Tau PET Imaging: A Comprehensive Review of Scientific Principles, Clinical Applications, and Future Directions in Neurodegenerative Disease

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Alzheimer’s disease (AD) and other tauopathies represent a significant global health challenge, characterized by the pathological accumulation of hyperphosphorylated tau protein into neurofibrillary tangles (NFTs). The advent of Positron Emission Tomography (PET) imaging for tau has revolutionized the in vivo study of these pathologies, offering unprecedented insights into disease progression, diagnosis, and therapeutic monitoring. This report provides a comprehensive review of Tau PET imaging, delving into the intricate scientific principles underpinning its functionality, the evolution and specific applications of various radiotracers, its pivotal role in advancing clinical trials for novel Alzheimer’s therapies, and the persistent challenges related to accessibility and cost-effectiveness. Furthermore, it explores future advancements in neuroimaging techniques, including the integration of artificial intelligence and multimodal approaches, poised to enhance early disease detection and prognosis. This expert-level analysis aims to consolidate current knowledge, highlight critical limitations, and project the trajectory of Tau PET as a transformative tool in neurodegenerative disease research and clinical practice.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting millions globally, with projections indicating a substantial increase in prevalence in the coming years [21, 24]. Its neuropathological hallmarks include extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein [5, 10]. While amyloid pathology has long been a primary focus of research, the strong correlation between tau pathology burden and cognitive decline, as well as disease severity and progression, has increasingly highlighted tau as a critical therapeutic target and biomarker [9, 24, 27]. For decades, the definitive diagnosis of AD and other tauopathies relied on post-mortem neuropathological examination. However, the development of Positron Emission Tomography (PET) technology has enabled the non-invasive, in vivo visualization and quantification of these pathological protein aggregates in the living human brain [1, 2, 38].

Amyloid PET imaging emerged first, allowing for the detection of plaques years before symptom onset [17, 21]. However, the spatial dynamics and direct correlation with clinical symptoms are often more closely tied to tau accumulation [2, 9]. The ability to directly visualize tau pathology has been a significant breakthrough, offering a powerful tool for early diagnosis, differential diagnosis, prognostic assessment, and monitoring treatment efficacy in clinical trials [1, 2, 24, 27]. This research report aims to provide a detailed, expert-level examination of Tau PET imaging, exploring its foundational scientific principles, the characteristics and utility of different generations of tracers, its crucial role in drug development, the practical challenges hindering its widespread adoption, and the exciting future directions in neuroimaging for neurodegenerative disorders.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. The Neurobiology of Tau and its Pathological Manifestations

Tau, a microtubule-associated protein (MAP), plays a crucial role in maintaining the structural stability and assembly of microtubules within neurons, particularly in axons [5, 6]. Under physiological conditions, tau undergoes phosphorylation, a reversible process that regulates its binding to microtubules [5, 10]. In neurodegenerative diseases, however, tau becomes abnormally hyperphosphorylated and detaches from microtubules, leading to their destabilization and impaired axonal transport [5, 6, 9]. These hyperphosphorylated tau molecules then misfold and aggregate into insoluble filaments, forming paired helical filaments (PHFs) and straight filaments (SFs) that coalesce into NFTs, a hallmark of AD and other tauopathies [5, 10, 22].

Genetic evidence from frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTLD-17), caused by mutations in the microtubule-associated protein tau (MAPT) gene, unequivocally established that tau dysfunction alone is sufficient to trigger neurodegeneration, even in the absence of amyloid-beta pathology [5, 6, 22]. This underscores tau’s intrinsic pathogenic potential. The aggregation of tau disrupts neuronal structure and function, ultimately leading to neuronal death and the progressive clinical symptoms characteristic of these disorders [6]. The distribution and density of these tau tangles in the brain correlate strongly with disease progression and cognitive decline in AD [9, 24]. In AD, tau pathology typically begins in the entorhinal cortex and hippocampus, key regions for memory, and then spreads in a predictable pattern to neocortical areas, following the Braak staging scheme [9, 17, 27]. Beyond AD, abnormal tau accumulation is also observed in a range of primary tauopathies, including Pick’s disease (PiD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and Chronic Traumatic Encephalopathy (CTE) [5, 22, 27]. These tauopathies are characterized by distinct tau isoform compositions (3R, 4R, or mixed 3R/4R tau) and unique anatomical distributions of tau pathology, which present specific challenges for PET imaging [3, 5, 16]. The interplay between Aβ and tau pathology in AD is also complex; while Aβ deposition is thought to precede tau accumulation, Aβ oligomers can induce tau hyperphosphorylation and subsequent neurofibrillary deposition, forming a vicious cycle that contributes to cognitive decline [6]. Understanding these intricate neurobiological processes is fundamental to appreciating the value and limitations of Tau PET imaging.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Scientific Principles of Tau PET Imaging

Positron Emission Tomography (PET) is a functional molecular imaging technique that utilizes radiotracers to visualize and quantify specific biochemical processes in vivo [34]. For Tau PET, this involves injecting a small amount of a radiolabeled ligand that selectively binds to aggregated tau protein in the brain. The radiotracer, typically labeled with a positron-emitting isotope like Fluorine-18 (¹⁸F) due to its longer half-life compared to Carbon-11 (¹¹C), emits positrons that annihilate with electrons, producing two gamma rays detected by the PET scanner [34, 39]. These detections allow for the three-dimensional reconstruction of the radiotracer’s distribution, providing a quantitative map of tau pathology [34].

The fundamental principle relies on the radiotracer’s ability to cross the blood-brain barrier (BBB) and selectively bind to the β-sheet rich structures of pathological tau aggregates (paired helical filaments or PHFs) with high affinity and specificity [8, 12, 41]. An ideal tau tracer should exhibit low nanomolar affinity for tau filaments while showing minimal or no binding to other brain components, including normal physiological tau, amyloid-beta plaques, and other non-specific targets like monoamine oxidase (MAO) enzymes or neuromelanin [8, 12, 15, 18, 41]. Non-specific or off-target binding is a significant challenge, as it can obscure the true tau signal and complicate quantitative analysis, particularly in subcortical regions or in non-AD tauopathies [1, 3, 13, 15].

