In 2018, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) published a research framework for Alzheimer’s disease classification based on biomarkers, which are biological indicators of disease that can be measured by cerebrospinal fluid (CSF) tests, brain scans, and other assays. The 2018 framework was designed to support the classification of Alzheimer’s disease in the context of research studies, not general clinical work. However since then, scientific advances have propelled the Alzheimer’s disease field forwards, with the development of blood-based biomarkers and the regulatory approval of new PET tracers and CSF tests. At a special symposium during the Alzheimer’s Association International Conference (AAIC), the NIA-AA Work Group released a draft update to the 2018 research framework, extending it to criteria for diagnosing Alzheimer’s disease in the clinic. These revised guidelines incorporate fluid and imaging biomarkers in a clinical framework for diagnosing Alzheimer’s disease (AD). The 2023 update distinguishes clinical symptoms such as memory loss from the biological causes of AD – such as amyloid plaques and tau tangles, which can be measured using a range of blood, CSF and imaging biomarkers.
Core principles of the Framework state that:
• AD is defined by its biology, and is first evident when people are asymptomatic, but have amyloid plaques and tau tangles in the brain, and
• Clinical symptoms, such as memory problems, are not necessary to diagnose AD, which can be diagnosed using disease-specific biomarkers.
To support the biological diagnosis, staging and prognosis of AD, the updated guidelines identify specific fluid and imaging biomarkers that can be used to determine whether patients are at the initial, early, intermediate or advanced biological stage of AD. Core biomarkers for AD are those that directly connected to amyloid or tau, which are identified as the defining biological drivers of AD. For example, someone at the initial biological stage of AD might have a positive amyloid PET scan and a negative tau PET scan, or a positive blood test for the biomarkers pTau181 or pTau217. The guidelines also include a framework for the clinical staging of patients based on symptoms, with clinical stage 1 being asymptomatic but with biomarker positivity, and clinical stage 6 being AD dementia with severe functional impairment.
An integrated biological and clinical staging framework incorporates both biological and clinical parameters, providing classifications for patients at different stages of AD. For example, a patient at stage 2b would have some subtle symptoms of cognitive decline (clinical stage 2) with biomarkers that indicate an “early biological stage” (biological stage b). This represents a paradigm shift for the clinical diagnosis of AD, which is most frequently diagnosed in the symptomatic stages using tests for cognition or executive function alongside physical examinations and evaluation of the patients’ medical history. The NIA-AA Work Group, which is chaired by Clifford Jack of the Mayo Clinic and includes 21 other experts from academic institutions, regulatory agencies, Alzheimer’s Associations and industry, hopes that the updated framework will support earlier, more accurate diagnosis and swifter access to treatments and clinical trials. The framework will be available for public comment on the Alzheimer’s Association website until 16 August. Read the revised clinical guidelines: https://aaic.alz.org/nia-aa.asp#workgroup
