Header: How to handle people who are positive for Alzheimer biomarkers, but negative for symptoms?
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In June 2024, a big spash in publishing Alzheimer's Association Workgroup criteria for the diagnosis and staging of Alzheimer's disease. See Jack et al., in the journal Alzheimer's and Dementia. This concensus article prioritized the rapid increase in precision and publications for Alzheimer proteomics, especially plasma biomarkers which had been a "Holy Grail" in this field for thirty years.
But November 2024, see another big splash from the "International Working Group" and published in JAMA Neurology. This one is Dubois et al., which opens by acknowledging the status of the "Alzheimer's Association Workgroup" by highlights some disagreements coming from these authors, the "International Working Group."
The IWG recommends a category of "at risk for Alzheimer's" for the earliest phases where only 1 biomarker is positive and the evolution is still uncertain (at least, within a reasonable clinical forecast). The IWG still maintains a diagnosis of "presymptomatic Alzheimer's disease" but requires an escalation in biomarkers past the minimum.
See the new consensus article from IWG as Dubois et al. in JAMA Neurology here. See an Op Ed by Peterson et al. here. See coverage at Precision Medicine Online here.
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For those who'd like to read more, here, this is an extended quotation from Peterson et al.
[IWG] contend that persons who possess varying degrees of biomarker positivity but are clinically unimpaired do not warrant a label of AD. They emphasize that specific risks factors (eg, age, ApoEe4 genotype) and biomarkers (ie, degree of positivity) will alter age of onset and lifetime risk. Therefore, the IWG specifically recommends the nomenclature of at risk for AD for those with AD biomarkers but low lifetime risk and presymptomatic AD for those with AD biomarkers with a very high lifetime risk of progression.
A major issue of contention between the 2 groups pertains to the issue of the basic definition of AD. The AA group states that because most people who have positive core 1 biomarkers, such as a positive amyloid PET scan, also have intermediate to high AD neuropathological changes in the brain, the core 1 biomarkers represent both plaques and tangles. The IWG group does not accept this rationale, suggesting the core 1 biomarkers may only represent amyloid positivity, and many asymptomatic persons who are positive for amyloid (A+) will never develop clinical symptoms.
The IWG provides important considerations in an era of early detection and increasing knowledge of lifetime risk of symptoms. Nonetheless, a key element in the 2 positions pertains to the semantics of the term AD, ie, is AD a biologic entity or a clinical-biologic entity?
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AI Corner
In addition to the long quote above, and the original sources, here is an AI summary of Dubois and Peterson.
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The new Dubois consensus article from the International Working Group (IWG) advocates for a nuanced, clinical-biological framework for Alzheimer’s disease (AD) that avoids premature diagnosis in asymptomatic individuals. The IWG’s new criteria emphasize a separation between “asymptomatic at risk” (one biomarker, no cognitive symptoms) and “presymptomatic Alzheimer’s disease” (more biomarkers with a higher risk of progression to AD symptoms). They argue that the earlier Alzheimer Association (AA) approach, which allowed for a biological diagnosis based on a single biomarker, risks overdiagnosing cognitively normal individuals who may never progress to symptomatic AD. By setting a higher biomarker threshold for "presymptatomic" AD diagnosis, IWG aims to prevent the potential psychological and societal impacts of labeling individuals with AD before clear clinical signs appear and in whom disease evolution is uncertain, e.g. at risk.
The Peterson op-ed works to balance the AA and the IWG perspectives, acknowledging the benefits of early biomarker use in AD research while critiquing the risks highlighted by the IWG. Peterson acknowledges IWG’s concerns over labeling asymptomatic individuals as having AD but also underscores the need for accessible biomarker data in research. The op-ed raises the question of whether AD should be treated purely as a biological condition or as a clinical-biological syndrome, stressing that clearer guidelines for clinical application are necessary to bridge biological frameworks with real-world practice. Both articles agree on the potential of biomarkers in establishing the disease’s pathology and recognize a need for caution in applying these biomarkers clinically, but they differ on how liberally biomarkers should be used to label asymptomatic individuals
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Finally, I next asked Chat GPT for a more nuanced and academic review of the articles.
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Title:
Revisiting Alzheimer’s Diagnostic Criteria: Perspectives from the Dubois IWG Framework and the Peterson Op-Ed
Abstract
The recent recommendations by the International Working Group (IWG), led by Bruno Dubois, challenge the Alzheimer Association’s (AA) approach to the presymptomatic diagnosis of Alzheimer’s disease (AD), advocating for a revised clinical-biological framework. While the AA criteria emphasize a more biologically grounded diagnosis, the IWG framework stresses a cautious approach to applying diagnostic labels in asymptomatic individuals. This article explores the nuanced differences between these perspectives, drawing on the Dubois et al. paper and the Peterson et al. editorial commentary to outline implications for clinical practice and future AD research.
Introduction
Alzheimer’s disease (AD) diagnosis has evolved significantly with the advent of sensitive biomarkers, creating the potential to identify pathology years before clinical symptoms arise. Historically, AD diagnosis has been reserved for those presenting with cognitive impairment and neuropathological findings. However, with increasing reliance on biomarkers, earlier identification in asymptomatic individuals is now possible, prompting a debate within the research and clinical communities. The IWG, in its recent Dubois-led recommendations, argues for a stringent bifurcation in diagnostic categories, emphasizing risk assessment rather than direct labeling of AD in asymptomatic individuals. In response, the Peterson et al. editorial provides critical insights into the advantages and challenges of the IWG’s clinical-biological stance.
Methodological Foundations and Perspectives of Dubois et al.