Quantitative analysis of Tau PET data typically involves calculating standardized uptake value ratios (SUVRs), which normalize regional tracer uptake to a reference region, often the inferior cerebellar gray matter or eroded white matter for longitudinal studies [1, 38]. Kinetic modeling, while more complex and often requiring arterial blood sampling, provides more accurate measurements of tracer binding potential by accounting for tracer delivery and metabolism [3, 39]. Advanced image processing techniques, including partial volume correction, are also crucial to mitigate the effects of limited spatial resolution and improve the accuracy of regional quantification, especially for subtle tau signals in early disease stages [1, 13]. The evolution of these principles, from radioligand design to image analysis, has been a continuous process aimed at improving the sensitivity, specificity, and quantitative accuracy of Tau PET for clinical and research applications.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Evolution and Characteristics of Tau PET Tracers

The development of Tau PET tracers has progressed through several generations, each aiming to overcome the limitations of its predecessors, primarily concerning specificity and off-target binding. The requirements for an ideal tau tracer are stringent: high brain uptake, rapid clearance of unbound tracer, high affinity and selectivity for tau aggregates over other brain components, and no brain-penetrant radioactive metabolites [8, 39, 41].

First-Generation Tau PET Tracers

The first generation of tau PET tracers emerged around 2013, enabling the in vivo visualization of tau pathology [1]. Key examples include ¹⁸F-flortaucipir (also known as ¹⁸F-T807, ¹⁸F-AV1451, or Tauvid™), ¹¹C-PBB3, and the ¹⁸F-THK family (e.g., ¹⁸F-THK523, ¹⁸F-THK5105, ¹⁸F-THK5117, ¹⁸F-THK5351) [1, 3, 18].

• ¹⁸F-Flortaucipir: This is arguably the most widely applied and studied first-generation tracer, and the first to receive FDA approval for clinical use in May 2020 to estimate the density and distribution of aggregated tau neurofibrillary tangles in adult patients with cognitive impairment being evaluated for Alzheimer’s disease [1, 2, 18]. It demonstrates good binding to AD-type tau aggregates (3R/4R tau isoforms) in more advanced Braak stages (≥IV) [1]. However, it exhibits significant off-target binding in regions such as the substantia nigra, basal ganglia, choroid plexus, pituitary, and retina, primarily due to binding to neuromelanin and other non-tau targets [1, 3, 13, 15, 16]. While effective in distinguishing AD dementia from non-AD neurodegenerative diseases and cognitively unimpaired controls, its utility for detecting early tau pathology (Braak stages I-IV) is limited, and its off-target binding can complicate visual interpretation and quantitative accuracy [1, 4, 13].
• ¹¹C-PBB3: Derived from the same chemical family as the amyloid tracer Pittsburgh Compound B (PiB), ¹¹C-PBB3 showed initial promise for imaging both AD and non-AD tauopathies [3, 8]. However, it suffered from substantial off-target binding to amyloid deposits and monoamine oxidase B (MAO-B), significantly hampering its specificity for tau pathology [1, 3, 8, 13, 15]. It also had issues with low specific binding and brain-penetrant radioactive metabolites [3].
• ¹⁸F-THK Family (e.g., ¹⁸F-THK5351): These tracers also exhibited off-target binding to MAO-B, particularly in the basal ganglia and midbrain, which complicated their interpretation and limited their specificity for pure tau pathology, especially in non-AD tauopathies [3, 12, 14, 15, 28]. Some THK tracers also showed high white matter binding, potentially reflecting binding to β-sheet structures in myelin basic protein, further reducing their clinical utility [14, 41].

Critically, most first-generation tracers demonstrated lower affinity for the 3R and 4R tau isoforms characteristic of many primary tauopathies, possibly due to lower aggregate densities or differing tau conformers, limiting their applicability beyond AD [1, 3, 12, 16].

Second-Generation Tau PET Tracers

Recognizing the limitations of the first generation, a concerted effort has led to the development of second-generation tracers with improved specificity, reduced off-target binding, and often, higher signal-to-background ratios [1, 19, 40]. These tracers aim to provide cleaner images and better differentiation of various tauopathies.

• ¹⁸F-MK-6240: Developed by Merck, this pyridine isoquinoline amine derivative has shown promising characteristics, including favorable kinetics, significant binding in AD tauopathy regions, and a better off-target binding profile compared to first-generation tracers, though some binding to neuromelanin in the substantia nigra is still observed [1, 16]. It has demonstrated good correlation with clinical endpoints [3].
• ¹⁸F-RO948 (RO6958948): A derivative of ¹⁸F-AV1451, ¹⁸F-RO948 aims to improve upon its predecessor’s off-target binding profile. It shows high affinity for NFTs and excellent selectivity against Aβ plaques [12]. Extensive screening revealed no off-target binding to MAO-A and MAO-B, which is a significant improvement [16, 40].
• ¹⁸F-PI-2620: Another pyrido-indole-based derivative, ¹⁸F-PI-2620 has shown good properties as a tau PET tracer, distinguishing AD subjects from healthy controls [3]. It exhibits a lack of non-target binding in several areas problematic for first-generation tracers, including the choroid plexus, basal ganglia, and venous sinuses [28, 37]. It also showed ambivalent binding to 3R-tau from PiD brain and 4R-tau from PSP samples, suggesting broader utility for non-AD tauopathies [16].
• ¹⁸F-APN-1607 (¹⁸F-PM-PBB3): This tracer, a derivative of PBB3, has shown specific binding with tau aggregates in both AD and PSP, and notably improved off-target binding, with no binding observed in the basal ganglia and thalamus or to MAO-A and MAO-B [16, 37]. This suggests a greater potential for differential diagnosis across various tauopathies.

While second-generation tracers represent a significant leap forward in addressing off-target binding and expanding utility to non-AD tauopathies, the field continues to refine these tools. The ultimate goal remains to develop tracers with absolute specificity for particular tau conformers, enabling precise diagnosis and therapeutic monitoring across the diverse spectrum of tau-related neurodegenerative diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Clinical Applications and Impact of Tau PET in Alzheimer’s Disease

Tau PET imaging has rapidly become an indispensable tool in the clinical landscape of Alzheimer’s disease, offering capabilities that extend beyond traditional diagnostic methods to provide crucial insights into disease progression and heterogeneity. Its primary utility stems from its ability to directly visualize and quantify the spatial distribution of tau pathology in living individuals, which correlates strongly with the stage and severity of cognitive impairment [2, 9, 24].

