Current understanding of AD pathophysiology and impact of amyloid‐beta targeted treatments on biomarkers and clinical endpoints
Year: 2022
Type: article
Abstract: The Spring 2022 Alzheimer's Association's Research Roundtable (AARR) convened leaders from around the world to discuss the topic, "Current Understanding of AD Pathophysiology & Impact of Amyloid-beta Targeted Treatments on Biomarkers and Clinical Endpoints." Alzheimer's disease (AD) is a fatal, neurodegenerative disease whose pathogenesis includes the buildup of amyloid beta (one of the defining brain changes of AD) years before clinical symptoms appear. Anti-amyloid beta therapeutics that target the complex underlying AD disease pathophysiology have been the focus of many recent clinical trials, representing a viable option that may ultimately slow cognitive decline in some patients. Evidence has been accumulating within the science community that plaque-removing monoclonal antibodies can impact amyloid beta, tau, and neurodegeneration, the hallmarks of AD.1-4 The Spring 2022 Alzheimer's Association's Research Roundtable (AARR) convened leaders from industry and academia, as well as patients, clinicians, and government scientists and regulatory agencies, to discuss the topic, "Current Understanding of AD Pathophysiology & Impact of Amyloid-beta Targeted Treatments on Biomarkers and Clinical Endpoints." The meeting addressed two fundamental questions: (1) What is the evidence regarding the relationship between amyloid beta and tau? and (2) What does the evidence show about how anti-beta amyloid therapies alter clinical function? The meeting opened with a series of presentations to lay the groundwork on what we know about the biology of AD, including a primer on various species of amyloid beta and how animal models may inform our understanding of disease progression. The meeting continued with representatives from active, observational studies sharing how biomarker and clinical data contribute to our understanding of amyloid beta, tau, and other pathologies, and subject matter experts who presented modeling data to advance AD treatment strategies. Several major pharmaceutical companies who are AARR members also presented current evidence from multiple phase 2 and phase 3 clinical trials that manipulation (or removal) of amyloid beta has a clear downstream impact on tau, neurodegeneration, and cognitive/functional measures. At the conclusion of the 2-day meeting, presenters, panelists, and the AARR membership in attendance came to several conclusions based on the scientific evidence presented, discussed and debated: The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on amyloid beta is helping our understanding of the downstream effects and overall importance of lowering amyloid beta. Based on data from multiple phase 2 and phase 3 clinical trials of monoclonal antibodies, there is evidence to support that a change in amyloid beta is associated with a change in tau and clinical endpoints. And finally, biomarker changes in amyloid beta are reasonably likely to predict changes in clinical outcome measures and should be considered meaningful to all patients who may potentially benefit from these treatments. The Spring 2022 AARR meeting not only furthered our understanding of the pathophysiology of AD, but also brought to light the strength of the evidence supporting the hypothesis that a change in amyloid beta can produce meaningful change in biomarkers and clinical endpoints. There is much work to be done, and the scientific community needs to stay focused on defining those tools most appropriate to capture these changes, the populations best suited to enroll in clinical trials, and defining our expectations of what changes can be expected over a particular interval of time. A more detailed report of this meeting will appear in a future issue of Alzheimer's & Dementia. R.P. is a full-time employee of Mayo Foundation for Education and Research and a consultant for Biogen, Inc., Roche, Inc., Merck, Inc., Genentech Inc. (DSMB), and Eisai, Inc. A.G. is a full-time employee of NovartisPharma AG. M.C.C., C.J.W. are full-time employees of the Alzheimer's Association. Author disclosures are available in the supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
DOI: 10.1002/trc2.12361
Institutions: Mayo Clinic, Novartis (Switzerland), Alzheimer's Association
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,200
OpenAlex ID: W4307498210