Alzheimer’s disease as a clinical-biological construct: recommendation of an international working group.

Antonio Javier Sutil presents in this article the most relevant data from the study “Alzheimer’s Disease as a Clinical-Biological Construct: Recommendations from an International Working Group”.

Modification of Alzheimer’s Diagnostic Criteria

Recently, the Alzheimer’s Association proposed a modification of Alzheimer’s diagnostic criteria to be based solely on biological evidence. This would allow for Alzheimer’s disease (AD) diagnoses in cognitively healthy individuals who present biomarkers. This could have a significant societal impact, as these newly proposed criteria are not recommended for cognitively healthy individuals, raising important new issues that need to be addressed.

On the one hand, this would have a significant impact on research environments. Evidence on associated biomarkers has been increasing in recent decades, enabling a paradigm shift from post-mortem research to studying the evolution of the disease from earlier stages. This change has not only fostered an increase in observational research but also in clinical trials, allowing for dynamic in vivo monitoring.

However, it would also have an impact on clinical settings, where the use of biomarkers is considered particularly relevant, as they are expected to provide information about pathological lesions or neurodegenerative processes.

Biomarkers in Alzheimer’s Disease

Nevertheless, the so-called primary biomarkers would not be sufficient on their own to explain all the underlying mechanisms of the disease. Particularly in clinical settings, biomarkers such as tau or amyloid would serve to support or refute a clinical suspicion of diagnosis due to the high heterogeneity of cases.

For instance, post-mortem studies have documented cases where an individual’s brain shows lesions, yet the person did not experience cognitive or functional decline in life. Additionally, due to the prevalence of comorbidities among neurodegenerative pathologies, the detection of new biomarkers could lead to confusion rather than clarification. This occurs because, according to the logic of the new criteria, such biomarkers could likely result in the diagnosis of multiple neurodegenerative diseases simultaneously in a cognitively normal individual.

This study argues that the influence of biomarkers depends on the context, as they alone cannot determine the disease. It is suggested that the contribution of biomarkers should be integrated with the clinical perspective, particularly to assess whether individuals present cognitive decline.

Consequently, this reviewed work proposes reconsidering the definition suggested by the Alzheimer’s Association. It also offers an alternative definition based on a clinical-biological construct to more accurately reflect the existing evidence on biomarkers.

Possible Cases

To more accurately address the perspective defended here, three possible cases with positive biomarkers and the recommended interpretations for each situation are presented.

Asymptomatic at Risk for Alzheimer’s Disease (ARAD)

This refers to cognitively normal individuals at risk of developing cognitive decline due to a specific biomarker profile. This risk of progression is higher compared to individuals without biomarkers. This case would not be considered Alzheimer’s, as it does not indicate a definitive future progression.

Associated biomarker profile: cerebral amyloidosis, either isolated or associated with tauopathy limited to medial temporal regions, or a positive p-tau (phosphorylated tau) biomarker in fluids.

Presymptomatic Alzheimer’s (PA)

This refers to cognitively normal individuals with a specific biomarker pattern associated with a very high, almost deterministic risk of progression. This subgroup could be redefined due to future studies identifying different biomarkers.

Examples of biomarker profiles associated with this case include:

• Highly penetrant autosomal dominant genetic variants with a near 100% lifetime risk of developing clinical Alzheimer’s disease: APP, PSEN1, PSEN2.
• Individuals with Down syndrome.
• Homozygous individuals for the APOE e4 allele combined with SORL1 loss of function. In these profiles, age and parental age are additional factors to consider for determining the onset age of clinical AD expression.
• Changes in sporadic AD biomarkers (± genetic background) associated with a very high lifetime risk of clinical AD, such as the combination of positive amyloid PET and positive tau PET in neocortical regions.

Alzheimer’s Disease (AD)

This refers to individuals with cognitive impairment who meet established criteria, potentially at a stage with functional loss (dementia) or at a prodromal stage where functionality has not yet been lost.

The established criteria are:

• Specific clinical phenotypes: common (hippocampal-type amnestic syndrome, logopenic aphasia, posterior cortical atrophy) or uncommon (corticobasal syndrome, behavioral and dysexecutive variants).
• Positive AD pathophysiological biomarkers in cerebrospinal fluid or PET. Plasma biomarkers, such as p-tau 217, may soon become part of routine clinical evaluation.

