Alzheimer’s disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these ...successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.
•Therapeutics that target specific pathology to slow or arrest disease progression are urgently needed in neurodegenerative disease.•Tau pathology correlates better with cognitive impairment than Aβ, ...thus tau-targeted therapeutics may be a more effective.•Tau-targeted therapies aim to either ameliorate gain of toxic function from harmful aggregates or replace loss of tau function.•This article reviews 24 tau-targeted therapies tested in clinical trials with 16 agents currently in active development.
Tauopathies are a group of over 20 clinicopathological neurodegenerative diseases including Alzheimer's disease (AD), the most common type of dementia, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, among others. Tauopathies are defined by neurodegeneration and the presence of tau aggregates in affected brains regions. Interestingly, regional tau aggregation burden correlates with clinical phenotype and predicts cognitive status. Autosomal dominant mutations in the MAPT gene lead to tau deposition and clinical FTD syndromes with cognitive, behavioral, and motor impairment. Polymorphisms in or around the MAPT gene have also been strongly linked to other proteinopathies including synucleinopathies. Taken together these findings suggests that tau plays a critical role in neurodegeneration and proteinopathies, supporting the idea that tau targeted approaches can be disease-modifying and lead to clinically meaningful benefits in slowing or reversing disease progression. Increasingly, human clinical trials are testing this hypothesis. This article reviews tau-targeted therapies tested in clinical trials as well as agents currently in active development based on publicly disclosed information. We describe the therapeutic approaches of these trials based on the potential pathogenic mechanism they target.
Frontotemporal dementia (FTD) is a common form of dementia with heterogeneous clinical presentations and distinct clinical syndromes. This article will review currently available therapies for FTD, ...its related disorders and their clinical evidence. It will also discuss recent advancements in FTD pathophysiology, treatment development, biomarker advancement and their relation to recently completed or currently ongoing clinical trials as well as future implications.
Frontotemporal dementia (FTD) is a type of dementia with distinct clinical syndromes. Current treatments involve off‐label use of medications for symptomatic management and cannot modify disease course. Advancements in FTD pathophysiology, genetics, and biomarkers have led to development of small molecules targeting the underlying pathology in hopes of achieving a disease‐modifying effect. This article will review current therapies for FTD, discuss advancements in FTD pathophysiology, therapy development, biomarker advancement, their relation to recent clinical trials and future implications.
This article is part of the Frontotemporal Dementia special issue.
Frontotemporal dementia (FTD) is a type of dementia with distinct clinical syndromes. Current treatments involve off‐label use of medications for symptomatic management and cannot modify disease course. Advancements in FTD pathophysiology, genetics, and biomarkers have led to development of small molecules targeting the underlying pathology in hopes of achieving a disease‐modifying effect. This article will review current therapies for FTD, discuss advancements in FTD pathophysiology, therapy development, biomarker advancement, their relation to recent clinical trials and future implications.
This article is part of the Frontotemporal Dementia special issue.
Summary Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated ...with a characteristic 4-repeat tau neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic criteria include syndromes with few or mild symptoms that are suggestive of underlying PSP pathology and could provide an opportunity for earlier therapeutic interventions in the future. These criteria also include definitions for variant PSP syndromes with different patterns of movement, language, or behavioural features than have been conclusively associated with PSP pathology. Data from new diagnostic biomarkers can be combined with the clinical features of disease to increase the specificity of the new criteria for underlying PSP pathology. Because PSP is associated with tau protein abnormalities, there is growing interest in clinical trials of new tau-directed therapies. These therapies are hypothesised to have disease-modifying effects by reducing the concentration of toxic forms of tau in the brain or by compensating for loss of tau function. Since tau pathology is also central to Alzheimer's disease and chronic traumatic encephalopathy, a successful tau therapeutic for PSP might inform treatment of other neurodegenerative diseases.
Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. ...Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.
Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well as nonclinical ...translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. However, a number of tau-targeting therapies with various mechanisms of action have shown little promise in clinical trials in different tauopathies. We review what is known about tau biology, genetics, and therapeutic mechanisms that have been tested in clinical trials to date. We discuss possible reasons for failures of these therapies, such as use of imperfect nonclinical models that do not predict human effects for drug development; heterogeneity of human tau pathologies which may lead to variable responses to therapy; and ineffective therapeutic mechanisms, such as targeting of the wrong tau species or protein epitope. Innovative approaches to human clinical trials can help address some of the difficulties that have plagued our field's development of tau-targeting therapies thus far. Despite limited clinical success to date, as we continue to refine our understanding of tau's pathogenic mechanism(s) in different neurodegenerative diseases, we remain optimistic that tau-targeting therapies will eventually play a central role in the treatment of tauopathies.
Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value ...of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes.
In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18–99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test.
Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years SD 13, 294 50% women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years SD 10) relative to cognitively unimpaired controls (n=118, mean age 61 years SD 18; AUC=0·98 95% CI 0·95–1·00 for p-tau217, AUC=0·97 0·94–0·99 for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years SD 12) versus pathologically confirmed FTLD (n=68, mean age 67 years SD 8; AUC=0·96 0·92–1·00 for p-tau217, AUC=0·91 0·82–1·00 for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years SD 9; AUC=0·93 0·91–0·96 for p-tau217, AUC=0·91 0·88–0·94 for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 0·88–0·94) than was p-tau181 (n=214, AUC=0·89 0·86–0·93; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230).
Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology.
US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.
The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal ...dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design. In this article, we review what is known about the biology and genetics of tau, placing it in the context of current and failed clinical trials. We highlight potential reasons for the lack of success to date and offer suggestions for new pathways in therapeutic development. Overall, our viewpoint to the future is optimistic for this important group of neurodegenerative diseases.
Frontotemporal dementia comprises a group of clinical syndromes that are characterised by progressive changes in behaviour, executive function, or language. The term frontotemporal lobar degeneration ...encompasses the neurodegenerative diseases that give rise to these clinical syndromes and involve proteinopathies associated with frontotemporal network dysfunction. Improvements in clinical, genetic, and molecular characterisation have provided new insights into frontotemporal dementia and frontotemporal lobar degeneration, with a much broader range of signs and symptoms at presentation than has been previously considered. Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition. Advances in plasma and CSF biomarkers, and innovations in structural and functional imaging, will prove useful for future clinical trials in people with frontotemporal dementia.
IMPORTANCE: The positron emission tomography (PET) tracer 18Fflortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but ...its diagnostic utility is unclear. OBJECTIVE: To examine the discriminative accuracy of 18Fflortaucipir for AD vs non-AD neurodegenerative disorders. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment MCI, of whom 65.9% were amyloid-β Aβ positive ie, MCI due to AD, 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders). EXPOSURES: The index test was the 18Fflortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls. MAIN OUTCOMES AND MEASURES: The reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of 18Fflortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of 18Fflortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of 18Fflortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined. RESULTS: Among 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-β positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. 18Fflortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index–derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 18Fflortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P < .001). Diagnostic performance of the 5 18Fflortaucipir ROIs were lower in MCI due to AD (AUC range, 0.75-0.84). CONCLUSIONS AND RELEVANCE: Among patients with established diagnoses at a memory disorder clinic, 18Fflortaucipir PET was able to discriminate AD from other neurodegenerative diseases. The accuracy and potential utility of this test in patient care require further research in clinically more representative populations.
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