Since 1984, the Alzheimer’s Association has been instrumental in shaping the criteria for diagnosing Alzheimer’s disease. Initially, a joint effort between the Alzheimer’s Association and the National Institutes of Health (NINCDS-ADRDA) established the leading criteria for clinical trials and diagnoses. This remained the standard until the 2011 National Institute on Aging and Alzheimer’s Association (NIA-AA) clinical guidance. Further building upon this foundation, the 2018 NIA-AA research framework contextualized current scientific understanding, outlining research needs and hypotheses for deeper investigation.
The article “Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease” published on June 27, 2024, in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association, along with accompanying commentaries in Nature Medicine and Nature Aging, introduces the 2024 version of these crucial criteria. This updated version integrates the most recent scientific advancements to more comprehensively define the Alzheimer Diagnosis Criteria and staging of Alzheimer’s.
These new criteria are designed to advance Alzheimer’s diagnosis by incorporating scientific breakthroughs and technological progress, aiming to:
- Enhance the accuracy of current diagnostic practices.
- Provide a framework for a biological definition of Alzheimer’s, guiding the next wave of clinical trials.
- Establish a basis for personalized Alzheimer’s treatment strategies rooted in biological understanding.
The Evolution of Alzheimer’s Diagnosis Criteria
The 2024 criteria offer a structured approach to the diagnosis and staging of Alzheimer’s disease, built upon several fundamental principles:
- Alzheimer’s disease should be defined by its biological underpinnings, rather than solely on clinical syndromes.
- The disease progresses along a continuum, starting with brain changes associated with disease processes in asymptomatic individuals. These changes evolve through stages of increasing severity, eventually leading to the emergence and progression of clinical symptoms.
- Diagnosis of Alzheimer’s disease relies on the detection of abnormalities in core biomarkers.
It’s important to note that these criteria are not currently intended for evaluating Alzheimer’s disease-related brain changes in asymptomatic individuals for routine clinical care, but rather within the context of observational or therapeutic research studies.
In early 2022, the Alzheimer’s Association established a steering committee, led by Dr. Clifford Jack from Mayo Clinic, to translate the 2011 diagnostic guidance and the 2018 research framework into these newly proposed diagnostic criteria. It is emphasized that these new criteria are not clinical practice guidelines recommendations.
The workgroup, under Dr. Jack’s leadership, presented their findings at various scientific conferences, including the Alzheimer’s Association International Conference® (AAIC®) 2023, Clinical Trials in Alzheimer’s Disease (CTAD) 2023, and AD/PD 2024.
Why the 2024 Update for Alzheimer’s Diagnosis Criteria is Necessary
The update to the alzheimer diagnosis criteria is timely and crucial, particularly as treatments targeting the underlying biology of Alzheimer’s disease become available and continue to develop. This document marks a progression from a research-focused framework to diagnostic criteria intended for both clinical application and research purposes.
The 2018 framework relied on validated biomarkers from cerebrospinal fluid (CSF) assays or imaging. Significant advancements have since led to the development and clinical validation of plasma-based biomarkers with high diagnostic accuracy. The 2024 criteria acknowledge these developments by incorporating plasma biomarkers into the updated framework for biomarker categorization, disease diagnosis, and staging.
Furthermore, research has indicated that imaging and fluid biomarkers within the same category, while often consistent, are not always interchangeable in clinical settings. Therefore, the 2024 criteria include updated biomarker classification to account for the potential non-equivalence between fluid and imaging biomarkers within a category.
Recommended Use of the Updated Criteria
These updated alzheimer diagnosis criteria are designed to provide general principles for diagnosing and staging Alzheimer’s, reflecting the latest scientific understanding, rather than to dictate step-by-step clinical practice guidelines, clinical workflow, or specific treatment protocols. They also set forth a research agenda to identify biomarkers that can signal the onset of presymptomatic brain changes.
According to the criteria, the clinical application of Alzheimer’s biomarkers is currently recommended for evaluating individuals showing symptoms, not those who are cognitively unimpaired. The criteria explicitly state, “[T]he clinical use of [Alzheimer’s] biomarkers is presently intended for the evaluation of symptomatic individuals, not cognitively unimpaired individuals. … At the present time disease-targeted therapies have not been approved for cognitively unimpaired individuals with [Alzheimer’s]. For this reason, we currently recommend against diagnostic testing in cognitively unimpaired individuals outside the context of … research studies.”
The Alzheimer’s Association is taking proactive steps to ensure the practical implementation of these criteria. A collaboration is being initiated with clinical experts, subject-matter specialists, methodologists, external organizations, and patient representatives to develop guidelines for the clinical implementation of Alzheimer’s disease staging criteria and treatment. This important work is scheduled to commence later in 2024.
The Expert Workgroup Behind the 2024 Criteria
The workgroup responsible for the 2024 revised alzheimer diagnosis criteria was carefully selected to encompass a broad spectrum of scientific expertise. It included representation from diverse institutions—public, academic, and private—and professional organizations involved in Alzheimer’s research, as well as geographic and gender diversity. Recognizing the criteria’s crucial role in supporting clinical intervention research, the workgroup also included regulatory science expertise through a representative from the U.S. Food & Drug Administration.
