’s Horizon Europe Research and Innovation Programme, Grant/Award Number: 101053962; Swedish Research Council, Grant/Award Number: 2019-02397.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
Sharmin, T., Doecke, J. D., Chatterjee, P., Sohrabi, H. R., Zetterberg, H., Ashton, N. J., Garg, M. L., Blennow, K., & Martins, R. N. (2026). Circulating metabolite signatures associated with amyloid positivity, cognitive performance and plasma P-tau181 levels in cognitively unimpaired older adults. Molecular Neurobiology, 63, Article 892. https://doi.org/10.1007/s12035-026-06184-1