Alzheimer's disease (AD) is a fatal, neurodegenerative disease whose pathogenesis includes the buildup of amyloid beta (Aß; one of the defining brain changes of AD) years before clinical symptoms appear. Anti-Aß therapeutics that target the complex underlying AD 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 Aß, tau, and neurodegeneration, the hallmarks of AD. 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 Aß and tau? and (2) What does the evidence show about how anti-Aß 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 Aß 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 Aß, tau, and other pathologies, and subject matter experts who presented modeling data to advance AD treatment strategies. Several major pharmaceutical companies that are AARR members also presented current evidence from multiple phase 2 and 3 clinical trials that manipulation (or removal) of Aß 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 Aß is helping our understanding of the downstream effects and overall importance of lowering Aß. Based on data from multiple phase 2 and 3 clinical trials of monoclonal antibodies, there is evidence to support that a change in Aß is associated with a change in tau and clinical endpoints. And finally, biomarker changes in Aß 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 Aß 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.
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