Introduction to the DETeCD‐ADRD special issue

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• This special issue contains multiple articles related to the DETeCD‐ADRD guideline.

1.

We have entered a new era of improved and emerging biologically‐based diagnostic biomarkers for Alzheimer's disease (AD) and AD‐related dementias (ADRD) that are rapidly impacting evaluation and care paradigms in every clinical setting: primary care, specialty care, and dementia subspecialty care. The integration of biomarkers—following appropriate use guidelines—into a person‐centered assessment of each person's risk profile for various types of dementia (taking into account both modifiable and non‐modifiable risk factors) ¹ , symptoms, and signs will add critical value to the diagnostic formulation and care plan for persons in whom there is a clinical concern for AD or an ADRD. This special issue highlights the new Diagnostic Evaluation, Testing, Counseling, and Disclosure of suspected Alzheimer's Disease and Related Disorders (DETeCD‐ADRD) Clinical Practice Guideline (CPG) that summarizes the process of diagnostic evaluation and disclosure for persons suspected of potentially having cognitive‐behavioral impairment due to AD or ADRD, which includes Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), vascular cognitive impairment and dementia (VCID), and a host of other diseases and conditions that may cause or substantially contribute to cognitive‐behavioral impairment. We greatly appreciate the solid foundations on which these recommendations rest, which, in the United States, include the 1994 American Academy of Neurology (AAN) practice parameter on dementia, ² followed by the 2001 AAN practice parameters on mild cognitive impairment (MCI) ³ and dementia, ⁴ and then by the 2018 AAN practice guideline on MCI ⁵ (now retired). Similar sets of recommendations have been published globally. ⁶ , ⁷ , ⁸ Most are aimed at specialists or dementia subspecialists. This CPG expands the scope of prior guidelines by providing recommendations for practicing clinicians on shared goal‐setting for a person‐centered clinical evaluation and on the diagnostic disclosure process. The DETeCD‐ADRD CPG does not propose diagnostic or staging criteria for diseases such as AD, LBD, and FTLD, which continue to evolve. ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Rather, it provides an overarching framework for a high‐quality process that aims to enable clinicians to establish etiology and contributing factors for any syndromic diagnosis, emphasizing the importance of a three‐step diagnostic formulation including cognitive functional status, cognitive‐behavioral syndrome, and likely etiology(‐ies). The CPG also does not provide guidance on diagnostic studies or testing obtained for treatment purposes—for example, it provides guidance regarding apolipoprotein E (APOE) testing for diagnostic evaluation purposes (not recommended) but does not address the role of such testing in the context of AD treatment consideration for amyloid plaque–lowering therapies.

With this comprehensive guideline, we attempt to provide rigorous, evidence‐ and practice‐informed foundational steps that capture the core elements of a high‐quality evaluation and disclosure process formulated into practical recommendations that are applicable to any practice setting, including primary care, along with additional guidance for specialists and subspecialists. In this special issue of Alzheimer's & Dementia, the three executive summaries by the DETeCD‐ADRD workgroup distill these recommendations, briefly summarize the evidence supporting them, and attempt to operationalize them as a series of steps in an evaluation process—starting with patient‐centered goal‐setting and ending with compassionate disclosure of results. A comprehensive report hosted online provides extensive details about the guideline development methodology, evidence review process, peer review process, rationale and recommendations for implementation, and specific narratives with evidence supporting each recommendation. This 2024 CPG provides a comprehensive foundation for a person‐centered diagnostic evaluation and disclosure process within which some details will likely require modification as new clinical tools and biomarkers transition from research settings and become sufficiently validated, approved, accessible, and covered by payors for appropriate clinical use in real‐world practice. For example, we expect that in the next 12–18 months some AD blood‐based biomarkers (BBMs) (e.g., phosphorylated tau‐217 [p‐tau217] and related ratios and multiplex tests) may be sufficiently validated, U.S. Food and Drug Administration (FDA) approved, reimbursed, and will have appropriate use recommendations (AURs) available to support their inclusion as part of another DETeCD‐ADRD CPG formal recommendation and to be slotted into the evaluation process pathways in primary, specialty, and subspecialty settings. Other tools and biomarkers that will likely sufficiently mature soon and have AURs to be considered for more formal inclusion as CPG recommendations and in the process pathways include tau positron emission tomography (PET) and alpha‐synuclein assays (e.g., skin biopsy or cerebrospinal fluid (CSF)–based seed amplification assays), whereas biomarkers of inflammatory pathways (e.g., glial fibrillary acidic protein or GFAP) and TAR DNA‐binding protein 43 (TDP‐43) may be further away from readiness for transitioning from research to clinical practice.

This special issue also includes eight related articles, which we briefly summarize.

In “The Role of Neuropsychological Assessment in the Evaluation of Patients with Cognitive‐Behavioral Change Due to Suspected Alzheimer's Disease and Other Causes of Cognitive Impairment and Dementia,” Drs. Shaughnessy and Weintraub provide an insightful perspective summarizing the critical role that neuropsychological evaluation plays in supporting early and accurate diagnosis and staging, characterizing the clinical profile, assessing trajectory over time, and providing recommendations specifically tailored to the individual and other providers on their care team. In this era of advanced neuroimaging and molecular biomarkers, neuropsychological assessment will continue to play many valuable roles in clinical assessment and care, a proposition that was also well‐supported by the CPG evidence review regarding the important role of neuropsychological evaluation in delineating cognitive‐functional status and syndromes and probabilistically informing potential etiological drivers and contributors.

