Therapeutic Modalities Targeting Tau Protein in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD), the most frequent neurodegenerative disorder worldwide, is characterized by two key pathological features: extracellular amyloid beta plaques and intracellular highly phosphorylated tau protein aggregates known as neurofibrillary tangles. While in the last decades intensive research related to anti-amyloid disease-modifying therapies for AD was conducted, there has been less interest in treatments targeting tau protein. However, this paradigm is slowly changing, as recent studies have shown the increasing importance of tau protein in the onset and evolution of AD. In this context, this review aims to offer a practical overview of currently available therapies targeting tau protein and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and tau-related kinase dysregulations, considering their role in physiological versus AD conditions. Subsequently, the most relevant classes of drugs modulating tau protein formation, aggregation, and post-translational modifications are presented, with appropriate examples from clinical trials. Finally, unexplored research directions regarding tau-targeting therapies are discussed, with active and passive immunotherapies a promising research direction. Therapies targeting tau protein are a valuable treatment modality in AD, with current drug classes expected to diversify soon.

1. Introduction

Alzheimer’s disease (AD) is the most frequent progressive neurodegenerative disorder, responsible for 50–75% of dementia cases worldwide [1]. According to the latest available epidemiological data, approximately 6.5 million people aged 65 and older in the USA are living with clinical AD, and this number is projected to continuously rise in the absence of a curative treatment [2]. From the clinical point of view, AD patients suffer from gradual memory loss and cognitive decline. Several aspects of daily living are affected, such as communication and difficulties completing ordinary tasks, with the final stages characterized by behavioral changes, incontinence, and complete dependence [3]. AD is also a significant economic burden. The total medical costs for individuals with AD and other dementias are expected to grow from USD 321 billion in 2022 to nearly USD 1 trillion by 2050 [4]. Moreover, AD patients are more likely to develop other chronic conditions, which further exacerbate the financial burden of treating comorbidities, making AD a major global health issue [5].

Regarding current therapeutic strategies for AD, they primarily target the two key pathological features of the disease: specific isoforms of amyloid beta (Aβ 40–42), responsible for the formation of extracellular plaques, and hyperphosphorylated tau, which pathologically aggregates into intracellular neurofibrillary tangles (NFTs) [6]. It is widely accepted that pathological aggregates of Aβ play a pivotal role in the onset and evolution of AD, triggering tau pathology and sustaining other aspects of neurodegeneration [7]. Aβ can induce tau hyperphosphorylation and cleavage by activating related proteases, which promote tau aggregation and enhance tau-induced neurotoxicity [8]. Historically, Aβ and tau were thought to act independently without direct interaction. However, growing evidence now suggests a bidirectional relationship between Aβ and tau. For example, increased tau levels in cerebrospinal fluid (CSF) have been observed in APP/PS1 transgenic mice overexpressing Aβ, while tau deletion decelerates plaque formation and deposition in a tau-deficient AD mouse model [9]. The combined effects of Aβ and phosphorylated tau work synergistically to reduce glucose metabolism, sustain neuroinflammation, lead to mitochondrial dysfunction, and cause brain atrophy, clinically correlating with cognitive decline [10].

Pathologically phosphorylated tau protein and NFTs are also relevant from the therapeutic point of view, as these molecules are becoming targets for an increasing number of experimental treatments [11]. This is particularly important when considering the limited number of anti-dementia drugs approved nowadays, represented mainly by the classical acetylcholinesterase inhibitors such as Donepezil, Galantamine, and Rivastigmine [12], and the N-methyl-D-aspartate (NMDA) receptor antagonist Memantine [13]. It is only a few years since anti-amyloid monoclonal antibodies have received Food and Drug Administration (FDA) approval, but need more open-world clinical experience before demonstrating their superior efficacy [14]. While the currently available therapies temporarily delay AD progression and partially ameliorate symptoms, their main drawback is related to the impossibility of preventing or reversing the neurodegenerative process, neuronal loss, and brain atrophy [15]. Thus, with increasing evidence suggesting that tau pathology, compared to Aβ, could be priorly related to the hippocampal synaptic dysfunction leading to cognitive decline in AD [16], the tau hypothesis is regaining importance in the scientific world, with promising perspectives also for future effective treatments.