Diagnostic Utility

One of the most significant impacts of Tau PET is its diagnostic accuracy, particularly in differentiating AD dementia from other neurodegenerative diseases that may present with similar clinical symptoms but lack significant AD-type tau pathology [1, 2, 24]. While amyloid PET helps rule out AD by detecting Aβ plaques, tau PET provides direct evidence of the neurofibrillary tangles that are more closely linked to symptomatic decline [17, 24, 30]. For instance, quantitative analysis of ¹⁸F-flortaucipir PET can accurately distinguish clinically diagnosed AD dementia from non-AD neurodegenerative diseases and cognitively unimpaired controls [2]. The US Food and Drug Administration (FDA) approval of ¹⁸F-flortaucipir for clinical use reflects this established diagnostic utility [1, 2]. However, the differential diagnostic performance may decrease at the mild cognitive impairment (MCI) stage, and its sensitivity for detecting very early tau pathology (Braak stages I-IV) is still limited [1, 4]. Despite this, new visual interpretation methods are being developed to enhance both research and clinical applications [2].

Prognostic Value

Beyond diagnosis, Tau PET holds substantial prognostic value. An elevated tau PET signal, even in cognitively unimpaired individuals with positive amyloid-beta, is a strong predictor of future cognitive decline and brain atrophy [1, 24]. This makes Tau PET a more reliable early indicator of cognitive decline than amyloid PET alone in some contexts, as tau deposition is closely associated with clinical changes [2, 24]. In symptomatic stages of AD (MCI or AD dementia), an increased baseline tau PET retention consistently forecasts future cognitive decline [1]. The spatial dynamics captured by Tau PET, reflecting the Braak staging, allows for a more granular assessment and prediction of disease progression and clinical outcomes [2, 17, 24]. This ability to stage biological disease severity and provide information on prognosis is a core utility proposed in the 2024 revised diagnostic criteria by the Alzheimer’s Association Workgroup [4, 17].

Understanding Disease Heterogeneity and Progression

Tau PET allows researchers to observe the spread of tau pathology in vivo, providing invaluable data on the heterogeneity of AD and its progression. It shows that tau deposition typically follows an anatomical progression, starting in the medial temporal lobe and spreading to neocortical regions in AD patients [27, 35, 38]. This visualization helps to understand the variability in clinical presentation and cognitive profiles observed in AD, as different patterns of tau accumulation might underlie distinct clinical phenotypes. Furthermore, the correlation between tau PET measures and other regional pathological changes, such as synaptic loss, hypometabolism (as measured by FDG-PET), and brain atrophy (as measured by MRI), provides a more comprehensive picture of the disease’s impact on the brain [2, 27, 29]. The integration of Tau PET with fluid biomarkers, such as cerebrospinal fluid (CSF) and plasma phosphorylated tau (p-tau) levels, further enhances its diagnostic and prognostic capabilities, as these modalities often show strong correlations but capture different aspects of tau pathology (spatial vs. soluble) [2, 9, 11, 27].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Tau PET in Clinical Trials for Alzheimer’s Therapies

The landscape of Alzheimer’s disease therapeutic development has been profoundly impacted by the advent of biomarkers, particularly Tau PET imaging. Its ability to directly visualize tau pathology in vivo positions it as a critical tool across various stages of clinical trials, from patient selection to monitoring treatment efficacy [2, 4, 27]. The continuous failures of amyloid-targeting drugs in earlier trials, partly due to challenges in identifying appropriate patient populations or monitoring target engagement, underscored the necessity for robust biomarkers like Tau PET [8].

Patient Selection and Stratification

Tau PET is increasingly employed in clinical trials for selecting participants who are most likely to benefit from specific interventions [2, 4]. For anti-amyloid therapies, identifying individuals with both amyloid and tau pathology (A+T+) can ensure that treatments are administered to those with underlying AD pathophysiology, rather than individuals with amyloidosis alone who may not yet have significant neurodegeneration [17, 26]. Some studies even suggest that a positive tau PET scan is strongly associated with amyloid positivity in individuals with early symptomatic AD, potentially streamlining trial enrollment by reducing the need for separate amyloid PET scans in certain contexts [26]. This is particularly relevant given the modest benefits of new amyloid-targeting drugs, which are most pronounced in patients with the mildest symptoms and lower levels of tau protein [20]. Tau PET can help to stage disease severity, allowing for more precise stratification of participants into groups based on their tau burden, which may influence their likelihood of response to specific treatments [17, 24]. This approach aims to match the right patient to the right therapy, enhancing trial efficiency and the probability of detecting a treatment effect.

Monitoring Treatment Efficacy

Beyond patient selection, Tau PET serves as a crucial biomarker for monitoring the efficacy of new Alzheimer’s therapies. For anti-tau therapies, a reduction in tau PET signal would directly indicate target engagement and a beneficial effect on tau pathology accumulation or clearance [2, 27]. For amyloid-targeting therapies, while their primary action is on Aβ plaques, secondary effects on tau pathology can be monitored. Given that tau accumulation is downstream of amyloid in AD, a successful amyloid-reducing therapy might be expected to slow down or reduce tau spread over time, and Tau PET can capture these changes longitudinally [27]. Accurate quantification of tau burden is critical to determining treatment efficacy and monitoring treatment response [35]. The dynamic range of the tau PET signal allows for a more granular assessment of disease progression and, by extension, treatment response [24]. This capability is invaluable in understanding how novel compounds modify the disease course, providing objective evidence of biomarker engagement and phenotypic modification. As the field moves towards personalized medicine, the ability of Tau PET to provide nuanced insights into an individual’s specific tau pathology will be paramount for tailoring treatment strategies.

