New Alzheimer's disease guidelines focus on risk, not diagnosis, in healthy adults

Latest Alzheimer's disease guidelines aim to reduce misdiagnosis by focusing on at-risk individuals and empowering clinicians and patients to make informed decisions about cognitive health and preventive care .

Special communication: Alzheimer's disease as a clinical biological construct—recommendations of an international working group. Image credit: Shutterstock AI

In 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 believe that individuals who are cognitively normal but positive for Alzheimer's disease biomarkers should not be diagnosed with Alzheimer's disease, avoiding potentially distressing or unnecessary labeling and potentially developing symptoms. They concluded that they should rather be classified as “at risk” in order to focus on people with high risk.

background

The Alzheimer's Association (AA)'s latest criteria propose defining Alzheimer's disease based solely on the presence of certain biological markers, such as a specific ratio of amyloid-beta and tau in the cerebrospinal fluid. 217 Alzheimer's disease can be diagnosed in cognitively normal individuals if they have the core Alzheimer's disease biomarkers (CSF) or plasma phosphorylated tau (p-tau), 217 and amyloid positron emission. Confirmed by tomography (PET) imaging.

However, these standards do not recommend routine behavior. biomarker Testing in cognitively normal individuals has raised concerns about the role and impact of biomarkers in the diagnosis of Alzheimer's disease. In response to these criteria, IWG researchers provided updated recommendations based on a literature review, emphasizing a clinical biological approach rather than solely biomarker-based definitions.

The value of biomarkers

The 2007 IWG criteria introduced the use of biomarkers to improve the accuracy of AD diagnosis in patients with cognitive impairment. Since then, biomarkers have been validated and incorporated into the diagnostic process, particularly in research and clinical trials. Although these biomarkers enable real-time monitoring of pathological changes, they are insufficient to fully represent the complexity of Alzheimer's disease, as they primarily signal risk rather than confirming a definitive diagnosis.

Clinically, biomarkers are used to support or exclude a suspected diagnosis of Alzheimer's disease, but multiple neurodegenerative pathologies often coexist, complicating the diagnosis of a single disease. Biomarkers should be carefully and contextualized, especially in cognitively normal individuals. For this reason, the IWG asserts that biomarkers should indicate pathological processes and not simply define specific diseases.

Contribution of biomarkers in cognitively impaired patients

According to the IWG, the combination of specific clinical phenotypes (common phenotypes, such as amnestic syndrome, and rare phenotypes, such as corticobasal syndrome) and amyloid- and tau-positive biomarkers can reduce Alzheimer's disease clinically. It is defined as a biological entity, consistent with the classical description of Alois Alzheimer's disease.

This approach allows for early diagnosis at 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 differ in their approach to cognitively normal individuals, making it difficult to make a purely biological diagnosis. is still disputed.

Contribution of biomarkers in cognitively normal individuals

Research believes that amyloid clearance, similar to treatment for vascular risk, may reduce future cognitive impairment, and early intervention is being pursued for those at risk. However, in clinical practice, diagnosing AD in cognitively normal individuals based solely on biomarkers (as suggested by the revised AA criteria) remains difficult, especially when the lifetime risk of developing symptoms remains low. Sporadic cases raise ethical and practical concerns.

The IWG approach proposes classifying cognitively normal individuals with biomarkers into two groups: (1) those “at risk” for AD, who have a high but uncertain risk of developing symptoms; and (2) people who are on the AD pathway before symptoms appear. Unavoidable based on advanced biomarker profile. By differentiating between these groups, this framework allows for customized management and further investigation of potential modulators that influence progression.

Pathophysiological framework

The stochastic amyloid cascade model modifies the traditional cascade by suggesting a range of risks based on genetic and environmental factors. This model shows that the likelihood of developing AD symptoms increases from autosomal dominant mutations (nearly complete penetrance) to apolipoprotein (APOEε4) carriers (moderate risk) and non-carriers (lowest risk), due to additional factors such as non-APOE genes. ). and environmental exposure.

This model shows that cerebral amyloidosis in cognitively normal individuals is a risk factor for dementia, especially in APOEε4 carriers. The IWG suggests that using amyloid, tau, and other biomarker data in combination with personal factors can better estimate risk and support Alzheimer's disease diagnosis in symptomatic individuals. .

social impact

The distinction between classifying cognitively normal individuals positive for Alzheimer's disease biomarkers as asymptomatic, at risk, or already suffering from the disease influences management strategies. The IWG believes that diagnosing AD in individuals who are unlikely to develop symptoms can lead to significant psychological stress and potentially harmful social consequences, and that these nuances cannot be effectively communicated. I emphasize that it is important.

Routine diagnostic testing is clearly not recommended in this population, and biomarkers may be considered risk indicators rather than definitive diagnoses.

The Future: Defining Risk in Cognitively Normal Individuals

The IWG proposes a conceptual framework that distinguishes between asymptomatic at-risk individuals and Alzheimer's disease patients, highlighting the need for research focused on the former group. The IWG suggests that genetic, biomarker, lifestyle, and resilience factors need to be considered to understand the cumulative risk of progression to cognitive impairment in these individuals.

Creating an accurate risk profile is considered essential. The task force is working on practical solutions such as brain health services for dementia prevention, focusing on risk assessment, communication, and interventions targeting modifiable risk factors.

conclusion

In conclusion, the IWG advocates AD as a clinical-biological entity, and diagnosis integrates clinical phenotype and ancillary biomarkers. Although most biomarker-positive individuals should be classified as asymptomatic at risk, only a small subset are considered presymptomatic due to genetic factors or high-risk profile.