Considering the effervescence of clinical trials and drug development in recent years, this narrative review offers a practical overview of currently available therapies targeting tau protein and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and its role in AD. Subsequently, the most relevant classes of drugs modulating tau protein formation and aggregation are presented, with a focus on the most relevant examples from clinical trials. Finally, insufficiently explored research directions regarding tau-targeting therapies, such as active and passive immunotherapies, are discussed, opening the pathway for promising future experiments.

2. Search Strategy and Study Selection Criteria

Despite not being a systematic review, the authors conducted, in February 2025, a thorough literature review to provide a comprehensive and practically oriented overview of tau-targeting therapies in AD. Peer-reviewed articles, clinical and fundamental research trials, and relevant review papers written in English were identified using three relevant databases, namely PubMed, Scopus, and Web of Science. Keywords used in the search included “Tau protein,” “Alzheimer’s disease,” “tau aggregation,” “tau-targeting therapies,” “tau immunotherapy,” “clinical trials,” and different combinations of these terms. The authors included studies published between 2000 and 2025, emphasizing recent findings and pivotal studies that contribute significantly to the field.

Selected articles were screened for relevance based on the following inclusion criteria: research investigating therapies targeting tau protein, their mechanisms of action, and results from preclinical or clinical trials. Reviews and meta-analyses providing significant insights were also included. Articles not related to tau-targeting therapies, those focusing exclusively on β-amyloid without reference to tau, or studies with insufficient methodological details were excluded.

The extracted information was arranged within several chapters: first, the pathophysiological mechanisms of tau protein aggregation and its involvement in AD, and subsequently, the therapeutic strategies targeting tau, categorized into small-molecule inhibitors, tau aggregation inhibitors, tau kinases, tau acetylation modulators, and tau immunotherapies. For each therapeutic category, relevant trials with promising partial results were included.

3. The Role of Tau Protein in Alzheimer’s Disease

Tau protein, encoded by the microtubule-associated protein tau (MAPT) gene located on chromosome 17q21, is predominantly found in neuronal axons [17]. The adult human brain contains six tau isoforms, ranging from 37 to 46 kDa, produced by alternative splicing of exons 2, 3, and 10 of the MAPT gene [18]. The differences in splicing are relevant for tau’s structural properties and interactions with other protein structures; for example, exon 2 and 3 variations might affect tau solubility and aggregation tendency, while exon 10 imbalance is associated with tauopathies [19]. In physiological conditions, tau is an intrinsically disordered protein that stabilizes microtubules, regulates their assembly, and influences axonal morphology and growth by ensuring proper axonal transport [20]. Microtubules are essential for maintaining the structural integrity of neurons and supporting intracellular transport processes of various cellular materials, including proteins, lipids, and vesicles, along the length of the axon [21]. Disruptions in microtubule stability might impair the transport of vital cellular components, leading to cellular dysfunction or death [22]. Tau’s role in stabilizing microtubules is particularly important for long, highly specialized axons, such as those found in central nervous system (CNS) neurons, where efficient transport is crucial. For example, tau helps regulate the dynamics of axonal microtubules by facilitating their polymerization, ensuring the proper extension of axons and dendrites during development and neural plasticity [23]. In addition, tau also plays a vital role in the growth and morphology of neurons. During development, tau contributes to the elongation of axons and the branching of dendrites, essential processes for forming neural networks [24]. These structural changes are vital for establishing synaptic connections between neurons involved in learning, memory, and cognition. This hypothesis is confirmed in animal models (such as the Mapt^−/− mouse model), where tau deletion led to aging-dependent short-term memory deficits, hyperactivity, and synaptic plasticity defects [25]. Tau’s involvement in regulating neuronal growth and morphology is modulated by post-translational modifications, such as phosphorylation, which can influence tau’s ability to bind to microtubules and regulate microtubule dynamics. Additionally, tau’s role extends beyond simple microtubule stabilization, as it also interacts with other proteins, such as heat shock proteins or Fyn tyrosine kinase, involved in signaling and cellular organization [26]. This enables tau to integrate multiple cellular processes, including those involved in synaptic plasticity and neuronal signaling.

