{'fraction_non_alphanumeric': 0.03268945022288262, 'fraction_numerical': 0.016840019811788013, 'mean_word_length': 5.1664122137404584, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Does the Anti‐Tau Strategy in Progressive Supranuclear Palsy Need to Be Reconsidered? Yes

The prevailing framework for neurodegeneration posits that a wide range of clinical manifestations converging on a given pathology constitutes a disease. Further, the pathology of such disease must be pathogenic. Two logical consequences arise from this framework: (1) a measurement of the disease-defining pathology represents a biomarker of that disease, and (2) the targeted elimination of that pathology would mean the end of that disease. Theory does not meet practice. Validation of diseases as toxic proteinopathies has been challenged from a variety of sources. These include the lack of correlation between brain burden of these pathologies and disease severity or neuronal loss; the generation of behavioral and degenerative phenotypes in the absence of protein aggregation in knockout and knockdown animal models for tau, APP (whose cleavage produces amyloidβ), and α-synuclein; and the rarity for a single pathology to dominate the disease it defines. In progressive supranuclear palsy (PSP), for example, tau-only pathology occurs in only 8% of cases whereas co-pathology with several other proteins is the rule. The most important argument against equating pathology with pathogenesis arises from trials of putative disease-modifying interventions: success in brain protein reduction has yielded either no behavioral changes or worsening. While most of that evidence over the past two decades has come from antiamyloid approaches, anti-tau and anti-synuclein interventions appear set to dominate in this decade (Fig. 1). Tau accumulation is a terminal event in neurodegenerative disorders. Because the increase of tau in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) occurs closer to the onset of neurodegeneration than the decrease of amyloid-β 42 (Aβ42), tau has been shown to correlate to a greater extent with dementia than Aβ42, with insoluble tau predicting dementia better than insoluble amyloid-β. However, a reduction in CSF (soluble) Aβ42 levels is the strongest predictor of conversion to AD (hazard ratio [HR], 16), an effect size four times greater than the increase in t-tau (HR, 2.8) or p-tau 2.6 (HR, 2.6), and of greater magnitude than the corresponding increase in brain amyloid burden. In the ‘primary tauopathy’ of PSP, it is not tau but a different marker of axonal cytostructural integrity, neurofilament light (NF-L), which exhibits the closest association with neuronal loss and therefore the best prediction of PSP progression. But like tau, NF-L is an undifferentiated marker of neuronal loss, a common end to many disorders, not the beginning of any. Despite a combined negative output of 40 Phase II or III antiamyloid trials in AD, the strong allure of the gain-of-function toxic protein model of neurodegeneration has fostered a robust anti-protein clinical trial pipeline, including one against tau. Of 12 anti-tau therapies in development for AD, the first phase II trial of semorinemab, an IgG4 humanized anti-tau antibody against the N-terminal epitope, showed no differences in the rates of cognitive decline in any subgroup analyses of prodromal or mild AD patients compared with placebo. Two monoclonal antibodies binding to the N-terminus of human tau have already shown futility in phase II trials in PSP: gosuranemab (BIIB092, PASSPORT trial, NCT03068468) and tilavonemab (C2N-8E12, ARISE trial, NCT02985879). The results of the gosuranemab trial remain unpublished but we suspect may be similar to those from tilavonemab. As with gosuranemab, tilavonemab was terminated earlier than anticipated at an interim evaluation by virtue of futility in changing the primary efficacy endpoint, the Progressive Supranuclear Palsy Rating Scale (PSPRS). This double-blind, placebo-controlled trial randomly assigned 378 PSP patients to placebo, tilavonemab 2000 mg, or tilavonemab 4000 mg, infused on days 1, 15, and 29, and every 28 days throughout the 52-week study. There are