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

Updated Alzheimer’s guidelines aim to reduce misdiagnoses by focusing on at-risk individuals, helping clinicians and patients make informed decisions about cognitive health and preventive care.

Special Communication: Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation. Image Credit: Shutterstock AISpecial Communication: Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation. Image Credit: Shutterstock AI

In a recent study published in JAMA Neurology, researchers 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 distressing or unnecessary labeling and to focus on those at a higher likelihood of developing symptoms.

Background

The Alzheimer’s Association’s (AA) updated criteria suggest defining AD based solely on the presence of specific biological markers, allowing for an AD diagnosis in cognitively normal people if they have core AD biomarkers, such as specific ratios of amyloid β and tau in cerebrospinal fluid (CSF) or plasma phosphorylated tau (p-tau) 217, confirmed by amyloid positron emission tomography (PET) imaging.

However, these criteria recommend 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, researchers from the IWG have provided updated recommendations based on a literature review, emphasizing a clinical-biological approach rather than a biomarker-based definition alone.

The value of biomarkers

The 2007 IWG criteria introduced biomarker use to enhance 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 enable real-time monitoring of pathological changes, yet, on their own, they are insufficient to fully represent the complexity of AD, as they primarily signal risk rather than confirm a definitive diagnosis.

Clinically, biomarkers are used to either support or rule out a suspected AD diagnosis, yet they must be carefully contextualized, particularly in cognitively normal individuals, as multiple neurodegenerative pathologies often coexist, complicating single-disease diagnostics. For this reason, IWG asserts that biomarkers should indicate pathological processes but not solely define specific diseases.

Contribution of biomarkers in patients with cognitive impairment

The combination of specific clinical phenotypes (common ones like amnestic syndrome and rare ones like corticobasal syndrome) with positive amyloid and tau biomarkers defines AD as a clinical-biological entity according to the IWG, aligning with the classical description of Alois Alzheimer’s work.

This approach allows for early diagnosis during the prodromal stage, supporting the FDA’s recent approval of anti-amyloid drugs for early AD. While the IWG and AA criteria agree in diagnosing AD in symptomatic individuals with biomarkers, they diverge in their approach to cognitively normal individuals, where a purely biological diagnosis remains contested.

Contribution of biomarkers in cognitively normal individuals

In research, early intervention is pursued for those at risk, with amyloid clearance seen as potentially reducing future cognitive impairment, similar to treating vascular risks. However, in clinical practice, diagnosing AD in cognitively normal individuals solely based on biomarkers (as suggested by revised AA criteria) presents ethical and practical concerns, especially for sporadic cases where the lifetime risk of developing symptoms remains low.

The IWG approach proposes that cognitively normal individuals with biomarkers are categorized into two groups: (1) "at risk" for AD with an increased but uncertain risk of symptom development, and (2) those on a presymptomatic AD path, where symptoms may be inevitable based on advanced biomarker profiles. By distinguishing these groups, this framework allows tailored management and further research into potential modulating factors that influence 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 nearly complete penetrance) to apolipoprotein (APOEε4) carriers (intermediate risk) and non-carriers (lowest risk) due to additional factors, such as non-APOE genes and environmental exposures.

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 estimate risk and support AD diagnosis in symptomatic individuals.

The societal 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, as diagnosing AD in individuals unlikely to develop symptoms can lead to significant psychological stress and potentially detrimental societal consequences.

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

The future: Defining the risk in cognitively normal individuals

The IWG proposes a conceptual framework that differentiates asymptomatic at-risk individuals from those with AD, emphasizing the need for research focused on the former group. IWG suggests that understanding the cumulative risk of progression to cognitive impairment in these individuals requires consideration of genetic, biomarker, lifestyle, and resilience factors.

Developing an accurate risk profile is deemed essential. Task forces are working on practical solutions, such as Brain Health Services for Dementia Prevention, which will focus on risk evaluation, communication, and interventions targeting modifiable risk factors.

Conclusion

In conclusion, the IWG advocates for AD as a clinical-biological entity, where a diagnosis integrates clinical phenotypes with supportive biomarkers. Most biomarker-positive individuals should be classified as asymptomatic at risk, with only a small subset considered presymptomatic due to genetic factors or high-risk profiles.

Journal reference:
Dr. Sushama R. Chaphalkar

Written by

Dr. Sushama R. Chaphalkar

Dr. Sushama R. Chaphalkar is a senior researcher and academician based in Pune, India. She holds a PhD in Microbiology and comes with vast experience in research and education in Biotechnology. In her illustrious career spanning three decades and a half, she held prominent leadership positions in academia and industry. As the Founder-Director of a renowned Biotechnology institute, she worked extensively on high-end research projects of industrial significance, fostering a stronger bond between industry and academia.  

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