Recent studies have shown that tau can interact with various signaling pathways, such as the PI3K-Akt or the glycogen synthase kinase-3 beta (GSK-3β) pathways, influencing cellular processes beyond its microtubule-binding activity. Tau regulates the axonal transport of signaling molecules, including neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), or serotonin, and their related receptor proteins, which are essential for synaptic function [27]. Furthermore, tau’s interactions with other proteins, such as those involved in regulating actin filaments [28] and vesicle trafficking [29], suggest that tau plays a broader role in regulating the complex organization of the synaptic environment [30]. The balance of tau phosphorylation, which can either promote or inhibit its interaction with microtubules, is an essential factor in regulating tau’s role in signaling pathways. These properties of tau also explain the role played in neuronal development and repair after injury.

While tau’s impact on CNS development and physiological functioning is relevant and continues to be intensively studied, tau is of increased relevance in pathological conditions, including AD. In AD and other tauopathies such as progressive supranuclear palsy and Pick’s disease, tau undergoes abnormal aggregation and post-translational modifications, leading to insoluble deposits that contribute to synaptic dysfunction and neuronal death [31]. In AD, tau aggregates into NFTs, following a distinct progression and localization pattern across the six Braak stages, from early silent stages (I-II) to fully developed AD (V-VI) [32]. The spread of tau pathology, still incompletely understood, is believed to occur through a prion-like mechanism, where abnormal tau aggregates induce conformational changes in normal tau, promoting further aggregation and the spread of tau pathology to other brain regions [33]. Several reviews have extensively addressed pathological tau aggregation’s molecular aspects [34,35,36]. From the practical/clinical point of view, some aspects need to be clarified before the immersion into therapeutic modalities. Tau pathology is characterized by extensive post-translational modifications (PTMs), including hyperphosphorylation, acetylation, truncation, and glycosylation. Hyperphosphorylation is a hallmark of pathological tau and results from increased activity of tau kinases and decreased activity of protein phosphatase 2A (PP2A) [37]. This process is often triggered by Aβ, which directly or indirectly activates tau kinases (GSK-3β and MARK), promoting tau phosphorylation and aggregation [38]. Tau undergoes aberrant phosphorylation at specific residues, such as Ser202, Thr205, Ser396, and Ser404, under the action of multiple kinases, with the most relevant being GSK-3β, cyclin-dependent kinase 5 (CDK5), and MARK. While GSK-3β is the prominent kinase responsible for phosphorylating tau at several of these sites, CDK5 becomes hyperactive under pathological conditions (e.g., Aβ-induced cleavage) and phosphorylates tau at overlapping and distinct sites [39]; MARK kinases phosphorylate tau at KXGS motifs within the microtubule-binding region, reducing its affinity for microtubules, being often one of the earliest events in tau dysfunction. Hyperphosphorylation leads to tau mislocalization, decreased microtubule binding, and misfolding, all contributing to neurodegeneration. The extent and patterns of phosphorylation change with disease progression and vary between tauopathies, as well as familial mutations in the tau-encoding gene (MAPT), which can exacerbate this process.

While less consistent than hyperphosphorylation, acetylation of tau similarly disrupts microtubule binding, decreases protein solubility, and impairs degradation, further driving tau aggregation [40]. Drugs such as salsalate and diflunisal, which inhibit the p300 acetyltransferase, have shown promise in reducing tau acetylation and have been linked to a decreased incidence of AD [41]. Truncation, another critical PTM, is promoted by Aβ through caspase activation, though it can also occur independently of Aβ [42]. Truncated tau fragments reduce microtubule binding, facilitate aggregation, and exacerbate synaptic and organelle dysfunction. Caspase inhibitors such as minocycline and VX-765 have shown positive effects in preclinical AD models, with minocycline advancing to clinical trials [43].

Glycosylation modifications also play a dual role in tau pathology. Protective O-GlcNAcylation, which promotes microtubule binding and reduces phosphorylation, is decreased in AD [44]. Conversely, N-glycosylation and non-enzymatic glycosylation (glycation) increase, promoting tau phosphorylation, misfolding, and impaired degradation [45]. Clinical trials on drugs targeting O-GlcNAcylation suggest potential therapeutic benefits by reducing tau aggregation and restoring its function [46]. These PTMs alter tau’s structure and function, contributing to the molecular cascade leading to neurodegeneration in AD and other tauopathies.