In their recommendations, Dubois and colleagues advocate a clinical-biological construct for diagnosing AD, distinguishing between asymptomatic individuals at risk and presymptomatic AD based on specific biomarker thresholds. This new framework reflects an increased caution in directly labeling cognitively unimpaired, biomarker-positive individuals as having AD. The IWG defines:
Asymptomatic at Risk for Alzheimer’s Disease: This category includes cognitively normal individuals who display only one AD biomarker, typically indicating amyloidosis. Dubois et al. argue that while amyloid positivity may elevate lifetime AD risk, it does not justify an AD diagnosis in the absence of symptoms.
Presymptomatic Alzheimer’s Disease: This category applies to cognitively normal individuals with a higher combination of AD biomarkers, which, the IWG posits, confers a near-deterministic risk of symptomatic progression. This group often includes individuals with biomarker profiles showing both amyloid and tau positivity across cortical and medial temporal regions or those carrying high-risk genetic mutations, such as autosomal-dominant AD variants.
The IWG justifies this approach by reviewing longitudinal studies and biomarker validation efforts, suggesting that the lifetime risk in biomarker-positive, asymptomatic individuals is heterogeneous. The IWG also considers factors like comorbid neuropathologies (e.g., Lewy bodies, TDP-43), resilience mechanisms, and other patient-specific variables that may influence disease progression. These complexities, they argue, necessitate a conservative approach to presymptomatic AD diagnosis to avoid mislabeling individuals with indeterminate risk profiles.
Peterson et al. Op-Ed: A Response to the IWG Framework
In their editorial, Peterson and colleagues address key elements of the IWG's recommendations, framing the AD diagnostic debate within the context of evolving medical nomenclature and societal considerations. Peterson et al. appreciate the IWG's emphasis on maintaining a clinical-biological basis for AD but argue that the cautionary stance on labeling cognitively normal, biomarker-positive individuals may lean overly conservative.
Peterson critiques the IWG’s concerns on two primary grounds:
Semantics and the Definition of Disease: Peterson questions the IWG's restrictive interpretation of AD, noting that the AA’s biological framework aligns with evolving definitions in other medical fields, such as oncology, where presymptomatic stages (e.g., in situ cancers) are routinely identified. They suggest that the IWG’s clinical-biological model may conflate risk status with disease status, arguing that the term "Alzheimer’s disease" could encompass those with high biomarker positivity even in asymptomatic stages, potentially benefiting from early intervention and lifestyle modifications.
Risk and Benefit of Early Diagnosis: While the IWG emphasizes the potential psychological harm of labeling asymptomatic individuals with AD, Peterson calls for a more evidence-based assessment of this impact. The editorial suggests that knowledge of AD biomarker status could empower individuals to make proactive lifestyle changes, citing analogies from cardiovascular and oncological care. However, Peterson et al. support the IWG’s reservations regarding direct-to-consumer testing and emphasize the need for rigorous guidance in clinical application to mitigate misuse or misinterpretation of biomarker data.
Implications for Clinical Practice
The distinctions between these perspectives underscore a significant shift in AD diagnostic frameworks and their applications. The IWG’s model emphasizes differential risk stratification, proposing that biomarkers in cognitively normal individuals be used primarily for risk assessment rather than definitive AD diagnosis. This model posits that asymptomatic amyloid- or tau-positive individuals be categorized as “at risk” rather than diagnosed with AD, unless multiple biomarkers confirm a high, near-deterministic risk.
Peterson et al., however, support a more integrative approach to AD pathology, suggesting that high biomarker positivity alone may sufficiently justify an AD diagnosis in asymptomatic individuals, provided there are clinical protocols to safeguard patient welfare and interpret biomarker status within a probabilistic framework. They propose that the field may be better served by embracing a flexible model that encompasses both biological and clinical entities of AD, potentially allowing for earlier pharmacologic and non-pharmacologic interventions under monitored conditions.
Research Implications and Future Directions
The IWG's recommendations, if adopted, may influence future research by shifting focus from early diagnosis in asymptomatic individuals toward risk assessment studies in genetically or biomarker-predisposed populations. These studies could clarify the impact of amyloid and tau burden in predicting clinical outcomes and identify secondary risk factors modulating AD progression. Moreover, population-based cohort studies and trials may need to adapt to incorporate broader definitions of AD risk, including lifestyle, genetic, and resilience factors, to refine individual patient profiles and therapeutic targets.
Conversely, Peterson’s stance implies that research should not exclude biomarker-positive individuals from AD diagnostic categorization but rather adapt clinical criteria to accommodate evolving evidence about biomarker impact. This stance suggests a need for appropriate-use criteria for biomarkers, potentially establishing a consensus on which asymptomatic biomarker profiles warrant closer clinical monitoring and preventive intervention trials.
Conclusion
Both the IWG and Peterson et al. converge on the necessity for biomarker integration in AD diagnosis but diverge on the semantics and clinical application of AD labels in cognitively normal individuals. The IWG’s clinical-biological construct provides a conservative, risk-focused approach, reserving AD diagnosis for individuals with tangible clinical symptoms or robust, near-deterministic biomarker evidence. Peterson et al., however, argue for a more inclusive diagnostic model, emphasizing that early biomarker identification could offer preventive insights and treatment benefits.
The ongoing debate highlights a critical need for appropriate-use frameworks and consensus definitions in AD diagnosis, where both risk stratification and early intervention paradigms must be balanced. As biomarker technologies advance, a unified, patient-centered approach that addresses both scientific rigor and clinical pragmatism will be essential in shaping the future of AD diagnosis and care.
This synthesis draws from the detailed perspectives of both papers, translating their recommendations into actionable insights for AD diagnostic criteria. By framing AD as both a clinical and biological entity, these articles invite further exploration into how best to integrate biomarkers into nuanced, real-world applications.
