The updated Alzheimer’s disease guidelines aim to reduce the number of misdiagnoses by focusing on individuals at risk and helping doctors and patients make informed decisions about cognitive health and preventive care.
Special communication: Alzheimer’s disease as a clinical-biological construct – a recommendation from an international working group. Image credits: Shutterstock AI
From a recent study published in JAMA Neurologyresearchers from the International Working Group (IWG) reviewed the literature and proposed updated diagnostic criteria for Alzheimer’s disease (AD). They concluded that individuals who are cognitively normal but positive for AD biomarkers should not be diagnosed with AD, but rather classified as “at risk” to avoid potentially troubling or unnecessary labeling and to focus on those more likely on developing symptoms.
Background
The updated Alzheimer’s Association (AA) criteria suggest defining AD based solely on the presence of specific biological markers, allowing an AD diagnosis in cognitively normal people if they have core AD biomarkers, such as specific ratios of amyloid β and tau in the cerebrospinal fluid. CSF) or plasma phosphorylated tau (p-tau) 217, confirmed by amyloid positron emission tomography (PET) imaging.
However, these criteria advise against routine biomarker testing in cognitively normal individuals, raising concerns about the role and impact of biomarkers in diagnosing AD. In response to these criteria, IWG researchers have provided updated recommendations based on a literature review, focusing on a clinical biology approach rather than just a biomarker-based definition.
The value of biomarkers
The 2007 IWG criteria introduced the use of biomarkers to improve the accuracy of AD diagnosis in patients with cognitive deficits. Since then, biomarkers have been validated and incorporated into diagnostic processes, especially for research and clinical trials. These biomarkers allow real-time monitoring of pathological changes, but by themselves are insufficient to fully capture the complexity of AD because they primarily signal risk and do not confirm a definitive diagnosis.
Clinically, biomarkers are used to support or rule out a suspected AD diagnosis, but they must be carefully contextualized, especially in cognitively normal individuals, as multiple neurodegenerative pathologies often coexist, complicating the diagnosis of single diseases. For this reason, IWG claims that biomarkers should indicate pathological processes, but not only define specific diseases.
Contribution of biomarkers in patients with cognitive disorders
The combination of specific clinical phenotypes (common phenotypes such as amnestic syndrome and rare ones such as corticobasal syndrome) with positive amyloid and tau biomarkers defines AD as a clinical-biological entity according to the IWG, in line with the classic description of Alois’ work Alzheimer’s.
This approach allows early diagnosis during the prodromal stage, supporting the recent FDA approval of anti-amyloid drugs for early AD. Although the IWG and AA criteria agree in diagnosing AD in symptomatic individuals with biomarkers, they diverge in their approach to cognitively normal individuals, with a purely biological diagnosis remaining contested.
Contribution of biomarkers in cognitively normal individuals
Research is pursuing early intervention for those at risk, viewing amyloid clearance as potentially reducing future cognitive impairment, similar to treating vascular risk. However, in clinical practice, diagnosing AD in cognitively normal individuals based solely on biomarkers (as suggested by revised AA criteria) poses ethical and practical difficulties, especially for sporadic cases where the lifetime risk of developing symptoms is low stays.
The IWG approach proposes that cognitively normal individuals with biomarkers be classified into two groups: (1) “those at risk” for AD with an increased but uncertain risk of symptom development, and (2) those on a presymptomatic AD pathway where symptoms may be present. inevitably based on advanced biomarker profiles. By distinguishing these groups, this framework allows for tailored management and further investigation of potential modulatory factors influencing progression.
The pathophysiological framework
The probabilistic amyloid cascade model revises the traditional cascade by suggesting a spectrum of risk based on genetic and environmental factors. The model proposes that the likelihood of developing AD symptoms decreases from autosomal dominant mutations (with almost complete penetrance) to apolipoprotein (APOEε4) carriers (intermediate risk) and non-carriers (lowest risk) due to additional factors, such as non-APOE genes. and environmental exposure.
This model indicates that brain amyloidosis in cognitively normal individuals is a risk factor for dementia, especially for APOEε4 carriers. The IWG suggests that using combined amyloid, tau and other biomarker data, along with personal factors, can better assess risk and support the diagnosis of AD in symptomatic individuals.
The social impact
The distinction between labeling cognitively normal individuals with positive AD biomarkers as asymptomatic, at risk, or already affected by the disease influences management strategies. The IWG emphasizes that effective communication of these nuances is crucial because diagnosing AD in individuals who are unlikely to develop symptoms can lead to significant psychological distress and potentially harmful societal consequences.
Routine diagnostic testing is specifically not recommended in this population, and biomarkers may be considered risk indicators rather than definitive diagnosis.
The future: Defining risk in cognitively normal individuals
The IWG proposes a conceptual framework that distinguishes asymptomatic at-risk patients from those with AD, emphasizing the need for research that focuses on the former group. IWG suggests that understanding the cumulative risk of progression to cognitive impairment in these individuals should take into account genetic, biomarker, lifestyle and resilience factors.
Developing an accurate risk profile is considered essential. Task forces are working on practical solutions, such as Brain Health Services for Dementia Prevention, which will focus on risk assessment, communication and interventions targeting modifiable risk factors.
Conclusion
In conclusion, the IWG advocates AD as a clinical-biological entity, where a diagnosis integrates clinical phenotypes with supporting biomarkers. Most biomarker-positive individuals should be classified as asymptomatic and at risk, with only a small subset considered presymptomatic due to genetic factors or risk profiles.