While PTMs are the most studied tau protein alterations, targeted by several classes of drugs, other tau mechanisms are also of interest from the pathophysiological and therapeutic point of view. The different tau aggregates, from monomers to oligomers and multimers, are all of interest in the seeding process, blocking NFT development. Among tau forms, oligomeric tau is identified as the primary pathogenic species, causing acute toxicity, nuclear and mitochondrial impairments, and disruptions in synaptic function and protein degradation [47]. Extracellular tau oligomers can induce templated seeding in naive cells, exacerbating pathology. Larger tau aggregates may initially offer a protective mechanism, but long-term NFT accumulation correlates with synapse loss, gene expression changes, energy deficits, and disrupted axonal transport [48]. Therapeutic efforts are underway to develop small molecules that target tau aggregation to mitigate its pathological spread. Additionally, tau aggregates disrupt autophagy processes essential for protein clearance [49]. AD is characterized by reduced autophagy component expression [50], impaired lysosomal activity [51], increased ubiquitinated proteins [52], and disrupted signaling pathways. Tau pathology further inhibits autophagosome formation and fusion, sequesters autophagy components, and interferes with endosomal functions, exacerbating its accumulation and toxicity [53]. These findings, summarized in

Table 1. The roles of tau protein in physiological conditions and relevant aspects related to Alzheimer’s disease.

Roles/Functions of Tau Protein in Physiological Conditions	Relevant Aspect Related to AD
Stabilization of axonal microtubules Support for intracellular transport	Disruption leading to intracellular transport failure and neuronal dysfunction
Post-translational modifications (PTMs)	Hyperphosphorylation Acetylation Truncation Glycosylation
Monomer aggregation	High toxicity of tau oligomers Modulation of tau expression
Ensures normal structure and function of synapses by interacting with actin and other cytoskeletal elements	Synaptic disruption Pathological signaling
Autophagy and protein clearance	Impairment of autophagy-lysosomal pathways, leading to toxic protein accumulation
Neural development and repair Promotion of axon extension and dendrite formation	Axonal destruction and dendrite loss Impaired synaptic plasticity Memory loss and learning problems

, underscore the critical need for interventions targeting tau clearance and the restoration of neuronal homeostasis.

With tau assembly and tau clearance as potential targets for anti-tau drugs, the following chapter systematically addresses the heterogeneous classes of drugs modulating tau behavior in AD.

4. Therapies Targeting Tau Protein

The group of therapies targeting tau protein is very heterogeneous and is expanding continuously due to the many clinical trials currently in progress. The authors have classified the multitude of significant medications according to the targeted mechanisms to maintain a logical approach. Table 2 summarizes the main tau-targeting therapeutic classes, their most relevant representatives, and the main conclusions of clinical trials.

From a didactic point of view, tau-targeting therapies can be classified into the following categories, each including some intensely discussed molecules relevant for future drug development: drugs reducing tau expression, such as tau antisense oligonucleotides (ASOs), medications targeting PTMs, drugs inhibiting tau aggregation, and immunotherapies. The most relevant trials are reviewed below, with a focus on the preliminary outcomes, as in the case of many molecules, research is still ongoing, and no clear conclusions can be stated yet.

ASOs are designed to reduce tau protein expression by targeting MAPT mRNA. Notable developments include the tau ASO MAPTRx (BIIB080), which has shown promise in early clinical trials. A phase Ib trial (NCT03186989) in patients with mild Alzheimer’s disease (AD) demonstrated that MAPTRx is safe and reduces the levels of total tau (t-tau) and phosphorylated tau (p-tau) in CSF in a dose-dependent manner [54]. By 2023, additional data revealed significant decreases in CSF tau levels, and PET scans confirmed reductions in tau across all brain regions analyzed [55]. Mild to moderate adverse events were observed. Reductions in p-tau181, the inflammatory marker YKL40, and the ratio of t-tau to Aβ42 in CSF were also reported, although no improvements in cognitive or functional measures were observed. A phase II trial (NCT05399888) focusing on cognitive outcomes in patients with mild cognitive impairment (MCI) or mild AD is underway and will conclude in December 2026 [56].

Another tau ASO, NIO752, was evaluated for safety and efficacy in several trials across various neurodegenerative conditions. Worth mentioning is a phase 1 trial in progressive supranuclear palsy (PSP) conducted between February 2021 and October 2024, which included 64 PSP patients across multiple sites in North America, Germany, and the U.K. who received intrathecal injection of escalating doses of NIO752 over three months, followed by a nine-month monitoring period regarding safety, based on observing adverse events, physical and neurological exams, vital signs, and CSF infection monitoring [57]. Another interesting phase 1b Trial was conducted in 24 early AD patients with positive CSF biomarkers for amyloid and tau who received a single intrathecal dose of NIO752 or placebo, with six months of follow-up. The primary outcome is the change in CSF total tau levels at three months, along with safety and pharmacokinetics evaluations [57].

