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Abstract 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.

Abstract The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease‐modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1–2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies.

Abstract Introduction An Elecsys® Amyloid β (Aβ [1–42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated. Methods Cerebrospinal fluid samples collected from patients with mild‐to‐moderate Alzheimer's disease were analyzed by Elecsys® immunoassays: (1) Aβ (1–42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Aβ [1–42] and ratios with tau) were estimated by method comparison between AlzBio3 (n = 206), mixture modeling (n = 216), and concordance with florbetapir F 18 imaging‐based classification (n = 75). Results A 1065‐pg/mL (95% confidence interval: 985–1153) Elecsys® Aβ (1–42) cutoff provided 94% overall percentage agreement with AlzBio3. Comparable cutoff estimates (95% confidence interval) were derived from mixture modeling (equally weighted: 1017 [949–1205] pg/mL; prevalence weighted: 1172 [1081–1344] pg/mL) and concordance with florbetapir F 18 imaging (visual read: 1198 [998–1591] pg/mL; automated: 1198 [1051–1638] pg/mL). Discussion Based on three approaches, a 1100‐pg/mL Elecsys® Aβ (1–42) cutoff is suitable for clinical trials with similar populations and preanalytical handling.