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
Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ− and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ− individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration. (Figure presented.).
Keywords
sphingomyelins, tau protein, Alzheimer’s disease, metabolomics, biomarkers, neurodegeneration
Document Type
Journal Article
Date of Publication
5-1-2026
Volume
170
Issue
5
PubMed ID
42104655
Publication Title
Journal of Neurochemistry
Publisher
Wiley
School
School of Medical and Health Sciences
Funding Information
The authors acknowledge the Macquarie University Research Seeding Grant, awarded to Pratishtha Chatterjee and Ralph N. Martins, which supported the measurement of plasma metabolites. The authors express their gratitude to the Australian Commonwealth Government for funding the International Research Training Program (iRTP) scholarship awarded to Tahmida Sharmin for her Doctor of Philosophy in Medicine at Macquarie University. The authors also acknowledge the Macquarie University Higher Degree Research (HDR) Fund for additional essential support to this research. Henrik Zetterberg is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356, #2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962 and Swedish State Support for Clinical Research (#ALFGBG-71320).
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Comments
Sharmin, T., Doecke, J. D., Chatterjee, P., Pedrini, S., Sohrabi, H. R., Ashton, N. J., Zetterberg, H., Garg, M. L., Blennow, K., & Martins, R. N. (2026b). Circulating sphingomyelins correlate with plasma T‐TAu in cognitively unimpaired older adults at risk of developing Alzheimer’s disease. Journal of Neurochemistry, 170(5), e70436. https://doi.org/10.1111/jnc.70436