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Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

In Alzheimer’s disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab—a monoclonal antibody to N-terminal tau—in patients with early Alzheimer’s disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized ( n  = 654); received ( n  = 650) low-dose (125 mg once every 4 weeks (q4w), n  = 58; 375 mg q12w, n  = 58), intermediate-dose (600 mg q4w, n  = 106) or high-dose (2,000 mg q4w, n  = 214) gosuranemab or placebo (q4w, n  = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid ( n  = 327) and/or tau positron emission tomography ( n  = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant ( P  < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

Background: Behavioral and psychological symptoms of dementia (BPSD) and associated disturbances in Alzheimer's disease (AD) are a source of distress and burden for spouses, professional caregivers, and others with responsibilities for the care of individuals with AD. BPSD with behavioral disturbances are also associated with more rapid institutionalization and increased morbidity and mortality for persons with AD. Objectives: In this review and commentary, we discuss the history of the development of BPSD and behavioral disturbance assessments, which are distinct from those evaluating cognitive and functional symptoms of AD. In particular, we review the informant-based Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the related, potentially more sensitive, BEHAVE-AD Frequency-Weighted Severity Scale (BEHAVE-AD-FW), and the direct subject evaluation-based Empirical BEHAVE-AD Rating Scale (E-BEHAVE-AD). The kinds of medications that alleviate behavioral symptoms on these measures as well as the problems and possibilities for further advances with these medications are discussed. Finally, the importance of distinguishing BPSD and behavioral disturbance remediation in AD from the treatment of cognitive decline and other aspects of AD is emphasized in the context of appropriate assessment methodology. The objective of this paper is to provide a framework for further advances in the treatment of BPSD and associated behavioral disturbances in AD and, consequently, a framework for continuing improvements in the lives of individuals with AD and those who share the burden of the disease with the AD person.

The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta‐amyloid and tau. Recent clinical trial readouts implicate a variety of non‐amyloid/non‐tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13–14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs. Participants also discussed the current definition of therapies that target underlying AD pathophysiology, what endpoints best define what is considered a meaningful change beyond the current approved definition for clinical efficacy, and how the recent NANT findings should inform the development of future guidelines for AD classification and personalized treatment strategies. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government to review the current state of non‐beta amyloid and non‐tau (NANT) targets on underlying Alzheimer's disease (AD) pathophysiology. The totality of scientific and clinical evidence supports the hypothesis that emerging NANT targets play a role in cognitive decline and neurodegeneration in AD. New biomarkers based on NANT targets must be globally developed and implemented with specific consideration of fluid biomarkers as a cost‐effective clinical option, to ensure better, more equitable treatment options for AD.

Background TANGO was a Phase 2 clinical study designed to assess the safety and efficacy of gosuranemab, an anti‐tau monoclonal antibody, in participants with mild cognitive impairment due to Alzheimer’s disease (AD) or with mild AD dementia. Despite robust target engagement of unbound N‐terminal tau, the clinical efficacy endpoint was not met. In this exploratory analysis of TANGO participants, we examine plasma p‐tau217 levels to assess the feasibility of using this biomarker to identify patients with AD pathology and predict disease progression. Methods Plasma was collected from 554 randomized TANGO participants at baseline and up to Week 78. Plasma p‐tau217 was measured using the ALZpath Quanterix Simoa assay. Plasma p‐tau181 was measured using the Quanterix Simoa p‐tau181 V2 Advantage assay. Tau PET was measured in a sub‐study of 357 participants at baseline and Weeks 52 and 78 using 18F‐MK‐6240. Amyloid PET was measured at screening using 18F‐florbetapir in n = 322 participants Clinical decline was measured using the CDR‐SB, MMSE, ADAS‐Cog13 and ADCS‐ADL cognitive assessment scales. Statistical analysis was performed using Spearman correlation coefficient. Results Plasma p‐tau217 and plasma p‐tau181 were correlated at baseline (Spearman = 0.7617, p‐value <0.0001). Baseline plasma p‐tau217 levels were correlated with both baseline amyloid PET using SUVR in a composite region of interest (Spearman = 0.4294, p‐value <0.0001) and baseline Tau PET using SUVR in composite regions of interest corresponding to Braak stages I‐II, III‐IV, and V‐VI (Spearman range = 0.4075‐0.6163, p = value <0.0001). Participants with higher concentrations of plasma ptau217 at baseline showed a greater rate of clinical decline at Week 78. Conclusions The correlations of plasma p‐tau217 with amyloid and tau PET at baseline suggest a relationship with both underlying pathological hallmarks of AD. Similar to results from observational cohorts, correlation of baseline plasma p‐tau217 and clinical decline observed during the TANGO trial supports the utility of plasma p‐tau217 as a potential prognostic biomarker of disease. Data from additional studies are needed to define appropriate use cases and relevant thresholds for plasma p‐tau217 as a biomarker of disease pathology that can be used to prescreen patients in clinical trials.