Summary Table of Differences Between the Two Proposals

	Alzheimer’s Association	International Working Group
Definition of Alzheimer’s Disease	Biology-based.	Based on clinical and biological criteria.
Clinical Diagnosis	Presence of a fundamental biomarker is required.	Biomarker and objective presence of cognitive deficits are required.
Example	A person with normal cognition and a fundamental biomarker is diagnosed with AD.	A person with normal cognition and a fundamental biomarker is considered at risk for AD.

The explanation for this mentioned classification is based on the pathophysiology of the amyloid cascade. This is a probabilistic model that postulates different levels of influence based on the APOEε4 gene combined with other environmental factors and pathologies.

In this model, gene carriers are identified as individuals at risk, suggesting that progression toward cognitive decline is related to the other mentioned factors. These at-risk individuals should be monitored in longitudinal cohorts to identify factors that might modulate progression toward dementia. On the other hand, individuals already progressing toward dementia could be identified.

Impact on Society

Alzheimer’s diagnostic criteria based on biomarkers could have a significant societal, political, and economic impact. This study advocates for a clinical-biological perspective, as labeling individuals with positive biomarkers as having Alzheimer’s disease or being asymptomatic at risk will influence the coping strategies adopted by institutions and individuals. The narrative generated around communicating these results will be critical for the patient experience.

A cognitively normal person with positive amyloid biomarkers could be interpreted as diseased, while such at-risk individuals might never develop cognitive decline.

A clear example is evident in drug use. For instance, an individual starting gantenerumab, a medication designed for amyloid removal, whose clinical effectiveness has not been demonstrated.

Would it be beneficial for this individual to take medication for years without certainty of progression or certainty of the medication’s effects on cognitive and behavioral aspects?

Additionally, potential diagnostic errors must be considered, as protein biomarkers, like in this case, do not offer deterministic distinctions like genetic ones but rather probabilistic ones. This is even more relevant considering that it could lead to significant regional differences, such as between North America and Europe.

A example of the impact would be diagnosing a patient who visits their doctor with benign memory complaints due to other conditions or age and who, with positive biomarkers, represents a false positive. This risk would increase if tests were directly marketed to consumers without a doctor’s intervention, likely leading to a higher incidence of diagnoses in cognitively normal people and, consequently, increased use of medications to prevent cognitive decline.

The Alzheimer’s Association criteria do not support the use of biomarkers in cognitively normal individuals, but controlling access to Alzheimer’s disease diagnosis and treatment based solely on biomarkers under these criteria is unrealistic. Therefore, a clearer message on this topic is necessary.

Conclusions and Relevance

The International Working Group advocates for defining Alzheimer’s disease as a clinical-biological entity. The clinical diagnosis of Alzheimer’s is made based on an established clinical phenotype and pathophysiological biomarkers indicating Alzheimer’s disease (AD) pathology, encompassing both prodromal phases (pre-dementia) and dementia stages, as these phases are part of the same disease continuum.

The International Working Group discourages the use of biomarkers to diagnose Alzheimer’s in cognitively normal individuals, even with subjective complaints. Instead, they suggest that these biomarkers be used in research to assess future risks, communicate those risks, and implement preventive strategies.

Studying cognitively normal individuals with positive biomarkers is key to developing predictive algorithms and determining progression risks. From this perspective, only a small group would be considered presymptomatic due to genetic variants or high-risk biomarker profiles, while the rest should be classified as asymptomatic at risk.

Future research should focus on cognitively normal individuals:

1. On the one hand, conducting longitudinal observational studies to simultaneously analyze biomarkers and lifestyle-related risk factors.
2. On the other hand, conducting interventional clinical trials to evaluate the effectiveness of pharmacological treatments and other strategies targeting Alzheimer’s disease.

Authors

This work is the result of an international collaborative effort by more than 40 authors. Among them, the first author, Bruno Dubois, stands out as a professor in the Department of Neurology at Salpêtrière Hospital and Sorbonne University in Paris. He is currently an associate researcher at the FrontLab group of the Paris Brain Institute, where he previously served as principal investigator. The FrontLab group focuses on studying the prefrontal cortex as a critical region for higher cognitive functions in health and disease. Additionally, Professor Dubois has published numerous studies on subcortical diseases and dementia and is one of the organizers of the expert consensus working on new diagnostic criteria for Alzheimer’s disease.

References

• Dubois B, Villain N, Schneider L, et al. Alzheimer’s Disease as a Clinical-Biological Construct—An International Working Group Recommendation. JAMA Neurol. Published online November 01, 2024. doi:10.1001/jamaneurol.2024.3770

If you enjoyed this blog post about Alzheimer’s disease as a clinical-biological construct: recommendation from an international working group, you may be interested in these NeuronUP articles: