Author Identifier
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
Document Type
Journal Article
Publication Title
Journal of Neurochemistry
Volume
169
Issue
2
Publisher
Wiley
School
School of Medical and Health Sciences
RAS ID
77120
Funders
MQ Research Seeding Grant, Macquarie University (2018-02532, 681712, 201809-20168620)
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.)
DOI
10.1111/jnc.16244
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., ... & 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