Anti-tau Therapies Research Articles

Anti-amyloid-β Antibodies and Anti-tau Therapies for Alzheimer’s Disease: Recent Advances and Perspectives

Anti-amyloid-β Antibodies and Anti-tau Therapies for Alzheimer’s Disease: Recent Advances and Perspectives

Alzheimer's Disease - A Comprehensive Review

Introduction: Alzheimer's disease (AD) remains a pervasive and challenging neurodegenerative disorder with profound implications for individuals, families, and societies. As the most prevalent cause of dementia globally, AD's prevalence is set to rise significantly in the context of an aging population. This introductory section emphasizes the urgent need for a comprehensive understanding of the disease, encompassing both its molecular intricacies and the socio-economic burden. With age being the primary risk factor, recent research has delved into the complex interplay of genetic predisposition and environmental influences, reshaping our understanding of AD from a multifactorial perspective.
 Current State of Knowledge: Advancements in Alzheimer's research have led to a nuanced understanding of its pathology. Traditionally characterized by amyloid-beta plaques and tau tangles, recent insights from neuroimaging and biomarker studies have revealed the intricate nature of these pathologies and their roles in disease progression. Genetic studies, including genome-wide association analyses, have identified susceptibility loci, notably the APOE gene. Simultaneously, environmental factors, such as air pollution and lifestyle choices, are recognized contributors to AD risk. The therapeutic landscape has evolved, with ongoing investigations into anti-amyloid and anti-tau therapies, lifestyle interventions, and precision medicine approaches. The synthesis of these diverse findings highlights the dynamic nature of Alzheimer's research and its potential to shape future treatment modalities.
 Summary: In summary, this article provides a comprehensive overview of the current state of knowledge regarding Alzheimer's disease. From understanding its evolving pathology to exploring the interplay of genetic and environmental factors, the multifactorial nature of AD is underscored. The therapeutic landscape is actively advancing, presenting a hopeful outlook for future treatments.

Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease

BackgroundReactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer’s disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques.ResultsFor the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden.ConclusionsConsidering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

The evolution of Alzheimer’s disease therapies: A comprehensive review

Abstract Alzheimer`s disease (AD) is a progressive neurodegenerative disease which accounts for most of the cases of dementia. The progression of the disease cannot be fully controlled by current medications, nor do they produce adequate therapeutic results. Understanding the molecular and cellular alterations linked to AD pathogenesis has advanced significantly in recent decades. Amyloid-peptide-containing cerebral plaques and thread-like neuronal structures made of the microtubule-associated protein TAU are two pathogenic features of the condition. Therefore, inhibiting amyloid formation, aggregation, or subsequent neurotoxic events is the primary goal of therapeutic drug development. Here, some newer therapeutic modalities are described, including anti-amyloid therapy, anti-tau therapy, antineuroinflammatory therapy, neuroprotective agents including N-methyl- d -aspartate (NMDA) receptor modulators, and brain stimulation. Drug repositioning may speed up the development of pharmaceuticals, but non-pharmacological therapies, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential to be used in therapeutic settings. Here we discussed current symptomatic therapy for AD as well as novel prospective disease-modifying medicines that are presently being investigated in phase I–III trials in this review. The study emphasizes how taking into account the intricate nature of AD pathogenesis and investigating drug repurposing strategies which can open the door to the creation of innovative AD therapies.

Comparative Efficacy of Anti-Amyloid and Non-Antiamyloid Drugs for Treatment of Alzheimer’s Disease: A Network Meta-Analysis

BACKGROUND: Alzheimer’s disease is a degenerative neurological disorder that contributes 60-80% of all dementia cases, typically occurring at the age of 65 years. Currently available therapeutics for treatment are only capable of limiting the progression of cognitive decline. The focus of many Alzheimer’s disease drug therapies involves the hypothesized cause of pathogenesis in the disease, beta protein in the brain. Based on the Preferred Reporting Items for Meta-Analysis (PRISMA) for Network Meta-Analyses (NMA) framework, the present study was conducted to compare the efficacy of such drugs that target beta-amyloid directly or indirectly, with that of other treatments studied in randomized controlled trials. METHODS: Utilizing a network meta-analysis, direct and indirect comparisons between interventions could be done, providing a ranking of intervention in terms of efficacy in treating cognitive symptoms of Alzheimer’s disease. RESULTS: A total of 33 studies were included in four analyses of intervention trials that reported cognitive outcomes measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or Mini-Mental State Examination (MMSE) score. Based on the findings, anti-amyloid agents did not show a marked advantage over other therapies in improving cognitive scores. Results showed that parasympathomimetic agents were consistently ranked higher in terms of Surface Under the Cumulative Ranking (SUCRA) score, with anti-tau agents providing a possible superiority over all other interventions at improving MMSE scores for treatments lasting longer than 24 weeks. High-dose anti-amyloid therapies were effective at improving MMSE score in short term treatments lasting not more than 24 weeks but fall behind other drugs in longer durations. CONCLUSION: For better understanding on the choice of anti-amyloid and non-antiamyloid therapies, future well-designed large studies including safety outcome and cost- benefit analyses on the different interventions are recommended. Additionally, anti-tau therapies show a clearer potential over anti-amyloid therapies and should thus be given more focus in future drug research.

