Diagnosing Alzheimer’s disease has been a continuously evolving field since 1984, with the Alzheimer’s Association playing a pivotal role in defining the criteria. Initially, the NINCDS-ADRDA criteria, a joint effort by the Alzheimer’s Association and the National Institutes of Health, served as the benchmark for clinical trials and diagnoses. This remained the standard until the 2011 NIA-AA clinical guidelines emerged, offering a revised perspective. Further building on this foundation, the 2018 NIA-AA research framework contextualized the growing scientific understanding and highlighted areas for future research. Now, the field takes another significant step forward with the release of the Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease in June 2024.
Published in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association, with accompanying commentaries in Nature Medicine and Nature Aging, the 2024 criteria represent a significant update. These new guidelines incorporate the latest scientific breakthroughs to provide a more comprehensive and precise framework for both diagnosing and staging Alzheimer’s disease. The overarching aims of these updated Dementia Diagnosis Criteria are to:
- Enhance the accuracy of current diagnostic practices.
- Establish a biological definition of Alzheimer’s to guide the development of next-generation clinical trials.
- Pave the way for personalized treatment approaches for Alzheimer’s, grounded in the biological underpinnings of the disease.
Core Principles of the 2024 Alzheimer’s Diagnosis Criteria
The 2024 criteria are built upon several fundamental principles that reflect the current understanding of Alzheimer’s disease. These core tenets include:
- Biological Definition: Alzheimer’s disease should be fundamentally defined by its biological characteristics, rather than solely based on clinical symptoms or syndromes. This shift emphasizes the underlying disease processes in the brain.
- Disease Continuum: Alzheimer’s is recognized as a continuum, starting with subtle brain changes associated with the disease process in individuals who are still asymptomatic. This progresses through stages marked by increasing levels of these brain changes, eventually leading to the manifestation and progression of clinical symptoms.
- Biomarker-Based Diagnosis: Diagnosis of Alzheimer’s disease in individuals is established through the identification of abnormalities in core biomarkers. These biomarkers provide objective measures of the biological processes associated with the disease.
It is crucial to note that the current criteria are not intended for evaluating Alzheimer’s-related brain changes in asymptomatic individuals for routine clinical care. Such evaluations are recommended to remain within the context of observational or therapeutic research studies at this time.
The development of these updated dementia diagnosis criteria was spearheaded by a steering committee convened by the Alzheimer’s Association in early 2022. Chaired by Dr. Clifford Jack from the Mayo Clinic, this committee aimed to translate the 2011 diagnostic guidance and the 2018 research framework into practical, updated diagnostic criteria. It’s important to emphasize that these new criteria are not clinical practice guidelines but rather a scientific framework to inform diagnosis. The workgroup’s findings were presented at major scientific conferences, including AAIC® 2023, CTAD 2023, and AD/PD 2024, reflecting a collaborative and rigorous development process.
The Need for Updated Dementia Diagnosis Criteria
The impetus for updating the Alzheimer’s diagnosis criteria stems from a significant shift in the landscape of Alzheimer’s treatment. We are now entering an era where treatments that directly target the underlying biology of Alzheimer’s disease are becoming available, and more are anticipated. This evolution necessitates diagnostic criteria that are not just for research but are also clinically relevant for diagnosis and staging in practice. The 2024 criteria bridge this gap, progressing from a research framework to clinically applicable guidelines.
A key advancement driving the update is the validation and incorporation of new biomarkers. The 2018 framework primarily relied on cerebrospinal fluid (CSF) assays and imaging techniques for biomarker validation. Since then, significant progress has been made in developing plasma-based biomarkers that demonstrate excellent diagnostic accuracy. The 2024 criteria integrate these plasma biomarkers into the updated framework for biomarker categorization, disease diagnosis, and staging, offering less invasive and more accessible diagnostic tools.
Furthermore, research has highlighted that biomarkers within the same category, such as imaging and fluid biomarkers, are not always interchangeable, despite often being concordant. To address this, the 2024 criteria include refined biomarker classification criteria that acknowledge the potential non-equivalence between fluid and imaging biomarkers within a category, leading to a more nuanced and accurate diagnostic approach.