Drug Development Challenges and Opportunities

Despite its promise, the integration of Tau PET into clinical trials presents challenges. The cost and availability of Tau PET scans remain significant barriers, especially for large-scale, multi-center trials [4, 20]. Standardizing image acquisition and analysis protocols across different sites and tracers is essential to ensure data comparability and reliability [1, 23, 35]. Furthermore, interpreting subtle changes in tau signal in response to treatment requires sophisticated quantitative methods and careful consideration of off-target binding effects [1, 3, 13]. However, the opportunities are immense. Tau PET can accelerate drug development by providing early indicators of therapeutic success or failure, allowing for quicker go/no-go decisions in the drug pipeline. It enables a deeper understanding of the mechanisms of action of new drugs and their impact on a key driver of neurodegeneration. As more disease-modifying therapies emerge, Tau PET will be integral not only to their development but also to their eventual clinical implementation, guiding treatment decisions based on an individual’s biological disease stage [17].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Challenges and Limitations of Tau PET Imaging

Despite its transformative potential, Tau PET imaging is not without its challenges and limitations. These issues span technical, financial, and interpretational domains, impacting its widespread accessibility and optimal application in both research and clinical settings.

Accessibility and Infrastructure

One of the most significant barriers to the broader adoption of Tau PET is its high cost and limited availability [4, 20, 23, 32]. PET scanners themselves represent a substantial capital investment, and the production and distribution of short-lived radiotracers require specialized cyclotron facilities and radiopharmacies, which are not universally accessible [23, 34]. This limits the number of centers capable of performing Tau PET scans, creating geographical disparities in access for patients and researchers alike [20, 21]. Even when available, the cost per scan, typically around $3,000 without insurance, can be prohibitive for many, and coverage by healthcare systems, such as Medicare, can be restricted [20, 32]. This financial burden can impede early diagnosis and subsequent access to new, expensive Alzheimer’s therapies that require PET imaging for eligibility and monitoring [20, 32]. Addressing these infrastructure and financial limitations will require collaborative efforts among governmental bodies, pharmaceutical companies, and healthcare providers.

Cost-Effectiveness

The high cost of Tau PET scans raises questions about their cost-effectiveness in routine clinical practice, particularly when considered in the context of long-term care and monitoring for a chronic disease like AD [20]. While Tau PET provides invaluable diagnostic and prognostic information, the economic impact on healthcare systems needs careful consideration. Strategies for improving cost-effectiveness could include optimizing the frequency of scans, integrating with less expensive blood-based biomarkers for initial screening, and exploring alternative funding models [11, 32]. The ultimate value proposition of Tau PET will likely be tied to its ability to guide personalized treatment decisions that significantly improve patient outcomes and potentially reduce long-term care costs, thus justifying the initial investment.

Standardization and Quantification Issues

Standardization across different Tau PET tracers, scanners, and analysis pipelines remains a critical challenge [1, 3, 35]. Each tracer has unique binding characteristics and off-target profiles, making direct comparisons of quantitative values (e.g., SUVRs) difficult across studies utilizing different ligands [1, 14, 38]. While efforts are underway to develop standardized quantitative tau PET scales, achieving consensus on optimal reference regions, partial volume correction methods, and visual read interpretations is an ongoing process [1, 38]. Variability in image acquisition protocols and reconstruction algorithms across PET centers can also introduce inconsistencies, impacting the reliability and reproducibility of results, particularly for subtle changes in early disease [23, 25, 35]. The presence of off-target binding in specific brain regions (e.g., basal ganglia, choroid plexus, substantia nigra) for even the second-generation tracers complicates accurate quantification of true tau pathology, especially in non-AD tauopathies where tau aggregate densities might be lower or conformers different [1, 3, 13, 15, 16].

Specificity in Non-AD Tauopathies

Although second-generation tracers have improved specificity, a major limitation for Tau PET is its variable affinity for the diverse tau conformers found in different primary tauopathies (e.g., PSP, CBD, PiD) [1, 3, 16, 19]. While most current tracers bind well to the mixed 3R/4R tau of AD, their binding to predominantly 3R or 4R tau aggregates in other tauopathies is often weaker or inconsistent, overlapping significantly with off-target binding regions [1, 3, 12, 16]. This limits the ability of current Tau PET to reliably quantify and visualize non-AD tau pathology in vivo and restricts its differential diagnostic utility in these conditions [1, 3, 15]. Further research is needed to develop novel tracers with high specificity for the distinct tau strains present in the various tauopathies, which would revolutionize their diagnosis and enable targeted therapeutic development for these devastating diseases.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Future Directions and Emerging Neuroimaging Techniques

The field of neuroimaging for neurodegenerative diseases, particularly concerning tau pathology, is dynamic, with ongoing advancements pushing the boundaries of early detection, precise diagnosis, and personalized prognostication. Future directions in Tau PET and complementary neuroimaging modalities are focused on enhancing sensitivity, specificity, and accessibility.

Next-Generation Tau Tracers

Building on the lessons learned from first and second-generation tracers, the development of ‘next-generation’ tau tracers is a key area of focus. These tracers aim for even higher specificity for different tau conformers (e.g., pure 3R or 4R tau), improved signal-to-noise ratios, and negligible off-target binding, particularly in subcortical regions that are often affected in non-AD tauopathies [15, 19]. Such advancements would allow for a more precise differential diagnosis of various tauopathies and a clearer understanding of their distinct pathological spread patterns. The goal is to design ligands that are truly selective for specific tau aggregates, enabling a more nuanced molecular classification of disease.

Multi-modal Imaging

Integrating Tau PET with other neuroimaging modalities offers a more comprehensive view of brain pathology and function. PET/MRI hybrid systems, for instance, combine the molecular sensitivity of PET with the high anatomical resolution and diverse functional capabilities of MRI (e.g., structural MRI for atrophy, fMRI for functional connectivity, DTI for white matter integrity) [29, 30]. This synergistic approach can provide richer datasets for understanding disease mechanisms and progression. Combining amyloid and tau PET scans is already standard practice in research settings, as it allows for the simultaneous assessment of both hallmark pathologies of AD, providing a biological staging of the disease based on the presence and extent of each protein [17, 38]. This multimodal approach is crucial for understanding the complex interplay between amyloid and tau and their cumulative impact on neurodegeneration and cognitive decline.