Tau-targeting therapies for Alzheimer disease: current status and future directions.

Alzheimer disease (AD) is the most common cause of dementia in older individuals. AD is characterized pathologically by amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain, with associated loss of synapses and neurons, which eventually results in dementia. Many of the early attempts to develop treatments for AD focused on Aβ, but a lack of efficacy of these treatments in terms of slowing disease progression led to a change of strategy towards targeting of tau pathology. Given that tau shows a stronger correlation with symptom severity than does Aβ, targeting of tau is more likely to be efficacious once cognitive decline begins. Anti-tau therapies initially focused on post-translational modifications, inhibition of tau aggregation and stabilization of microtubules. However, trials of many potential drugs were discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting agents in clinical trials are immunotherapies. In this Review, we provide an update on the results from the initial immunotherapy trials and an overview of new therapeutic candidates that are in clinical development, as well as considering future directions for tau-targeting therapies.

Alzheimer’s Disease Related Target and Therapies

Alzheimer's disorder (AD) affects about seven percent of people above the age of sixty-five and about forty percent of persons above eighty years, and the burden of the disease is likely to be threefold by 2040. The disease process is marked by a buildup of misfolded proteins, inflammatory changes, and oxidative destruction. Nowadays, four approved drugs: memantine, donepezil, rivastigmine, and galantamine have been used as first-line treatment approaches for AD because of their safety profiles and promising tolerability. However, their effectiveness and benefits are relatively limited and modest. The failure of these cholinesterase inhibitors to alter the disease process calls for more innovations for future therapies. The promising future therapies discussed include anti-amyloid, anti-tau therapy, microtubule stabilization, restore lysosomal acidification, ApoE Lipidation, and microglia targeted therapies. These potential disease-modifying interventions target the pathological features of the disorder, including the tau protein and the amyloid plaques. Further investigations are required to evaluate the efficaciousness and benefits of future therapies to lower the burden of the disease locally and internationally.

Toluidine blue O attenuates tau phosphorylation in N2a-APPSwe cells

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of amyloid-β peptide (Aβ), intracellular neurofibrillary tangles containing hyperphosphorylated tau protein and neuronal loss. Most of the FDA-approved AD drugs currently on the market are cholinesterase inhibitors, which are only effective in relieving the symptoms of AD. However, recent studies in AD drug discovery focus on multi-targeted strategies, including anti-amyloid and anti-tau therapy. In the current study, we have investigated the effects of toluidine blue O (TBO), a cholinesterase inhibitor, on amyloid precursor protein (APP) processing, tau phosphorylation, and tau kinases/phosphatase in N2a mouse neuroblastoma cells stably expressing the Swedish mutation of human APP695 (N2a-APPSwe). The results demonstrated that TBO reduces Aβ40/42 levels by decreasing expression levels of β-secretase 1 (BACE1), presenilin 1 (PS1) and total APP without causing cytotoxic effects in N2a-APPSwe cells. TBO also decreased the levels of both total tau and phosphorylated tau at residues Ser202/Thr205, Thr181, Ser396 and Ser 396/Ser404. Moreover, when the possible mechanisms underlying its effects on tau pathology were explored, TBO was found to decrease tau phosphorylation at those sites by reducing the expression levels of Akt, GSK-3β, Cdk5, inactive p-PP2A and increasing the expression levels of p-Akt Ser473 and inactive p-GSK-3β Ser9. Our new data support the idea that TBO may be a promising multi-target drug candidate for the treatment of AD.

Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.

Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology. One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40). Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 and TSC2 genes and autosomal dominantly inherited. These mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) pathway, leading to the development of nonmalignant masses involving various organ systems. Patients with TSC also experience neuropsychiatric symptoms collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorder (TAND). Due to research advancements in TSC, patients now live well beyond the age of 50. Many experience objective impairment of memory and executive function, supported by formal neuropsychological testing, beginning in their late 40s. Biomarker analysis has described elevated levels of phosphorylated tau-181 in the cerebrospinal fluid of patients with TAND. Tau-PET imaging has also shown focal accumulation of the radiotracer flortaucipir (AV1451), suggesting that TSC may be a neurodegenerative disorder arising from accumulation of phosphorylated tau. However, the flortaucipir tracer has been reported to have significant off-target binding, preventing definitive conclusions from being drawn about the molecular etiology of neurodegeneration in TSC. Therefore, we initiated the Colocalization of AV1451 and Phosphorylated Tau in Adult brain tissue (CAPA) study. This study aimed to determine if flortaucipir is bound to phosphorylated tau in brains of patients with TSC and further sought to determine the specific tau isoform seen in TSC. Our results show that flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer’s disease. However, amyloid staining was negative in brains of adult patients with TSC. Therefore, we conclude that TAND symptoms are due to the accumulation of the phosphorylated tau isoform seen in Alzheimer’s disease. This study suggests that hyperactivation of the mammalian Target of Rapamycin pathway may play a role in the amyloid-independent development of 3R/4R tau aggregation. Our findings could lead to a new era of anti-tau therapies used to treat both disorders.

Engineering a pathological tau-targeted nanochaperone for selective and synergetic inhibition of tau pathology in Alzheimer's Disease

Tau-targeting therapies for Alzheimer’s disease (AD) have received increasing attention in recent years, due to the clinical failure of various anti-amyloid β drugs and closer association between tau burden and cognitive impairments in AD patients. The intracellular tau aggregation is recognized as a vital event in tau pathway of AD progression. However, current developed tau aggregation inhibitors are still facing serious challenges on how to access the cytosol of cells where tau protein mainly located and differentiate pathological tau from normal tau. Herein, we report a customized biomimetic nanochaperone for targeting intracellular pathological tau, serving as a novel anti-tau therapy of AD. This nanochaperone was tailored by engineering VQIINK hexapeptide derived from tau protein onto the surface of self-assembly micelle equipped with chaperone-like hydrophobic microdomains and confined spaces. With the lysosomal microenvironment responsiveness of unique surface structure, the Tau-nChap can escape from lysosome and enter into cytoplasm to overcome the intracellular tau location challenge. More importantly, the cytosol-arrived nanochaperone can selectively capture pathological tau without interfering with normal tau and potently inhibit their aggregation through the synergic effect of tau-recognizing peptide and confined hydrophobic microdomain on surface. As a result, the tau-targeting nanochaperone rescues neuronal cells from tau-mediated neurotoxicity and ameliorates cognitive deficits of AD model mice. Therefore, we believe that this custom-built tau-nanochaperone represents a promising weapon for combating AD and provides valuable insights for the treatment of other neurodegenerative disorders induced by specific pathogenic proteins including Parkinson’s disease and Huntington’s disease.

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.

Reward motivation and cognitive flexibility in tau null-mutation mice

The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau−/−) and wild-type mice using progressive ratio and reversal learning tasks. Tau−/− mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau−/− mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies.

A Comprehensive Review of Alzheimer’s Association with Related Proteins: Pathological Role and Therapeutic Significance

Alzheimer’s is an insidious, progressive, chronic neurodegenerative disease which causes the devastation of neurons. Alzheimer's possesses complex pathologies of heterogeneous nature counting proteins as one major factor along with enzymes and mutated genes. Proteins such as amyloid precursor protein (APP), apolipoprotein E (ApoE), presenilin, mortalin, calbindin-D28K, c-reactive protein, heat shock proteins (HSPs), and prion protein are some of the chief elements in the foremost hypotheses of AD like amyloid-beta (Aβ) cascade hypothesis, tau hypothesis, cholinergic neuron damage, etc. Disturbed expression of these proteins results in synaptic dysfunction, cognitive impairment, memory loss, and neuronal degradation. On the therapeutic ground, attempts of developing anti-amyloid, anti-inflammatory, anti-tau therapies are on peak, having APP and tau as putative targets. Some proteins, e.g., HSPs, which ameliorate oxidative stress, calpains, which help in regulating synaptic plasticity, and calmodulin-like skin protein (CLSP) with its neuroprotective role are few promising future targets for developing anti-AD therapies. On diagnostic grounds of AD C-reactive protein, pentraxins, collapsin response mediator protein-2, and growth-associated protein-43 represent the future of new possible biomarkers for diagnosing AD. The last few decades were concentrated over identifying and studying protein targets of AD. Here, we reviewed the physiological/pathological roles and therapeutic significance of nearly all the proteins associated with AD that addresses putative as well as probable targets for developing effective anti-AD therapies.

