The Alzheimer's Disease Neuroimaging Initiative and the role and contributions of the Private Partners Scientific Board (PPSB).

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. HIGHLIGHTS: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities. PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations.

Benefits and risks of FDA-approved amyloid-targeting antibodies for treatment of early Alzheimer's disease: Navigating clinician-patient engagement.

The emergence of the United States Food and Drug Administration (FDA)-approved amyloid-targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease-modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid-related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families. As the landscape evolves with the approval of new Alzheimer's therapies, this resource stands poised for updates, ensuring its continued relevance in facilitating informed and meaningful patient-provider dialogues. HIGHLIGHTS: Effective communication of risks, benefits, burdens, and costs of FDA-approved amyloid-targeting antibodies is essential to patients, families, and healthcare providers. The Alzheimer's Association's Clinical Meaningfulness Workgroup provides language for physicians and healthcare providers around treatment eligibility, benefits, ARIA, APOE genotyping, and treatment costs. This supplementary resource may be updated as new AD therapies become approved.

Expectations and clinical meaningfulness of randomized controlled trials.

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.

Outcome measures for Alzheimer's disease: A global inter-societal Delphi consensus.

INTRODUCTION: We aim to provide guidance on outcomes and measures for use in patients with Alzheimer's clinical syndrome. METHODS: A consensus group of 20 voting members nominated by 10 professional societies, and a non-voting chair, used a Delphi approach and modified GRADE criteria. RESULTS: Consensus was reached on priority outcomes (n = 66), measures (n = 49) and statements (n = 37) across nine domains. A number of outcomes and measurement instruments were ranked for: Cognitive abilities; Functional abilities/dependency; Behavioural and neuropsychiatric symptoms; Patient quality of life (QoL); Caregiver QoL; Healthcare and treatment-related outcomes; Medical investigations; Disease-related life events; and Global outcomes. DISCUSSION: This work provides indications on the domains and ideal pertinent measurement instruments that clinicians may wish to use to follow patients with cognitive impairment. More work is needed to develop instruments that are more feasible in the context of the constraints of clinical routine.

Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

Comparative analytical performance of multiple plasma Aß42 and Aß40 assays and their ability to predict positron emission tomography amyloid positivity.

INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aß) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aß assays. Statistical tests were performed to determine whether the plasma Aß measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aß in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. HIGHLIGHTS: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aß) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aß42/40 predicted amyloid positron emission tomography status better than Aß42 or Aß40 alone.

The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid ß and tau.

The core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers amyloid beta (Aß42 and Aß40), total tau, and phosphorylated tau, have been extensively clinically validated, with very high diagnostic performance for AD, including the early phases of the disease. However, between-center differences in pre-analytical procedures may contribute to variability in measurements across laboratories. To resolve this issue, a workgroup was led by the Alzheimer's Association with experts from both academia and industry. The aim of the group was to develop a simplified and standardized pre-analytical protocol for CSF collection and handling before analysis for routine clinical use, and ultimately to ensure high diagnostic performance and minimize patient misclassification rates. Widespread application of the protocol would help minimize variability in measurements, which would facilitate the implementation of unified cut-off levels across laboratories, and foster the use of CSF biomarkers in AD diagnostics for the benefit of the patients.

Decision making in clinical trials: Interim analyses, innovative design, and biomarkers.

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.

Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations.

Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well-defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the basis of biomarker features and the two need to be coordinated. The Alzheimer's Association Research Roundtable (AARR) Spring 2021 meeting discussed the implementation of preclinical AD staging criteria, and provided recommendations for how they may best be incorporated into clinical trials research. Discussion also included what currently available tools for global clinical trials may best define populations in preclinical AD trials, and if are we able to differentiate preclinical from clinical stages of the disease. Well-defined AD staging criteria are key to improving early detection, diagnostics, clinical trial enrollment, and identifying statistically significant clinical changes, and researchers discussed how emerging blood biomarkers may help with more efficient screening in preclinical stages.

Building clinically relevant outcomes across the Alzheimer's disease spectrum.

Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a "clinically meaningful outcome" in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19-20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future.

The Worldwide Alzheimer's Disease Neuroimaging Initiative: ADNI-3 updates and global perspectives.

The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI-1, ADNI-GO, ADNI-2, and ADNI-3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW-ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer's Association convened WW-ADNI researchers who shared updates from ADNI-3 and their vision for ADNI-4.

Active immunotherapy and alternative therapeutic modalities for Alzheimer's disease.

As knowledge of Alzheimer's disease (AD) progression improves, the field has recognized the need to diversify the pipeline, broaden strategies and approaches to therapies, as well as delivery mechanisms. A better understanding of the earliest biological processes of AD/dementia would help inform drug target selection. Currently there are a number of programs exploring these alternate avenues. This meeting will allow experts in the field (academia, industry, government) to provide perspectives and experiences that can help elucidate what the pipeline looks like today and what avenues hold promise in developing new therapies across the stages of AD. The focus here is on Active Immunotherapies and Alternative Therapeutic Modalities. This topic includes active vaccines, antisense oligomers, and cell-based therapy among others, and highlights new clinical developments that utilize these modalities.

The pathway to secondary prevention of Alzheimer's disease.

Alzheimer's disease (AD) is a continuum consisting of a preclinical stage that occurs decades before symptoms appear. As researchers make advances in investigating the continuum, the importance of developing drugs for secondary prevention is garnering increased discussion. For efficacious drug development for secondary prevention it is important to define what are the earliest biological stages of AD. The Alzheimer's Association Research Roundtable convened November 27 to 28, 2018 to focus on pre-clinical AD. This review will address the biological approach to defining pre-clinical AD, detection, identification of at-risk individuals, and lessons learned from trials such as A4 and TOMMORROW.

Advancing combination therapy for Alzheimer's disease.

The study of Alzheimer's disease (AD) has led to an increased understanding of the multiple pathologies and pathways of the disease. As such, it has been proposed that AD and its various stages might be most effectively treated with a combination approach rather than a single therapy; however, combination approaches present many challenges that include limitations of non-clinical models, complexity of clinical trial design, and unclear regulatory requirements. The Alzheimer's Association Research Roundtable meeting on May 7-8, 2018, discussed the approaches and challenges of combination therapy for AD. Experts in the field (academia, industry, and government) provided perspectives that may help establish a path forward for the development of new combination therapies.

Injuries Depicted in Sport-Related Films.

The perception that children and adolescents have of injuries may be influenced by their depiction in sport-related films. The objective of this study was to determine the depiction of injuries in a select number of sport-related films. Forty-four films were analyzed. Injury category, on-the-field management, and long-term management were determined for each injury. Major injuries were defined as injuries requiring prompt intervention and immediate discontinuation of sport participation. A total of 49 injuries were depicted, categorized as fracture (n = 11), contusion (n = 10), brain concussion (n = 8), muscle cramps (n = 5), laceration/abrasion (n = 4), ligamentous knee injury (n = 4), shoulder dislocation (n = 2), rotator cuff injury (n = 2), ankle sprain (n = 2), and unspecified injury (n = 1). Of the 38 (78%) injuries considered major, immediate return to the game was the disposition for 13 injuries (34%). Pediatric health care providers, coaching staff, and parents should stress the importance of injury recognition/disclosure and realistic expectations for rehabilitation to pediatric athletes.