Abstract
BACKGROUND: TIA-1 (T-cell intracellular antigen 1) is an RNA-binding protein central to the formation of stress granules (SGs) and modulation of inflammatory responses. Recent research has identified TIA-1 as a key player in neurodegenerative diseases, especially those involving Tau pathology such as in Alzheimer’s disease (AD), in a subtype-dependent manner. Disease-modifying therapies for AD and related dementias are emerging, but their effectiveness hinges on timely and accurate diagnosis. This underscores urgent need for easily accessible and reliable blood biomarkers for early detection, disease monitoring, and subtype differentiation. METHODS: Accordingly, in this pilot study, we evaluated the plasma TIA-1 levels in healthy controls and across spectrum of neurodegenerative diseases to assess its clinical and biological significance. Plasma TIA-1 concentrations were measured in Alzheimer’s disease, mild cognitive impairment due to AD (MCI-AD), vascular cognitive impairment (VCI), and other neurodegenerative diseases (NDs: synucleinopathies and tauopathies), and compared to healthy controls. Receiver operating characteristic (ROC) analyses and correlation studies with established biomarkers and cognitive scores were performed. RESULTS: Plasma TIA-1 levels were significantly reduced in AD, MCI-AD, VCI, and non-AD neurodegenerative diseases (synucleinopathies and tauopathies) compared to healthy controls, with the greatest reductions observed in non-AD neurodegenerative diseases. Strikingly, combined measurement of plasma TIA-1 and glial fibrillary acidic protein (GFAP) improved differentiation of AD subtypes, particularly distinguishing rpAD from non-rpAD cases. Plasma TIA-1 levels correlated with key biomarkers of neurodegeneration (p-Tau, Aβ42, NFL) and cognitive decline, especially in early AD (MCI-AD). Notably, plasma TIA-1 mirrored the discriminatory patterns of CSF t-Tau and p-Tau, distinguishing non-AD neurodegenerative diseases from specifically rpAD subtype, indicating that plasma TIA-1 captures the same underlying pathophysiological processes as the “gold standard” CSF markers. CONCLUSIONS: Plasma TIA-1 is a promising biomarker candidate for neurodegenerative diseases, with alterations that reflect disease presence and severity. In this pilot cohort, its combination with GFAP noticeably improved discrimination between AD subtypes, supporting its potential added value in composite biomarker approaches. Given its accessibility, TIA-1 is a strong candidate for further evaluation as part of future blood-based biomarker panels, although it’s clinical utility still needs confirmation in larger, independent studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02020-9.