Besides drugs reducing tau expression, with ASOs as the main class, medications targeting PTMs are at least as important, considering the various PTMs of the tau protein relevant for the onset and evolution of AD. Drugs targeting PTMs can be classified into three main subgroups according to underlying action mechanisms: kinase inhibitors, acetylation modulators, and caspase inhibitors. Glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5) are key kinases in tau hyperphosphorylation. Among the most relevant GSK-3β inhibitors, worth mentioning is tideglusib, an orally available small-molecule studied as a potential treatment for AD and other tauopathies such as progressive supranuclear palsy (PSP). Preclinical studies demonstrated its neuroprotective effects, including reduced tau phosphorylation, amyloid burden, gliosis, and cognitive deficits in transgenic mouse models [58]. In clinical development, a Phase 2a trial in AD patients showed good tolerability and hinted at cognitive benefits, while a more significant Phase 2b trial (ARGO) failed to meet its primary endpoints [59]. In PSP, the TAUROS trial also did not reach its primary outcome, though a subgroup analysis suggested a potential reduction in brain atrophy [60]. Despite receiving orphan drug and fast-track designations, tideglusib’s clinical development faced setbacks, with the drug being repurposed for other conditions, including myotonic dystrophy [61]. While there are other relevant kinases, such as CDK5 and MARK, to date, no notable trials on drugs targeting CDK5 or MARK in AD animal models or patients could be included in this review.

Another critical PTM related to AD is tau acetylation, with histone deacetylase 6 (HDAC6), a cytoplasmic enzyme that modulates both α-tubulin and tau acetylation, as a key player and therapeutic target for restoring cytoskeletal dynamics and reducing tau pathology [62]. The inhibition of HDAC6 has been shown to reverse axonal transport deficits and normalize microtubule stability in animal models of tauopathy. Ricolinostat (ACY-1215), a selective HDAC6 inhibitor originally developed for cancer, has demonstrated neuroprotective and anti-aggregation effects in preclinical studies, including reduced levels of acetylated and aggregated tau species [63]. Similarly, other compounds, such as tubastatin A and ACY-1215, two selective HDAC6 inhibitors, were found to alleviate behavioral deficits, alter Aβ load, and reduce tau hyperphosphorylation in AD mice without apparent adverse effects [64]. Tubastatin A and ACY-1215 promoted tubulin acetylation, decreased production, and facilitated autophagic clearance of Aβ and hyperphosphorylated tau [64].

Remaining in the field of enzymes that slice tau protein in key positions, caspase-2 plays a particularly significant role in the cleavage of tau at the Asp314 site, producing fragments associated with synaptic dysfunction and memory impairment [65]. Pharmacological inhibition or genetic silencing of caspase-2 has shown protective effects in various tauopathy models, including reductions in tau truncation, aggregation, and neurotoxicity. These interventions have also been associated with improved synaptic plasticity and behavioral outcomes in preclinical studies [66]. Still, several key improvements are necessary to advance the clinical development of these molecules. Firstly, there is a great need for orally available, brain-penetrant Casp2 inhibitors capable of restoring synaptic function and reversing cognitive deficits in preclinical models. The design of such compounds will likely require innovative strategies like prodrug approaches. TRP601 (ORPHA133563), a prodrug of an irreversible Casp3/Casp2 inhibitor, has demonstrated neuroprotective effects in neonatal rodent models without significant off-target toxicity, achieving efficient brain penetration after intravenous administration [67]. Similarly, VX-765 (Belnacasan), an orally absorbed prodrug of a reversible Casp1 inhibitor, advanced to Phase II trials for epilepsy and psoriasis, although it did not progress further [68]. These examples highlight the feasibility of developing effective prodrug-based caspase inhibitors as an effective AD treatment.

