‘Tauopathies’ is a term used to describe the neurodegenerative diseases (NDDs) caused by abnormal accumulation of misfolded Tau protein. The misfolded protein causes it to be hyperphosphorylated, which subsequently damages the neuronal cells (Zheng et al., 2024). Simultaneously, neuroinflammatory reactions are also triggered, which results in progressive neurodegeneration and loss of brain function over time (Rankovic and Zweckstetter, 2019a). Depending on the etiology, the tauopathies are categorized as primary or secondary. A primary tauopathy like frontotemporal dementia (FTD) emerges from the tau protein deposits as a primary pathological process, while those initiated by other proteins are known as secondary tauopathies which include the multiple etiology disease - Alzheimer's disease (AD). These diseases eventually result in cognitive impairment and dementia (Wilczyńska and Waszkiewicz, 2020). Since discussing the complexities of tau pathology in all the tauopaties is beyond the scope of this paper, we will discuss them with Alzheimer's diseases in the prime focus.

Dementia affects around 55 million individuals globally, becoming the 7th leading cause of death. In May 2017, the World Health Organisation approved the Global Action Plan for the Public Health Response to Dementia 2017–2025, which includes a blueprint for research and innovation, thereby calling for immediate actions towards improving diagnostics and therapeutics (World Health Organization, 2025). Alzheimer's disease is generally diagnosed using standard clinical assessments at different stages that focus on symptomatic dementia and cognitive abilities (Burns, 2000). However, to understand the etiology, tau imaging techniques were invented (Brosch et al., 2017). Positron emission tomography (PET) imaging aided with tracers specific to tau fibrils has also been developed to visualize tau deposits in the brain. Magnetic resonance imaging (MRI) is the most widely used technology for assessing the disease state in people and animal models of tauopathies, as it provides structural and functional information (Brier et al., 2016). Recent research has highlighted various creative ways to improve diagnostic accuracy and accessibility, such as machine learning, biomarker analysis, and nanotechnology (Rankovic and Zweckstetter, 2019a; Hampel et al., 2018). For instance, Pengju Nie et al. developed a photo-affinity chemical probe to tau aggregates, which can be used to isolate pathogenic tau (Nie et al., 2025). Fluid biomarker tests and advanced methods will help in early diagnosis and patient prognosis. This is relevant because the pathological aggregation of proteins like tau precedes the clinical symptoms. Studies have suggested that the detection of P-tau (phosphorylated tau) and T-Tau (Total tau) in CSF (cerebrospinal fluid) helps determine the neurodegeneration in suspected AD cases (Porsteinsson et al., 2021). This emphasizes the importance of tau protein structure in diagnosis.

Understanding the mechanisms of tau aggregation and its role in neurodegeneration, particularly in AD cases, is critical for designing targeted therapeutics that aim to prevent or reduce the course of tauopathies. The human brain contains six different tau isoforms, each of which has a unique accumulation pattern associated with a particular tauopathy that affects how tau disease advances. Comprehending the biochemical properties of these isoforms is imperative in order to clarify the tau propagation theory and its consequences for the advancement of sickness (Takashima et al., 2019).

Tau protein alone is not the factor to trigger the disease pathology in AD, and has been studied along with other factors, mainly the amyloid beta (Aβ) protein (Kumar and Kumar, 2019). Although several studies have found soluble oligomers of tau to be the causative pathology, contradicting the conventional wisdom on the function of amyloid plaques. The relationship between tau and amyloid beta (Aβ) is essential, with tau aggregation being promoted by Aβ oligomers and vice versa (Ferreira and Klein, 2011). They are also linked by neuroinflammatory pathways, indicating a complicated interaction in the pathogenesis of the disease (Penke et al., 2020). Moreover, there are several issues with the current treatments for dementia-related diseases. Drugs like N-methyl-d-aspartate receptor antagonists and acetylcholinesterase inhibitors do not treat the fundamental causes but help control symptoms and limit the illness's course. There is also the debate regarding their cost-effectiveness, according to many researchers, which raises questions regarding the long-term financial sustainability of patient treatment regimens (Hedna et al., 2022). Therefore, proteins of interest like Aβ and tau have become the primary therapeutic targets. Monoclonal antibodies of Aβ that passed the US-FDA approvals in 2021 became a new hope for protein targets in therapeutics. However, long-term effectiveness and risks remain to be fully understood. Ongoing studies also explore their combination with tau-targeting approaches, which calls for a deeper understanding of the protein and its mechanisms in health and disease (Penke et al., 2020; Qiang et al., 2018; Baas and Qiang, 2019; Kanaan, 2024).

This review will attempt to understand the updates regarding tau research in the past few years, which will help us assess the information regarding its structure, functions, role as a biomarker, and therapeutic developments. It will emphasize the post-translational modifications in tau and its protein-protein interactions with other hallmarks in AD.