Author Identifier (ORCID)
James D. Doecke: https://orcid.org/0000-0003-2863-0293
Steve Pedrini: https://orcid.org/0000-0002-6409-8022
Ralph N. Martins: https://orcid.org/0000-0002-4828-9363
Abstract
Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ load. In addition, the P-tau181-linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ− and CN Aβ+ individuals. Significant positive associations of medium- and long-chain acylcarnitines (ACs) were observed with P-tau181 in the entire cohort, CN Aβ− and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation-mediated energy metabolism pathways. However, in CN Aβ−, additional linear associations of P-tau181 were observed with muscle metabolism and nitric oxide homeostasis-associated metabolites. Upon investigating the P-tau181-linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium- and long-chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET-Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET-Aβ status in older adults. Therefore, plasma P-tau181-linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross-sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings. (Figure presented.)
Document Type
Journal Article
Date of Publication
1-1-2025
Volume
169
Issue
2
Publication Title
Journal of Neurochemistry
Publisher
Wiley
School
School of Medical and Health Sciences
RAS ID
77120
Funders
MQ Research Seeding Grant, Macquarie University (2018-02532, 681712, 201809-20168620)
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Sharmin, T., Chatterjee, P., Doecke, J. D., Ashton, N. J., Huynh, K., Pedrini, S., Sohrabi, H. R., Heng, B., Eslick, S., Zetterberg, H., Blennow, K., Garg, M., & Martins, R. N. (2024). Circulating medium‐and long‐chain acylcarnitines are associated with plasma P‐tau181 in cognitively normal older adults. Journal of Neurochemistry, 169(2). https://doi.org/10.1111/jnc.16244