Integration with Fluid Biomarkers

The synergy between imaging biomarkers and fluid biomarkers (e.g., cerebrospinal fluid (CSF) and blood-based biomarkers) is rapidly evolving [9, 11, 27]. While Tau PET offers spatial information on tau deposition, fluid biomarkers, particularly highly sensitive plasma phosphorylated tau (p-tau) assays (e.g., p-tau181, p-tau217), provide a less invasive and more cost-effective way to screen for tau pathology and monitor disease activity [9, 11, 32]. The diagnostic accuracy of plasma p-tau, especially p-tau217, is showing promising correlation with amyloid and tau PET findings, and it could serve as a valuable initial screening tool, reserving more expensive PET scans for confirmation or detailed staging [11]. The future likely involves a diagnostic algorithm that leverages these complementary approaches, starting with blood tests, followed by PET or CSF analysis for confirmation or in cases of diagnostic uncertainty [32].

Artificial Intelligence and Machine Learning in Image Analysis

The increasing complexity and volume of neuroimaging data necessitate advanced computational approaches. Artificial intelligence (AI) and machine learning (ML) are poised to revolutionize Tau PET analysis [7, 29]. AI algorithms, particularly deep learning models like Convolutional Neural Networks (CNNs), can enhance feature extraction, pattern recognition, and predictive modeling from PET images, leading to improved accuracy in diagnosis and prognosis [7, 29]. For example, ML models can accurately classify tau PET scans and develop novel summary measures that account for the heterogeneity in tau deposition, potentially outperforming traditional region-of-interest approaches [36]. AI can also aid in automating image processing pipelines, reducing variability, and improving the efficiency of quantitative analysis [21, 23]. Furthermore, AI could facilitate the generation of synthetic PET images from other, more readily available imaging modalities (e.g., MRI, FDG-PET), thereby expanding access to tau burden assessment, especially in resource-limited settings [23]. Beyond AD, AI-driven analysis of Tau PET could help in distinguishing various tauopathies based on subtle, yet distinct, patterns of tau accumulation that might be imperceptible to the human eye.

Applications Beyond AD: Other Tauopathies

While AD has been the primary focus, the expansion of Tau PET imaging to other tauopathies (e.g., PSP, CBD, PiD, CTE) is a critical future direction [1, 19, 22, 27]. Improved tracers with specificity for non-AD tau conformers are essential for this endeavor. The ability to image these diverse tau pathologies in vivo would provide invaluable insights into their natural history, enable precise diagnosis, and facilitate the development of targeted therapies for these often-neglected neurodegenerative conditions. Tau PET has the potential to differentiate these disorders based on their unique regional tau accumulation patterns, which would significantly impact differential diagnosis and patient management [39].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

9. Conclusion

Tau PET imaging has emerged as a revolutionary tool in the field of neurodegenerative diseases, fundamentally altering our capacity to study, diagnose, and monitor Alzheimer’s disease and related tauopathies in vivo. The journey from initial tracer development to the clinical approval of agents like ¹⁸F-flortaucipir signifies a monumental achievement, enabling direct visualization of tau pathology, a hallmark closely correlated with cognitive decline and disease progression. Tau PET’s utility extends across critical domains: enhancing diagnostic accuracy by differentiating AD from other dementias, providing invaluable prognostic insights into future cognitive trajectories, and serving as a crucial biomarker in clinical trials for patient selection and monitoring therapeutic efficacy.

However, the widespread implementation of Tau PET faces significant hurdles, notably related to accessibility, high costs, and the need for further standardization of acquisition and analysis protocols. The challenges of off-target binding, particularly for first-generation tracers and in differentiating various tauopathies, underscore the continuous need for tracer development. The field is actively addressing these limitations through the pursuit of next-generation tracers with enhanced specificity for diverse tau conformers, the integration of multi-modal imaging techniques, and the synergistic use of blood-based biomarkers for a more comprehensive and accessible diagnostic pathway. Furthermore, the burgeoning application of artificial intelligence and machine learning in image analysis promises to unlock deeper insights from complex datasets, automate quantification, and potentially expand access through synthetic imaging approaches.

In my opinion, the true transformative power of Tau PET will be realized not merely as a standalone diagnostic test, but as an integral component of a multi-biomarker approach. This integrated strategy, combining advanced imaging with fluid biomarkers and sophisticated computational analysis, will enable earlier, more precise, and more accessible diagnosis of neurodegenerative diseases. This will facilitate personalized therapeutic interventions, ultimately shifting the paradigm from symptom management to disease modification. While substantial scientific and logistical challenges remain, the rapid pace of innovation in neuroimaging and biomarker research suggests a future where Tau PET, in conjunction with other cutting-edge techniques, will be pivotal in our collective fight against the devastating impact of Alzheimer’s and other tau-related disorders.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

