A workgroup convened by the Alzheimer's Association has published revised criteria for the diagnosis and staging of Alzheimer's disease that are based on the biology of the disease and reflect recent advancements in Alzheimer's research, diagnostics and treatment. The 2024 update includes an updated biomarker classification system that includes blood-based biomarkers (BBM) and a revised disease staging system.

"Revised Criteria for Diagnosis and Staging of Alzheimer's Disease: Alzheimer's Association Workgroup" was published online by Alzheimer's & Dementia®: The Journal of the Alzheimer's Association. DOI: 10.1002/alz.13859.

"These updated criteria for diagnosis and staging of Alzheimer's are driven by the latest developments and discoveries in Alzheimer's science," said Maria C. Carrillo, Ph.D., Alzheimer's Association chief science officer and medical affairs lead, and senior author on the newly published paper. "Our goal in sharing them now — even as the field and our knowledge continues to evolve — is to advance diagnosis, treatment and prevention in order to improve individual care and reduce the societal impact of Alzheimer's."

"Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases," said Clifford Jack, Jr., M.D., Mayo Clinic, Rochester, Minn., and the lead author on the paper. "An unchanging principle is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process."

"These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer's and we are able to measure those changes. Treatments that target one of these processes — buildup of amyloid beta — have been approved by regulators, and biomarker proof that the underlying biology is present must be confirmed to be eligible for treatment," Jack added. "Plus, the accuracy of some of the emerging Alzheimer's blood tests needs to be considered, and researchers and clinicians made aware and properly educated on their use."

The Revised Criteria define Alzheimer's disease as a biological process that begins with the appearance of Alzheimer's-related changes that happen in the brain before people exhibit memory and thinking problems. The authors state that progression, growth and expansion of these changes lead to the later appearance and progression of clinical symptoms, such as memory loss, disorientation, trouble with planning or organizing, and mental confusion.

According to the authors, symptoms and clinical syndromes commonly seen in people living with Alzheimer's may also be caused by other disorders, so clinical presentation alone is not diagnostic of Alzheimer's.

The Revised Criteria are not intended to provide step-by-step clinical practice guidelines for clinicians or specific treatment protocols. Rather, they contain general principles to inform diagnosis and staging of Alzheimer's that reflect current science.

"Our intent is to present objective criteria for diagnosis and staging of Alzheimer's, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care," Jack said. "Formal clinical practice guidelines will appear in a subsequent publication."

The newly published article acknowledges the vital role of clinicians — and clinical judgment — in Alzheimer's diagnosis: "The biologically based diagnosis of Alzheimer's disease is meant to assist rather than supplant the clinical evaluation of individuals with cognitive impairment. … Clinical judgment must always be used in the practice of medicine, and the application of diagnostic tests for [Alzheimer's] is no exception."

The Alzheimer's Association has initiated a collaboration with clinical and subject-matter experts, a variety of interested organizations, and patient representatives to develop guidelines for the clinical implementation of Alzheimer's diagnosis and staging criteria.

According to the workgroup, "[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."

Biomarkers and Diagnosis
The authors group biomarkers into three broad categories: (1) core biomarkers of Alzheimer's disease neuropathologic change (ADNPC), (2) non-specific biomarkers that are important in Alzheimer's but are also involved in other brain diseases, and (3) biomarkers of diseases/conditions that commonly co-exist with Alzheimer's. Core Alzheimer's biomarkers have two subtypes:

• Core 1 biomarkers become abnormal early in the disease course. This category of biomarkers (either PET or biofluid) directly measures either amyloid plaques or phosphorylated tau. An individual with an abnormal Core 1 biomarker will nearly always have both plaques and tangles at autopsy in sufficient levels to meet standard criteria for a diagnosis of Alzheimer's. Therefore, an abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer's and contribute to clinical decision-making throughout the disease continuum.
• Later-changing Core 2 biomarkers reflect deposits of aggregated tau in the brain, and can provide prognostic information. When abnormal, they increase confidence that Alzheimer's is contributing to symptoms.

The Revised Criteria consider the following to be Core 1 biomarkers: amyloid PET; CSF Aβ 42/40 ratio, CSF p-tau181/Aβ 42 ratio, CSF t-tau/Aβ 42 ratio; or "accurate" plasma assays, such as p-tau217. Core 2 biomarkers (biofluid and tau PET) have many uses but would typically not be used as standalone diagnostic tests for Alzheimer's.

History and Background
The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011, and single work groups in 2012 and 2018, to create recommendations for the diagnosis and characterization of Alzheimer's. The Alzheimer's Association is the convening organization for the new Revised Criteria.

The Revised Criteria incorporate these recent research developments:

• Treatments that target core disease pathology (i.e., anti-amyloid immunotherapies for Alzheimer's) have received regulatory approval. This highlights the importance of alignment among clinicians, industry, and academia.
• The most significant advance in Alzheimer's diagnostics in recent years has been the development of blood-based markers with some assays exhibiting accurate diagnostic performance. This makes the biological diagnosis of Alzheimer's more generally accessible and is projected to revolutionize clinical care and research.

Members of the Alzheimer's Association workgroup were selected to provide a range of relevant scientific and clinical expertise; to achieve a representative sample of professional stakeholders; and to achieve a balance of academic and industry representation, sex/ethnicity, and geographic location. Additional expert advisors provided reviews of the project. Full committee membership, funding and conflict of interest information are in the journal article.

"We will hear results from a variety of research on Alzheimer's biomarkers and diagnostic tools, including a presentation by Dr. Jack on these Revised Criteria, at the Alzheimer's Association International Conference® 2024, July 28 to Aug. 1 in Philadelphia and online," Carrillo said.