Another promising group of drugs is represented by small molecules that target tau protein aggregation into neurofibrillary tangles. Small-molecule inhibitors, such as methylene blue derivatives (notably LMTX), have been developed to disrupt tau self-assembly by binding to monomeric or intermediate species and preventing the formation of β-sheet-rich fibrillar structures. These agents aim to stabilize tau in non-pathogenic conformations, thereby reducing its propensity to form toxic oligomers and fibrils. Initial preclinical studies demonstrated that LMTX effectively inhibited tau fibrillization in vitro and reduced tau pathology and behavioral deficits in transgenic mouse models [69]. These encouraging findings led to clinical development, with two Phase 3 trials conducted in patients with mild to moderate AD. The first trial (TRx-237-015) enrolled over 800 participants and tested LMTX as monotherapy at 75 mg or 125 mg twice daily versus placebo. Despite the trial failing to meet its primary endpoint, showing no statistically significant cognitive or functional benefit in the overall study population, a post hoc subgroup analysis suggested that participants not receiving background AD medications (such as cholinesterase inhibitors or Memantine) experienced reduced brain atrophy and a slower rate of cognitive decline, hinting at possible drug–drug interactions or confounding effects [70]. A second Phase 3 study (TRx-237-005) further evaluated LMTX at a lower dose in 800 participants, aiming to test the hypothesis that this minimal dose, serving as a functional placebo in the previous trial, might represent the therapeutic threshold. However, this trial also did not meet its primary endpoint, though some exploratory analyses again showed modest benefits in the subgroup not receiving concomitant anti-dementia medications [71].

While indirectly modulating tau behavior, worth mentioning from a historical perspective are microtubule-stabilizing agents, compounds that promote the polymerization and stability of microtubules. These agents are of significant interest for stabilizing microtubule disassembly caused by hyperphosphorylated tau. The most relevant examples include paclitaxel (Taxol) and epothilones, which bind to β-tubulin [72]. Although some of these compounds were initially developed as anti-cancer therapies, modified versions with improved brain penetration and lower toxicity are being investigated for therapeutic use in tau-related neurodegeneration [73]. Their potential to compensate for tau loss of function makes them promising candidates in disease-modifying strategies.

Finally, the last group of anti-tau drugs is related to passive and active immunotherapies, a therapeutic direction with promising results when considering other pathophysiological aspects worth being targeted in AD, such as Aβ oligomers and amyloid plaques. Active immunotherapy involves vaccination strategies designed to elicit a sustained immune response against pathological tau species. AADvac1, a first-in-class peptide-based vaccine, targets a misfolding-specific epitope within the tau protein to induce antibody responses against aggregated tau while sparing physiological tau. Phase 1 and 2 studies demonstrated a favorable safety profile, immunogenicity, and potential reductions in CSF biomarkers associated with tau pathology [74]. Active immunization may offer several theoretical advantages, including prolonged antibody production and reduced treatment frequency. However, the risk of neuroinflammation or autoimmune responses remains a concern, especially given the need for repeated or long-term immunological engagement in elderly individuals. Other significant anti-tau active immunotherapies include ACI-35, which was tested in a placebo-controlled Phase 1b trial and subsequently launched to evaluate its safety, tolerability, and immunogenicity in patients with mild to moderate AD. Further optimization of antigen design and delivery platforms, along with careful patient selection, will be essential to realize the full potential of tau vaccines in AD prevention or treatment [75].

In contrast, passive immunotherapy targeting tau is more advanced, with several monoclonal antibodies designed to bind extracellular tau and block its trans-synaptic propagation having reached the clinical trials phase. Gosuranemab (BIIB092), targeting the N-terminal region of tau, was evaluated in the Phase 2 TANGO trial in early AD, where it showed robust target engagement and reductions in free tau levels in CSF, but failed to demonstrate cognitive benefit, leading to discontinuation [76]. Semorinemab, targeting the mid-region of tau, progressed through two major trials: the LAURIET study in moderate AD, which showed no significant effect on cognition [77], and the TAURIEL trial in prodromal to mild AD, which also failed to meet efficacy endpoints [78]. Zagotenemab, directed against a conformational epitope present in pathological tau aggregates, was assessed in the Janssen-ALZ100 trial but similarly yielded unsatisfactory cognitive outcomes despite evidence of target engagement [79]. Another humanized, monoclonal IgG4 antibody, Bepranemab, which binds to the central region of tau, is reported to inhibit pathologic tau seeds and is currently under study in a Phase 2 clinical trial involving 450 patients with MCI and mild AD [80]. The final results have not yet been published. Other molecules, such as E2814 [81] and many more, are currently under research, with preliminary results from human clinical trials expected to be revealed soon. Collectively, these results highlight the challenges of passive immunotherapy in AD, including suboptimal timing of intervention, limited access to intraneuronal tau, and the need for improved epitope targeting and biomarker-driven patient stratification in future trials. Still, similar to anti-Aβ passive immunotherapy, this group of anti-tau monoclonal antibodies seems to be the most promising research and therapeutic option among the heterogeneity of anti-tau drugs in the next few years.