[1] Journal of Nuclear Medicine. Tau PET Imaging in Neurodegenerative Disorders. 2022. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFnGbTRnASB_V3Chw4teW4HwcmaZyr6ozdr93s47IXlS8hVOlxjHGFKzBHEXAHQ52taICTJiV_hbvhfu1qL2P-vXdM8RdCW55i6gvfVETXjVxx6PHP_M5fa4-ob9qmFgPpi35ZfbQxAILKP3W5d7Y7rjg==
[2] Tau PET Visual Reads: Research and Clinical Applications and Future Directions. 2023. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFGiDBi13-6Q8OgCXEY_69bx2ZHY_d_v6OnCDS7JuS363OwDZNBjA76Pgyf9WX1IaXyZDuAwrKE6UPPqjE3PvbFAPlXE_tDAIHyBfqbBbQPspUXa5a8Nvx5OMnJFQeQT-aMRp51qrs=
[3] Tau positron emission tomography in tauopathies: A narrative review. 2023. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQE82YdLyI5v7rFqmbVO0schvpmhPMOTpTFRuPfpXG_aErthnv6lz-CKkPnlAsVIwi9gMYkI0VlrpA0otev0pkadX6loYS2_ZKKMLFtzMIh30KfZlcDKN9HRgE0oUarBnrucbJ5oSzGnWsKuQk4SE6ejTniPOxzVdqE8bOSIxZfGpsQ=
[4] Survey among experts on the future role of tau‐PET in clinical practice and trials. 2024. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGZ8L8Z4snf4e4yRQ7hFWfsDd9A__qaUtRWX4b_8Se9DiksKdny2R9LZv6kHd_XK6XpC4XHI0JKU2SsMZSgzjEGgmrFus-TyC9GidkasuVUrHMC9ZbDT92FA4avJaUmiYW73GkG0PlWmbHN3IQ=
[5] The Role of Tau in Alzheimer’s Disease and Related Disorders. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGqD9YjLEMB-O7pSfBTvqymv-gUg243Ix_GL9naASpnAjAMSpSjyYksizjY-rQDM1sbRoH4fKvHpSR1tCd213VNZHrc-udsuW9K9FQL5JVtJS-PCmc9KSt1CS7eL5n4bwOuqCUDMrPZsKlBuA==
[6] Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGaCz0wPFrLdT7B6dZwF0yQA2e7NmDBZHgSsTiEEcofSuxTw64Cenvg3GwdoPyKcrr6xicw9g31SpkH9AUfnJ8su9LMmeTrBTVBw6NiC_7eNBMJYYKtaMLXHzs13b7Qp4WedIw==
[7] Deep Learning for Neuroimaging-Based Brain Disorder Detection: Advancements and Future Perspectives. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGD0OdE93A91G2WXhUJJcNEuouPxqAMlhcy0CDKeSRUcd9R-f5bCLI1kISgrur_jPO2ayceD-Y4uvw9CdSlKrPaP7MEwNZKnUWuoeEPa9JT0iWB9uV4XxBkBWhb8X2XhGWQKou8rdl5l2McP3bhMQCnb-lKI23MGA==
[8] Review of the chemistry of first-generation Tau PET tracers. 2020. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFzKeri04DPliJTYQx5afqGcOMuAEkXn2tLbTKkleQSkdTP4XuRIyNzjrtZDvvP2fXt-IUxne0viIaK9s54T3qJYpPeOrT8gQBC0P2rkv0AbZCNr0GavAzvxgIjdvhk6CaKUnC_uWhfPJ29IfIYdkgVPg==
[9] Tau Protein and Alzheimer’s Disease: What’s the Connection? 2024. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQH-E_cgZQwTxsLsd_8DymL1B7qgwQM04NBW36dKuVhJnOL16WGI0c0naWDjAx452AQGR3QPsZPgZBrqp-gG6KWEjFWnudTtVgkzhlGQzDrL1o_iFxrfckS7RbDx5jqY0_VBjacW3duDYtQzmvsdD65dCorAMdHTquyxyx8o7UqoLYny6D8dhqk2sXI-D55n5iNcvobaEzoE
[10] Tau in Alzheimer Disease and Related Tauopathies. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQF3WdsLxV61-g27yRssJpGMws-jpfIkmwnG_i8MyYz4Bk_NuXypgIhF4U4LPrcP-0H5L3OSqt4rwMdj12g-x5nwk8A1VNQ_tUiYyKiPb6nwpDl9qBSBVra2V63UmooCszaDLXrqAi4hXOR5g==
[11] Advancements in the treatment of Alzheimer’s disease:. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQE1aG84ir1a2EHbPjmBua8jc-qPt9kL4FNDDZncfiqebFh-A-XQ3a-D3gjzJXGtZtX6aedFI7UOlkH_GGP5wBhSj2s3p7VlLJas5BL92cjKBaXWXiCEyNwNZIxS-uvbNfEDQbHmbmVjqtCfKl8pr9mQIqKjCyxKTeb7Ec7YKhKi6WTY6cIlwdImghvF4A9UwTSvHmorzHsobJsV9u2su50tjGEtcf7xFOOFIFGZbA==
[12] The development and validation of tau PET tracers: current status and future directions. 2018. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQG5MSZ7xJoliNOLY3k9qbvUDVmhQf9DebWE-ypI8FVwbuik-9SJW2mKZFPyMF0lXY7alyw00wws4OfhHsz7YLZvcumv8_X5rVb_SxszMgngGdUpnjOFKEJ2WDDDo7EqirreMPOXOVwE_uC7hQ==
[13] Effect of Off-Target Binding on 18F-Flortaucipir Variability in Healthy Controls Across the Life Span | Request PDF. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEfkUAAv6vqTm3-A4p1dLG6zlADWClMQyeMjYdPb4WPq1TXPUwUgnF7-VcpeQa6A_FUrYTMBzkTyJ5bQILXwKJJNR1z6EjDrUcFvriORxogwr_BxI2q_bH1kGD15dljpIY3g-IlaTiOCqifx8q5gU7e_GXRSCJm-2a4dzSRS1BFd1sOqbWhmtnLzoeVmkUomjG44wHTPM82TWia1GcNnumVegTbzzRmTYmfKTQjzEZXW_AA7ITfgvV2HaVQmt9XOwjn9dU2NfuH2Qh6RjVeihsAKvdM
[14] The Sensitivity of Tau Tracers for the Discrimination of Alzheimer’s Disease Patients and Healthy Controls by PET. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGN-YceA-Y_eR1CAtYNk34V5stKOln5Ag0NBSFmX9e6gIoFBQM9M1nSERkljT-fOCqNSzsh_FmdYFtxxJVEb_D-GBpbNArZ_GRVhYtaZ5mqqnuy3xJGHQq723BZpBVEGqTW