The criteria development process was transparent and inclusive, incorporating public feedback gathered at AAIC 2023, CTAD 2023, AD/PD 2024, and other forums. A public-facing website provided access to the most recent drafts, and opportunities were provided for web-based feedback submissions.
The distinguished members of the 2022-2024 workgroup include:
- Jeffrey Scott Andrews, PharmD, Takeda
- Thomas G. Beach, M.D., Ph.D., Banner Sun Health Research Institute
- Teresa Buracchio, M.D., U.S. Food and Drug Administration
- Maria C. Carrillo, Ph.D., Alzheimer’s Association
- Billy Dunn, M.D., Independent
- Ana Graf, M.D., Novartis
- Oskar Hansson, M.D., Ph.D., Lund University
- Carole Ho, M.D., Denali Therapeutics
- Clifford R. Jack Jr., M.D., Mayo Clinic
- William Jagust, M.D., University of California, Berkeley
- Eliezer Masliah*, M.D., National Institutes of Health
- Eric McDade, D.O., Washington University in St. Louis
- José Luis Molinuevo, M.D., Ph.D., Lundbeck
- Ozioma Okonkwo, Ph.D., University of Wisconsin, Madison
- Luca Pani, M.D., University of Miami, Former Italian Regulatory Agency
- Michael Rafii, M.D., Ph.D., University of Southern California
- Laurie Ryan*, Ph.D., National Institute on Aging
- Phillip Scheltens, M.D., Ph.D., Life Science Partners
- Eric Siemers, M.D., Acumen
- Heather M. Snyder, Ph.D., Alzheimer’s Association
- Reisa Sperling, M.D., Brigham and Women’s Hospital, Harvard
- Charlotte E. Teunissen, Ph.D., VU University Medical Center
* Advisory member of the workgroup
A Look Back: Previous Alzheimer’s Diagnosis Guidelines
Each workgroup involved in developing alzheimer diagnosis criteria has consistently sought public input on their proposed recommendations. The final, refined versions of these guidelines, reflecting feedback from the broader professional community, are published as freely accessible articles in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association.
2011 NIA-AA Diagnostic Guidelines: Three Stages of Alzheimer’s
The 2011 NIA-AA guidelines were developed to incorporate emerging scientific insights and technological advancements to improve diagnostic accuracy, enhance autopsy reporting of Alzheimer’s-related brain changes, and define a research agenda for earlier detection and improved diagnosis.
These guidelines categorized Alzheimer’s disease into three stages:
- Preclinical (presymptomatic or asymptomatic) Alzheimer’s.
- Mild cognitive impairment (MCI) due to Alzheimer’s.
- Dementia due to Alzheimer’s.
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Preclinical Alzheimer’s disease: This stage, newly defined in 2011, acknowledges that biomarker changes in the brain can precede noticeable symptoms by years. While identified as a stage, the 2011 guidelines for preclinical Alzheimer’s primarily aimed to guide future research in identifying and measuring biomarkers to confirm early Alzheimer’s-related changes, rather than establishing immediate diagnostic criteria for clinical use.
Mild Cognitive Impairment (MCI) due to Alzheimer’s disease: This stage involves measurable, noticeable mild changes in memory and thinking that are not severe enough to disrupt daily life. The 2011 guidance provided four levels of certainty for diagnosing MCI due to Alzheimer’s, with only the first level, based on core clinical criteria, recommended for general clinical practice at the time.
Dementia due to Alzheimer’s disease: This final stage is characterized by significant impairments in memory, thinking, and behavior that compromise independent living. The 2011 guidelines updated and clarified clinical criteria for diagnosing dementia from all causes and specifically from Alzheimer’s disease. These criteria were designed to be broadly applicable for community practitioners and specialists alike, regardless of access to advanced testing tools.
2012 NIA-AA Guideline: Neuropathologic Assessment
Building upon the clinical guidance, the Alzheimer’s Association and NIH also convened workgroups to establish criteria for documenting and reporting Alzheimer’s-related brain changes observed during autopsy. Key recommendations from the 2012 guideline included:
- Ranking the severity of Alzheimer’s pathology based on three key hallmark changes.
- Reporting these rankings as “Alzheimer’s disease neuropathologic changes,” irrespective of whether the individual was diagnosed with Alzheimer’s during life. This approach aimed to comprehensively understand the spectrum of brain changes in individuals with and without Alzheimer’s symptoms.
- Including assessments for Lewy bodies, vascular abnormalities, and other common co-existing brain changes.
These 2012 criteria have since become the standard for neuropathologic evaluation of Alzheimer’s disease and are considered the gold standard definition of the disease.
Conclusion
The 2024 revised alzheimer diagnosis criteria represent a significant step forward in our ability to diagnose and understand Alzheimer’s disease. By integrating biological definitions, incorporating plasma biomarkers, and refining the staging process, these criteria promise to improve diagnostic accuracy and pave the way for more personalized and effective treatment strategies in the fight against Alzheimer’s. The ongoing collaborative efforts to develop clinical implementation guidelines will be crucial in translating these advanced criteria into practical benefits for patients and healthcare providers.