The combined effect of amyloid-β and tau biomarkers on brain atrophy in dementia with Lewy bodies

BackgroundAlzheimer’s disease (AD)-related pathology is frequently found in patients with dementia with Lewy bodies (DLB). However, it is unknown how amyloid-β and tau-related pathologies influence neurodegeneration in DLB. Understanding the mechanisms underlying brain atrophy in DLB can improve our knowledge about disease progression, differential diagnosis, drug development and testing of anti-amyloid and anti-tau therapies in DLB. ObjectivesWe aimed at investigating the combined effect of CSF amyloid-β42, phosphorylated tau and total tau on regional brain atrophy in DLB in the European DLB (E-DLB) cohort. Methods86 probable DLB patients from the E-DLB cohort with CSF and MRI data were included. Random forest was used to analyze the association of CSF biomarkers (predictors) with visual rating scales for medial temporal lobe atrophy (MTA), posterior atrophy (PA) and global cortical atrophy scale-frontal subscale (GCA-F) (outcomes), including age, sex, education and disease duration as extra predictors. ResultsDLB patients with abnormal MTA scores had abnormal CSF Aβ42, shorter disease duration and older age. DLB patients with abnormal PA scores had abnormal levels of CSF Aβ42 and p-tau, older age, lower education and shorter disease duration. Abnormal GCA-F scores were associated with lower education, male sex, and older age, but not with any AD-related CSF biomarker. ConclusionsThis study shows preliminary data on the potential combined effect of amyloid-β and tau-related pathologies on the integrity of posterior brain cortices in DLB patients, whereas only amyloid-β seems to be related to MTA. Future availability of α-synuclein biomarkers will help us to understand the effect of α-synuclein and AD-related pathologies on brain integrity in DLB.

Anti-tau therapies-what can be expected?

Alzheimer's disease is histopathologically characterized by aggregation of two proteins, namely amyloid-beta peptide and tau protein. Whereas former intervention trials focused particularly on the amyloid pathology, recent therapeutic approaches are directed against the tau pathology. This article summarizes recent progress in anti-tau therapies, especially therapies based on anti-tau immunization and antisense oligonucleotides (ASO).

Synergistic Effect of Amyloid-β and Tau Disrupts Neural Circuits.

Alzheimer's disease (AD) is characterized by the coexistence of amyloid-β (Aβ) plaques and tau-based neurofibrillary tangles. Although studies have shown that the interaction between Aβ and tau causes enhanced AD pathology; there is a lack of precise understanding of the functional consequences for integrated neural circuits. A recent study revealed that the interaction between Aβ and tau pathologies impairs the functional integrity of neural circuits in the AD brain. Thus, not only Aβ but also tau determines the cognitive status. Therefore, developing anti-Aβ or anti-aggregated tau compounds may not be an effective strategy to treat AD. In fact, approaches combining anti-Aβ and anti-tau therapies might be a more promising therapeutic option rather than single therapy. The results have important therapeutic implications not only for AD but also for other tauopathies.

Anti-Tau Trials for Alzheimer's Disease: A Report from the EU/US/CTAD Task Force.

Efforts to develop effective disease-modifying treatments for Alzheimer's disease (AD) have mostly targeted the amyloid β (Aβ) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aβ protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.

Tau-targeting therapies for Alzheimer disease.

Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.

Comparison of 18F-T807 and 18F-THK5117 PET in a Mouse Model of Tau Pathology

Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance in vivo are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline 18FT807 and the pyridoindole 18FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of (N = 5–7) P301S and wild-type (WT) mice at 6 and 9 months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen’s d) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation ex vivo. Significantly elevated 18F-T807 binding in the brainstem of P301S mice was already evident at 6 months (+14%, p < 0.01, d = 1.64), and increased further at 9 months (+23%, p < 0.001, d = 2.70). 18F-THK5117 indicated weaker increases and effect sizes at 6 months (+5%, p < 0.05, d = 1.07) and 9 months (+10%, p < 0.001, d = 1.49). Regional similarity of binding of the two tracers was high (71%) at 9 months. 18F-T807 was more sensitive than 18F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.