[15] Tau positron emission tomography imaging in tauopathies: The added hurdle of off-target binding. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFfyt4q9T1eyF6BrMqQ6J4G8A_g-yLqRAQi-5CkYtRg3EB0o5wutwZvRKhNxDRiqudeNJSTcFVkueZK-fSNNJNTWfLTTANJUIipzNh3CcAsWXrQu-bSe0-Xi8ESqHbRyUwZM_T9uwfT9Tjj9A==
[16] Associations of [18F]-APN-1607 Tau PET Binding in the Brain of Alzheimer’s Disease Patients With Cognition and Glucose Metabolism. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQG0CHb2LVZYgOGa_cMIT9PSqMR_6hQomdAzlK8E_ecjmPiOY0hWh62qo3RU1jPsG-4irGrAGpZ6bH2sDPk3U2SFq7-NifuW_lgu4Zvgz2EJzcBVdikBxxnc6CywRNTXUhF_u0bkblfApA68rIEVJzmqGCJhI0lOGL9d_mmqmESv0Yyk6mt2xY-jA1pq0RYYGzhLaA==
[17] Talking about Tau: The Role of Tau PET Scans in Alzheimer’s Research and Care. 2025. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEPCrPPWw4sUHezcB6iY6dFyqZApLDuxq7sGXbBMGxFH6hdRN4f_WNiJNr_FPJm3vzkHmEpxV3ukuXZLs-iYeVpBwME1qTNFjayR-CxaCYI0rCwJ_xRNZUEKdFrqM8MFfHt6cf5kS4y5xppGP0OQh96uQ==
[18] Overview of tau PET molecular imaging. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFlLLxav5qmAGMbbzc5aPF2EM2wfkcPghfvMiEbSEStLerEkZEmc4gg0TQlSv3uYrZQVeObcPFtv7laWfcGZYOSy_TZBwq4VGlq0LpV_dIwa72KUJ8malHOQjYE9bH2fIZoz1OA7jJ8dwnn_w==
[19] Next-Generation Tau PET Tracers Strut Their Stuff | ALZFORUM. 2017. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEjMB5LXpX_cu_gN2MsXAZL8yo0k60zyvcUOg5eyQAfrOrycMl0oGKH0UDS1uT2Ux9KQj-39aOEs1auUA4ldLnxvcHrFhhcKF3qxrH_A3vrWTCyY5rwBPfNX50PttQEtwzZy6X4koSaAmBH3xy0TS3NFT9Z7g9bXFdDv2YkLuZoS4gt5cRvWRzexy9u2IKqND2KgJnyEsS7ISzLhVDw
[20] Evaluating the cost and benefit of amyloid pet scans and new Azheimer disease therapies. 2024. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEdFQktutxqq-bKRiIkydDoCB9rlhqg__ZtMFMfwM5H_GVvXdqYIj9UJi0yB1kEH3AJIuvTZ-XNx7HuVm_Vz2vb6OeP65dwrceBPB7FNMiZ0jAWMDyq86SuuI-DcOJ80tkx8Uo2YtrR6ASsqTPkafxGR4TFlivbKTTUMqlm-1JORx7dt4Hu_3-WjZlKaBxmXcUT5fovcpK4TcTEaqhseMlp1xJRl3IVBd_WgM5FQXa-EDCssH50JL4ykM3Cz62wfyxh-lAS_XxIe67C5yuHyooeh5c5Q==
[21] Neuroimaging in Alzheimer’s disease: current role in clinical practice and potential future applications. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQF2mD_yJbVP0tCNO__8OZD6S92UAcTSPkwG2feSfWGl0g0QymT_nJNY7gIj70o7K1E8x43DepXldwxGoN9CcJRBPg_wiVHSFUNPc803fPG9r_Fn3Bi1P3bPJZKWQxql5FNycAtfZ0ZEjtvleg==
[22] Editorial: Tau Pathology in Neurological Disorders. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGkk049-Clxj4-GKQxZINzB-CgbXDOsZQ-2yNQtHkjZ5jDGnZuOjSUyKD_CgvPBwDxnA9dVuZG25HcjGKspe5LuIlD7SN-GPkrSsdx5HO4rHbDRmcJU89NNx0G5cUr307fzXlDQT_L3QSyACx2QgshJslUs6EaBlfCaA1xPW7f_Silrhw5uVFam4OxNT61STww==
[23] Synthetic Positron Emission Tomography (PET) Scans: Generation, Application, and Preprocessing. 2024. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGAGVeysJ1xsC6oz9c5BXXhmWB04VQyHQNVMQbck_yxEFogN3bPFs2rtsdoCVxbZ_eShDxhRopp5WPoWitcjJSHP7FnLlKzqdUDB0nCrn-3o0IfaKkdjdelVdI5t5htAfL1EP1GZea_0hR86juoJCOE3l0r
[24] Tau Imaging: Use and Implementation in New Diagnostic and Therapeutic Paradigms for Alzheimer’s Disease. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEBI-c5PWs1p4d2ALtpvTotMoZsqEEcf27uO4wJP4D_jYemXflcKD8gMiAlyhealuD7HK8HZurXBeS59hF8l-NLj7JqkbNLoKChdF6nACe5gDgB7Igj10vVd9ue1bZkjWA==
[25] Recent Breakthroughs in PET-CT Multimodality Imaging: Innovations and Clinical Impact. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEFvj2hXcWz_r1_mjtUbxONW38JO4phzCM–5ebr9k0GLc3Dx8nFzBEIGTOf4yqtCJ5JgSJMxNiiIg4jPU3TTNwsjPGKpqQdu1Pf6upI1YCY2YNFFie0jeDAHVkojG9-C8UHQM=
[26] Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer’s disease. 2023. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQHUd2GxOtpEPAMYbsdcGxax1kR0vmhsRQMRk-YTfH_LaS-FHVWhUWEeO8pbnRYHlsCAoq0IIVGOtJTOj_Bd7N08AVmnSBGCzODtKVl9DwsAgVeIHZjsM7ZrtGArWnkpqHe6UI=
[27] Tau Imaging in Alzheimer’s Disease Diagnosis and Clinical Trials. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGuWcOkTGlVegMbD71Zc4m_TqGuewmjE2kdKQgsDdiHRtcDL7GXZzb91a86JGSuER-UdSqU5Z1AMUkNSRyoYFmD5Hh5caBuhQdvgDgDMAnEminP74MAyS-plMRVAA7NxJIcjDBuwexDCJ_-NQ==
