James Hendrix

Tau: From research to clinical development

Alzheimers Association Research Roundtable Fall 2015—Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimers and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau‐related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimers Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials.

Expert consensus document: Mind the gaps—advancing research into short-term and long-term neuropsychological outcomes of youth sports-related concussions

Sports-related concussions and repetitive subconcussive exposure are increasingly recognized as potential dangers to paediatric populations, but much remains unknown about the short-term and long-term consequences of these events, including potential cognitive impairment and risk of later-life dementia. This Expert Consensus Document is the result of a 1-day meeting convened by Safe Kids Worldwide, the Alzheimers Drug Discovery Foundation, and the Andrews Institute for Orthopaedics and Sports Medicine. The goal is to highlight knowledge gaps and areas of critically needed research in the areas of concussion science, dementia, genetics, diagnostic and prognostic biomarkers, neuroimaging, sports injury surveillance, and information sharing. For each of these areas, we propose clear and achievable paths to improve the understanding, treatment and prevention of youth sports-related concussions.

The roles of inflammation and immune mechanisms in Alzheimer's disease

The Alzheimers Associations Research roundtable met in April 2015 to explore the role of neuroinflammatory mechanisms in the progression of Alzheimers disease (AD). The ability of innate immune cells, particularly microglia and astrocytes, to mediate neuroinflammation in AD has been implicated as a significant contributor to disease pathogenesis. Adaptive immunity, which plays an important role in responding to injury and some diseases of the central nervous system, may contribute to neuroinflammation in AD as well. Communication between the central and peripheral immune systems may also be important in AD. An increased understanding of the physiology of the innate immune system may aid the identification of new therapeutic targets or mechanisms. The development of predictive animal models and translatable neuroinflammation biomarkers for AD would also facilitate the advancement of novel treatments for innate immunity. Important challenges impeding the advancement of new therapeutic agents and strategies to overcome them were discussed.

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

The Alzheimers Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimers disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public‐private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimers Association recognized these global efforts and formed Worldwide ADNI (WW‐ADNI). By creating a platform for international collaboration and cooperation, WW‐ADNIs goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW‐ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy

Given the complex neuropathology Alzheimers disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimers Association, have explored these challenges and here propose a strategy to facilitate proof‐of‐concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders.

AlzheimerâÂÂs and ParkinsonâÂÂs Diseases Face Common Challenges inTherapeutic Development: Role of the Precompetitive Consortium,Coalition Against Major Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) pose significant challenges for successful development of new therapies, with anextremely high drug trial failure rate and yet no approved disease modifying drugs available. Given the magnitude of the challenges, it has become clear that larger collaborations and multi-partner joint efforts, pooling resources and expertise,are required for theadvancement of methods and tools that are critically needed to support drug development studies. Critical Path Institute’s Coalition against Major Diseases was formed in 2008, at a time prior to the era of public private partnerships, with the mission of streamlining and de-risking drug development for AD and PD. Since its origin, the consortium has achieved several milestones including development of consensus data standards for AD and PD, a unified clinical trial database comprised of placebo data from AD therapeutic trials and regulatory endorsement of drug development tools. In addition, the consortium is progressing strongly on other initiatives, with ongoing regulatory interactions. The coalition held its annual conference at the U.S. Food and Drug Administration, where diverse stakeholders including industry, academic experts, government agency representatives, patient advocacy organizations and regulators gathered together to share their accomplishments and focus on the needs of the future. The current landscape was emphasized with focus on the need to expand the precompetitive space and enhance data sharing globally.

Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms

Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimers disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under‐recognized and often challenging to treat. With this in mind, the Alzheimers Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

Multiple comorbid neuropathologies in the setting of Alzheimer's disease neuropathology and implications for drug development

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimers disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist.

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

The Alzheimers Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for‐profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific support to ADNI through the Foundation for the National Institutes of Health. The PPSB serves as an independent, open, and precompetitive forum in which all private sector and not‐for‐profit partners in ADNI can collaborate, share information, and offer scientific and private‐sector perspectives and expertise on issues relating to the ADNI project. In this article, we review and highlight the role, activities, and contributions of the PPSB within the ADNI project, and provide a perspective on remaining unmet needs and future directions.

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease : Perspectives from the Research Roundtable

The Alzheimers Associations Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimers Association Research Framework for Alzheimers disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimers Association Research Framework. This review will summarize the “A, T, N System” (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.