Table 2. Therapies targeting tau protein: classes, relevant representatives, and significant conclusions from clinical trials.

Class of Tau-Targeting Therapies	Relevant Representatives	Development Status
Tau antisense nucleotides	BIIB080 [54,55,56]	Phase 1b Clinical Trials (NCT03186989)
PTM modulators	Kinase inhibitors—Tideglusib (GSK-3β inhibitor) [58,59,60]	Phase 2 Clinical Trials (ARGO)
	Acetylation modulators—Ricolinostat [63], Tubastatin [64], and ACY-1215 (HDAC6 inhibitor) [64]	Preclinical/Early Phase
	Caspase Inhibitors—TRP601 [67]	Preclinical
Aggregation inhibitors	Small-molecule inhibitors—LMTX (methylene blue derivatives) [69,70,71]	Phase 3 (TRx-237-005)
Immunotherapies	Passive immunotherapy—Gosuranemab [74], Semorinemab [75], Zagotenemab [76], and Bepranemab [80]	Phase 2/3 Clinical Trials (TANGO, LAURIET, TAURIEL, ALZ100, and TOGETHER)
	Active immunotherapy—AADvac1 [72] and ACI-35	Phase 2 Clinical Trials (NCT02579252) Phase 1b Clinical Trial (ISRCTN13033912)
Proteolysis-targeting chimera (PROTAC)	C004019 [82]	Preclinical

Table 2. Therapies targeting tau protein: classes, relevant representatives, and significant conclusions from clinical trials.

Class of Tau-Targeting Therapies	Relevant Representatives	Development Status
Tau antisense nucleotides	BIIB080 [54,55,56]	Phase 1b Clinical Trials (NCT03186989)
PTM modulators	Kinase inhibitors—Tideglusib (GSK-3β inhibitor) [58,59,60]	Phase 2 Clinical Trials (ARGO)
	Acetylation modulators—Ricolinostat [63], Tubastatin [64], and ACY-1215 (HDAC6 inhibitor) [64]	Preclinical/Early Phase
	Caspase Inhibitors—TRP601 [67]	Preclinical
Aggregation inhibitors	Small-molecule inhibitors—LMTX (methylene blue derivatives) [69,70,71]	Phase 3 (TRx-237-005)
Immunotherapies	Passive immunotherapy—Gosuranemab [74], Semorinemab [75], Zagotenemab [76], and Bepranemab [80]	Phase 2/3 Clinical Trials (TANGO, LAURIET, TAURIEL, ALZ100, and TOGETHER)
	Active immunotherapy—AADvac1 [72] and ACI-35	Phase 2 Clinical Trials (NCT02579252) Phase 1b Clinical Trial (ISRCTN13033912)
Proteolysis-targeting chimera (PROTAC)	C004019 [82]	Preclinical

5. Conclusions and Future Research Directions

With increasing incidence and prevalence worldwide and despite the myriad of clinical trials, AD remains a challenge in therapeutic terms, with no disease-modifying effective treatment. Based on the latest epidemiological, economic, and individual data, there is an increased need to develop new, more effective therapies. Or, with the most research focused on the modulation of the Aβ cascade but with insufficient results, addressing tau pathology is a natural direction to follow.

In this context, anti-tau drugs could become relevant therapeutic modalities in the near future. The most relevant drug research directions aim to reduce tau expression (tau antisense oligonucleotides), inhibit tau aggregation, target PTMs, or use passive or active immune-based approaches. We have summarized the most relevant representatives of each group in detail. According to the increasing number of molecules and clinical trials, the most promising direction is represented by anti-tau monoclonal antibodies. Additionally, the novel class of proteolysis-targeting chimeras (PROTACs), which selectively degrades tau protein from within cells, thus efficiently promoting tau clearance, could be another promising drug candidate for AD [82]. Still, several aspects need to be addressed to improve the potency of these still under research therapies: a better biomarker-based patient selection, structural and functional improvements of the epitopes, and targeting of both extra- and intraneuronal tau.