[28] PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFkoZ4DdLk_YZle9NEpruDmOSsIA3H0OWRaBa7lAO54CL0Kc2wNEYqUoYUEfuj1_LhGZVBwk__s64voIWqVQoj7CE8pOHdtZIM4ttovisMfTUV6dhCz4TSUjO40eWjVmnCs
[29] Neuroimaging Modalities in Alzheimer’s Disease: Diagnosis and Clinical Features. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQHjGOneUXOsjVWKDfscLuvKyRLOn9THtuWrj5ZMkTaaNvsJ0uaZsvc2yzZOE8Onp1UIOxdYg6aEFZ5_Mlcyxjwp0gwtAMe153M4K4cBWoB5odzHomkcZZuaXpgiH85GmRkWoLs=
[30] Neuroimaging in Dementia: More than Typical Alzheimer Disease. 2023. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFcyeLnPGOgL-YSYbrZnt_zENqzOg8SjsC7b0G86-bjcLU85xCAjhL-qCdEtb4sUV2Xvl1116CKJTrXcSferyH3ggJ9ZHHG3WoKyWpOM45Yd2tIstS1RKkAOAneeu0qJQK95fG1XUWV8NdJLP694Q==
[31] Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting | PLOS One. 2022. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEl34M2wTwj3epERJfmJl-WuJLEKFOeNGYvcq8x1jesDjm_OqZBgFWlcWfWoyJfwgCaSU6K6R5Kx–tK92ZybE-bpaVakKF3A5VUI4yOOoAXjP2GDIoHI9986Wpw1HO4GQcuQfNuCtujZvTKVBAMvfrP2pmgD9FzvS6jKH617Kd7M-oUg==
[32] Editor’s Note: Educated Guess? 2024. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGrude3q30t1whtydeL7iSaif0MO1B8CnHK_uqxx5AQJTBTsopUj60mUBYGVhbp31tHXDykWC6fss5dXvkr-t47EvidcFkN4lC3yygyHXAED3GCjGIcWB1HbHnGVVv92XdKZpHjitiwO__emxtFooEF0FE=
[33] Longitudinal Assessment of Tau-Associated Pathology by 18F-THK5351 PET Imaging: A Histological, Biochemical, and Behavioral Study. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGPMojSGqnQwmrrsl3UaYDzG_3ThCeou82X-4vI5zHSsu4CN3wxlNNGm8SzaYu-4erjiAXuIFOjlkZiFCdu3uHvXGgd_89_K9rc8J_aCNSlMW1BR7pfvyu_VXojBVnr29osVv8=
[34] Positron emission tomography. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFgmGRKpcJhlNq8AkkCT2CKyb5HlE-8wWqNAGRGRxTdfthcUtFOHKJTMPpqOuuP0KqhWktZj_W2vicp2XRVZ_dG31mp_3Cne8NeqWM2KF86BOuulVj2WF8YyLUeVydVs0v0aN_usUk3fUrESCb3Yr_QY04Jng==
[35] MRI-free processing of tau PET images for early detection. 2024. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQFpWPtrQAKQlPTdhBlOYoaMinRD9Rg6v9sfwD0RlWjjzX_oyfBrXfWq35BZSqCww0qaxtg31IL7lKnECoJ5NvAaQrmKajq-l9AHs4VMPDPDe_C4i4lN4QsTrTPz_AX6g8K4O3BMKO3M-B1GlF_vjzW2qQ14hFelNrupDvd9a_CtA8Pm_YnCYJ5VanJIuhpYjH6XRa7fhvrKPeMidJZtoV8e5ccI34K6NdrshqaV6w==
[36] Advancing Tau-PET quantification in Alzheimer’s disease with machine learning: introducing THETA, a novel tau summary measure. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEj4cfNMheKPWRMNl24sNsLykfjcOr__anvtgVpwQPHNcCS-c0GROZNG3wHiDJDC6dX-XGwc5D5iteZl78eMpZubf_-O4Ti-CXzn1i4A_oj4Z8jT9lWsZ8kbTNCrTsF1Vdn07T-qY33MmhE6Vg==
[37] PET images of second-generation Tau tracers. (APN-1607 Image courtesy… | Download Scientific Diagram. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQH-Kyx0LdL133qXnzPKdL2EbK_HUnfk25EzeyZ9_WZYbs5RImZJuyRFDGBBLCud3eUs3nqLhVNBSsvwE2h7OM_IxrWtqmrF3GgpQCSsXcHcUa4p4mPjey2aQuf6JZ6Tr9Wm01y21UTmqndHr2qFmo2LNnJe642vbDp1aUeXgsCrBSBba4i2YFro8wvWTQ008o-xt4tCkpyQcDE_eaxNEa08iGh-0WHhKCHhlPiL5KGmjwrRNpCMFi9yq23KYIm3_1pC5opo
[38] Updated Appropriate Use Criteria for Amyloid and Tau PET: A Report from the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging Workgroup. 2025. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGNyGr7xd3XPtEohNRVluZgpkBzygmGi7zhlmt3yxzdYq-ACxqEjc3Cax1IUX8SHOOzUXy4VASMcTI-B9xR1McBxTia4SSDF1MsTuwzC8rnD6ydEfLwOSFEPpvTQbsArWEaeGlwEkeUfseDdrfITK5fksw7_K61lsV8Gem8tSfXKA==
[39] PET imaging of tau protein targets: a methodology perspective. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQE_zDxPW2Mqtuwhx71rwQkwOG-Ub5gaxJv3YWeNCu2GeP9JPB3qTr7PFphJYmrSq49e_5P58rIj2AWNxc4MwAx743D3rZfIlx_UP-k0qsv8whXrTYWjHIz36cMxmn6Qz2feSWKD_kVn-UBetw==
[40] Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. 2021. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQEe7Jn9b6avwrZlyBgWKlBGbu1Le6KcND5pkvil30PMewum-hSu5ssRoMmw6Hf9vb8xMRmTb8FfX6ujJgguTqstpDZcykzuy9vUAZofQ8IE25YiT9XZVpGyD44uMczUsUBcb-BC5QZmfodq-Q==
[41] Characteristics of Tau and Its Ligands in PET Imaging. Available from: https://vertexaisearch.cloud.google.com/grounding-api-redirect/AUZIYQGOTWMIKis1fqQwxKuT-jXwjyOTFxF4CeGNxybk64UkV902FSFEBdbZylZnXKzbMX2Fjg3YiWRi8UV2LcPOAvo7TZXBVG3cnbQiRKTGTJAllwULHV7G_yWvynGaSkpO