Transthyretin as a therapeutic target: the future of disease-modifying therapies for Alzheimer's disease.

BACKGROUND

Alzheimer's disease (AD) is the most common neurodegenerative disease for causing memory deficits and primarily characterized by extracellular deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), and hyperphosphorylation of tau protein, all are pathological hallmarks for AD. Transthyretin (TTR) is a highly conserved homo-tetrameric protein, primarily synthesized in liver and choroid plexus, and most importantly involved in transport of T-T hormones and retinol.

OBJECTIVES

This review explores the dual role of TTR, with a greater emphasis on its neuroprotective action, particularly in AD.

METHODS

Based on the available literature, TTR's potential as a biomarker in the central nervous system (CNS), focusing its role in stabilizing Aβ aggregation and the senile plaque formation during neurodegeneration. Additionally, TTR's dual roles, in neurodegeneration and neuroprotection are studied, emphasizing its potential for improving AD diagnosis and treatment strategies.

RESULTS

Recent research has revealed that TTR is gradually showcasing its promise in neuroprotection and neuronal viability in AD by binding with Aβ and mitigating its neurotoxic effects. Current preclinical and clinical studies also support that TTR is actively involved in maintaining the blood-brain barrier (BBB) integrity and maintain neurotransmitter balance, all of which offer significant therapeutic promise through TTR stabilizers, such as Tafamidis, Acoramidis, and Vutrisiran, highlighting their potential in AD treatment CONCLUSION: This review concludes that TTR plays bidirectional role and gaining interest as a potential biomarker, though several challenges must be addressed before it can be established a novel therapeutic target in AD management in the modern era of drug discovery.