Recommended Use of the Updated Criteria
These updated dementia diagnosis criteria are designed to provide general principles that inform the diagnosis and staging of Alzheimer’s, reflecting the most current scientific understanding. They are not intended to be prescriptive, step-by-step clinical practice guidelines for workflow or specific treatment protocols. Instead, they propose a research-driven agenda focused on identifying biomarkers that can signal the very earliest, presymptomatic brain changes associated with Alzheimer’s.
The criteria explicitly state that the clinical application of Alzheimer’s biomarkers is currently intended for evaluating individuals who are already symptomatic, not those who are cognitively unimpaired. This recommendation is primarily due to the fact that disease-modifying therapies are not yet approved for individuals without cognitive impairment. Therefore, routine diagnostic testing in cognitively unimpaired individuals outside of research settings is not currently recommended.
Looking ahead, the Alzheimer’s Association is taking a proactive step to facilitate the clinical implementation of these new criteria. A collaboration is being initiated, bringing together clinical experts, subject-matter specialists, methodologists, external organizations, and patient representatives. This collaborative effort will focus on developing practical guidelines for the clinical implementation of Alzheimer’s disease staging criteria and treatment strategies, with work commencing later in 2024.
Collaborative Expertise Behind the Revised Criteria
The development of the Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease was a collaborative effort, involving a diverse workgroup selected to represent a wide range of scientific expertise, institutions (public, academic, and private), professional organizations involved in Alzheimer’s research, and geographical 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 development process was transparent and inclusive, incorporating public feedback gathered at conferences like AAIC 2023, CTAD 2023, AD/PD 2024, through a public website sharing drafts, and via online feedback submissions.
The distinguished members of the 2022-2024 workgroup included:
- 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
Building Upon Previous Diagnostic Frameworks
The 2024 updated dementia diagnosis criteria are not developed in isolation but are part of a continuous evolution of guidelines and frameworks. Previous workgroups have consistently issued recommendations that were made available for public comment, with final versions published as open-access articles in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association. These prior guidelines have been instrumental in shaping the current understanding and approach to Alzheimer’s diagnosis.
2011 NIA-AA Diagnostic Guidelines: Stages of Alzheimer’s Disease
The 2011 NIA-AA guidelines were a landmark achievement, focusing on the three distinct stages of Alzheimer’s disease:
- Preclinical Alzheimer’s: Defining the asymptomatic stage characterized by biomarker changes before clinical symptoms appear. This framework aimed to stimulate research into early detection biomarkers.
- Mild Cognitive Impairment (MCI) due to Alzheimer’s: Addressing the stage where subtle cognitive changes are measurable but do not yet impede daily life. The guidelines provided levels of certainty for diagnosing MCI due to Alzheimer’s.
- Dementia due to Alzheimer’s: Updating and clarifying the clinical criteria for diagnosing dementia caused by Alzheimer’s, applicable across various clinical settings.
These 2011 guidelines significantly advanced the field by providing a stage-based approach to Alzheimer’s diagnosis and highlighting the importance of preclinical detection.
2012 NIA-AA Guideline: Neuropathologic Assessment
Complementing the clinical guidelines, the 2012 NIA-AA guideline focused on neuropathologic assessment during autopsy. Key recommendations included:
- Standardizing the ranking of Alzheimer’s pathology severity based on hallmark brain changes.
- Establishing “Alzheimer’s disease neuropathologic changes” as a reporting standard, irrespective of prior clinical diagnosis.
- Emphasizing the assessment of co-occurring pathologies like Lewy bodies and vascular abnormalities.
These guidelines have become the gold standard for neuropathologic evaluation of Alzheimer’s and have significantly contributed to our understanding of the disease’s pathology.
In conclusion, the 2024 Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease represent a crucial step forward in our ability to accurately diagnose and understand Alzheimer’s. By incorporating biological definitions, new biomarkers, and acknowledging the disease continuum, these updated dementia diagnosis criteria promise to enhance clinical practice, guide future research, and ultimately pave the way for more effective, personalized treatments for Alzheimer’s disease.