In “Applying Recommendations for Diagnostic Disclosure of Mild Cognitive Impairment and Dementia: Practical Guidance for Clinicians,” Drs. O'Brien, Largent, and Karlawish provide thoughtful guidance for addressing the complexities of AD/ADRD diagnostic disclosure to build clinicians’ confidence in effectively communicating diagnostic findings and a plan of care. The authors discuss many of the nuances required to compassionately and clearly deliver a summary of the patient's diagnosis, including the need to assess the patient's understanding and appreciation of symptoms, goals for the evaluation, and desire for information.

“Precision Diagnosis of Cognitive Impairment Due to Alzheimer Disease for Therapeutic Interventions” is focused on the increasingly targeted diagnostic assessments that are necessary in our current era of amyloid plaque–lowering monoclonal antibody therapies that call for a new paradigm of care which currently contains substantial real‐world proficiency, resource, access, health equity, and implementation gaps. Of course, biomarker evidence of cerebral amyloid is necessary, moving our clinical practices squarely into the 21st century. Yet not all biomarkers are created equal, and Dr. Knopman astutely advocates for (and we each agree with) quantitative amyloid PET as well as fluorodeoxyglucose (FDG)–PET in some (or many) cases in specialist settings. He also discusses the challenges of trying to dissociate multiple etiologies in some patients to better understand the primary drivers of symptoms—a critically important gap that still exists in our knowledge and expanding arsenal of AD/ADRD biomarkers and which further highlights the importance of a thorough, holistic and person‐centered clinical evaluation process to best care for persons living with AD/ADRD and related conditions.

In “Clinical Use of Biomarkers in the Era of Alzheimer Disease Treatments,” Drs. Vandevrede and Schindler provide a broad overview of molecular biomarkers focused largely on AD, including PET, CSF, and emerging BBMs. They adeptly discuss not only the evidence base for these tests, but also factors that influence accessibility, the possibilities of false‐positive or false‐negative results, and challenges in interpreting results. They also provide a few clinical pearls on how to choose a specific biomarker test in symptomatic patients (they reinforce the idea that biomarker testing is not recommended in cognitively unimpaired people) and how to disclose results.

Mr. Karneboge, Dr. Rostamzadeh, and the author team of “Facing the New Diagnostic and Treatment Options of Alzheimer's Disease—The Necessity of Informed Consent” tackle the very timely topic of the capacity for informed consent in persons with mild cognitive impairment (MCI). They mindfully discuss this capacity in general and focus additional attention on the capacity to make decisions about biomarker testing as well as about treatment with disease‐modifying therapies. They cover the concept of supported decision‐making and provide a review of instruments to assist in the assessment of decision‐making capacity.

In “Counseling and Disclosure Practices in Predictive Alzheimer's Disease Diagnostics: A Scoping Review,” Ms. Perry, Dr. Rostamzadeh, and colleagues examine the literature on this topic in people with MCI, subjective cognitive decline, or clinically unimpaired individuals with biomarkers indicating increased risk of clinical progression to dementia due to AD. They skillfully synthesize 61 articles of a variety of types that target counseling, disclosure, or post‐disclosure follow‐up (or more than one of these topics), highlighting the wide variety of approaches to this topic. Their findings call attention to the need to further develop comprehensive and standardized guidelines for counseling, disclosure, and post‐disclosure follow‐up in the context of AD biomarker testing.

In “Paving the Way for Alzheimer's Blood‐Based Biomarkers in Primary Care,” Drs. Erickson, Largent, and O'Brien prudently echo many points made by Dr. Bolton and colleagues and explain some steps they view as necessary to prepare for the incorporation of AD BBMs into primary care. They thoughtfully emphasize four immediate challenges: (1) preparing primary care providers to order and disclose AD BBMs (primarily the need for education and training as well as support resources), (2) expanding the dementia‐capable workforce (including by making nurse practitioners fully independent and by adding more social work resources), (3) ensuring equitable uptake of AD BBM testing (by addressing a variety of factors contributing to health disparities), and (4) securing access to AD treatment (by developing primary care‐specialty care collaborations to facilitate efficient access to disease‐modifying therapies).

The remaining article in this special issue is a summary of a workshop led by Drs. Wolk and Schneider: the “Clinical Criteria for Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy.” Limbic Predominant Age‐related TDP‐43 Encephalopathy Neuropathologic Change (LATE‐NC) is highly prevalent in late life and a common co‐neuropathological change observed in conjunction with AD neuropathologic change. LATE‐NC is usually observed along with a slowly progressive, amnestic clinical syndrome. With the emergence of amyloid plaque–lowering therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. This expert work group proposes criteria for clinical diagnosis of LATE as an initial framework with the need for further validation.

CONFLICT OF INTEREST STATEMENT

Bradford C. Dickerson: Consulting: Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Ilios, and Takeda, WaveLifeSciences. Data Safety and Monitoring Board (DSMB): Lilly, Merck. Royalties: Cambridge University Press, Elsevier, Oxford University Press, and Up To Date. Alireza Atri: Consulting: Acadia, Alzheimer's Association, AriBio, Axovant, AZ Therapies, Biogen, Eisai, Grifols, JOMDD, Lundbeck, Life Molecular Imaging, Merck, ONO, Prothena, Roche/Genentech, Novo Nordisk, Qynapse, and Vaxinnity. Independent DSMB: Roche/Genentech. Royalties: Oxford University Press. Author disclosures are available in the Supporting Information.

Supporting information

Supporting Information

Dickerson BC, Atri A. Introduction to the DETeCD‐ADRD special issue. Alzheimer's Dement. 2025;21:e14483. 10.1002/alz.14483