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

Modification of the diagnostic criteria for Alzheimer’s disease

Recently, from the Alzheimer’s Association, the modification of the diagnostic criteria for Alzheimer’s disease has been proposed so that they are based solely on biological evidence. This would imply the possibility of making diagnoses of Alzheimer’s disease (AD) in cognitively healthy people who present biomarkers. This could have a great impact on society, since at the same time, these new proposed criteria are not recommended for cognitively healthy people, which raises new and important questions that must be resolved.

On one hand, this would have a great impact on research settings. The evidence on associated biomarkers has increased in recent decades, which has allowed a paradigm shift from postmortem research to the possibility of studying the disease progression from earlier stages. This change has not only favored an increase in observational research, but also in clinical trials, enabling dynamic in vivo monitoring.

However, this would also have an impact in clinical settings, where the use of biomarkers is considered especially relevant, since they are expected to provide information about pathological injury or the neurodegenerative process. 

Biomarkers in Alzheimer’s disease

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

For example, postmortem studies have documented cases in which the individual’s brain shows lesions, but they had not experienced cognitive or functional impairment in life. Furthermore, due to the prevalence of comorbidities among neurodegenerative pathologies, the detection of new biomarkers could end up confusing rather than clarifying. This happens because, according to the logic of the new established criteria, it is likely that such biomarkers will lead to the diagnosis of multiple neurodegenerative diseases simultaneously in a cognitively normal person.

This work argues that the influence of biomarkers would depend on the context, since these alone cannot determine the disease. It is suggested that the contribution of biomarkers should be integrated with the clinical perspective, especially to assess whether individuals present cognitive impairment or not.

Consequently, what is proposed in this reviewed work is to reconsider the definition suggested by the Alzheimer’s Association. Likewise, an alternative definition based on a clinical-biological construct is offered that seeks to more precisely fit the existing evidence on biomarkers.

The possible cases

To be able to address more precisely the perspective defended here, we will start from the three possible cases in which positive biomarkers have been obtained, and how it is recommended to interpret each of the situations.

Asymptomatic at risk for Alzheimer’s disease (ARA)

Refers to cognitively normal individuals who present a risk of developing cognitive impairment 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 disease, since it is not an index that determines future progression. 

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

Presymptomatic Alzheimer’s (PA)

Refers to cognitively normal individuals who present a specific pattern of biomarkers associated with a very high, almost deterministic risk of progression. This subgroup could be redefined by future studies that identify distinct biomarkers.

Examples of biomarker profiles associated with this case are:

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

Alzheimer’s disease (AD)

Refers to individuals with cognitive impairment who meet established criteria, who may be at a stage with loss of functionality (dementia) or at a prodromal stage where functionality has not 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 pathophysiological AD biomarkers in cerebrospinal fluid or PET. Plasma biomarkers, such as p-tau 217, could 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	Based on biology.	Based on clinical criteria and biology.
Clinical diagnosis	The presence of a core biomarker is required.	Biomarker and objective presence of cognitive deficit are required.
Example	A person with normal cognition and a core biomarker will be diagnosed as AD.	A person with normal cognition and a core biomarker will be considered at risk of developing 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 depending on the APOEε4 gene together with other environmental factors and pathologies.

In this model, carriers of that gene would be identified as individuals at risk and it suggests that progression toward cognitive impairment is related to the other factors mentioned. These individuals at risk should be followed in longitudinal cohorts to identify factors that may modulate progression toward dementia. On the other hand, individuals already on a path toward dementia could be identified.

Effect on society

Biomarker-based diagnostic criteria for Alzheimer’s could have a major social, political, and economic impact. This work defends the clinical-biological view, since the consideration of labeling biomarker-positive individuals as having Alzheimer’s disease or as asymptomatic at risk will influence coping strategies adopted by institutions and individuals. The narrative generated around the communication of these results will be crucial for the patient’s experience.

A cognitively normal person with positive amyloid biomarkers could be interpreted as ill, while these at-risk individuals might never develop cognitive impairment.

A clear example is visible in the taking of drugs. For example, an individual who begins taking gantenerumab, a medication designed for the removal of amyloid, but whose clinical effectiveness has not been demonstrated.

Would it be beneficial for this individual to receive medication for years without being sure that there will be progression, or without certainty that this medication has effects on cognitive and behavioral aspects?

In addition to this, the potential diagnostic error should be considered, since protein biomarkers, as in this case, do not offer a deterministic distinction like genetic markers, but a probabilistic one. This is even more relevant if we think that it could lead to significant differences between regions such as North America and Europe.

An example of the impact would be the diagnosis of a patient who visits their doctor with benign memory complaints due to other disorders or to age, and who, with positive biomarkers, would represent a false positive. This risk would increase if tests were marketed directly to consumers without the intervention of a physician, which could lead to a likely increase in the incidence of diagnoses in cognitively normal people and, therefore, to greater consumption of medications to prevent cognitive decline.

The Alzheimer’s Association criteria do not endorse the use of biomarkers in cognitively normal people, but it is unrealistic to control access to the diagnosis of Alzheimer’s disease and to treatment if it is based solely on biomarkers according to those criteria. Therefore, a clearer message on this matter would be necessary.

Conclusions and relevance

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

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

The study of cognitively normal people with positive biomarkers is key to developing predictive algorithms and determining risks of progression. From this point of view, 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 people:

1. On the one hand, by conducting longitudinal observational studies to simultaneously analyze biomarkers and lifestyle-associated risk factors.
2. And on the other hand, by conducting intervention clinical trials that evaluate the effectiveness of pharmacological treatments and other strategies targeted at Alzheimer’s disease.

Authors

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

Bibliography

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

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“This article has been translated. Link to the original article in Spanish:”
La enfermedad de alzheimer como constructo clínico-biológico: recomendación de un grupo de trabajo internacional