Recommendations from IWG stress importance of merging clinical and biomarker criteria

A diagnosis of Alzheimer’s disease (AD) should be made only in individuals with positive biomarkers and specific AD phenotypes, whereas individuals who are biomarker-positive but without cognitive impairment should only be considered at-risk for progression to AD, according to recommendations from the International Working Group (IWG).

“In 2018, the US National Institute on Aging and the Alzheimer’s Association proposed a purely biological definition of Alzheimer’s disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice,” wrote IWG authors, led by joint first authors Bruno Dubois, MD, and Nicolas Villain, MD, both of the Assistance Publique-Hôpitaux de Paris (AP–HP), France.

“For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity,” they added.

In a “Personal View” article published in Lancet Neurology, IWG authors presented their recommendations for biomarker use for the diagnosis of AD in a clinical setting. Based on their review of articles published between Jan. 1, 2018, and July 1, 2020, in PubMed, the IWG recommendations for the clinical diagnosis of AD include the following:

  1. A diagnosis of AD requires both phenotype positivity and biomarker evidence of AD pathology, including amyloid and tau positivity.
  2. Specific phenotypes of AD that are commonly associated with disease pathology include the following: typical, posterior cortical atrophy, and logopenic variant primary progressive aphasia. Less common AD-pathology-associated phenotypes include the behavioral, corticobasal, and primary progressive aphasia variants.
  3. In patients with common AD phenotypes, positivity for amyloid and tau biomarkers establishes a diagnosis of AD, and both are required.
  4. The recommended biomarker measures for amyloid β pathology include low CSF Aβ42, an increased CSF Aβ40-Aβ42 ratio, or amyloid PET evidence of high tracer retention. For tau pathology, recommended biomarkers include high CSF phosphorylated tau or tau PET evidence of increased ligand retention. The authors noted, however, that “Recommendation for amyloid PET and tau PET for use in clinical practice is conditional on regulatory approval and reimbursement by payers in different countries.”
  5. A diagnosis of AD must include expert assessment of clinical and biomarker results. When results of these assessments come close to cutoff points, a different work-up approach is recommended, such as repeat biomarker measurement, clinical follow-up, or testing using biomarkers of neurodegeneration such as 18F-fluorodeoxyglucose-PET.
  6. The priority rests on CSF investigation because it not only provides simultaneous information on amyloid β and tau but is also less expensive than amyloid or tau PET or both. In patients in whom lumbar puncture is contraindicated, PET is a viable alternative.
  7. The use of plasma biomarkers for amyloid β and tau pathology are promising but not currently recommended.
  8. In patients without cognitive impairment, testing for pathophysiologic biomarkers is not recommended, as they are poor predictors of future clinical manifestations of AD.
  9. Risk stratification of absolute risk is recommended if biomarker testing is done in patients with no cognitive impairments.
  10. “Subjective memory complaints and subjective cognitive decline, if isolated and not supported by objective cognitive impairment, are not specific enough to be considered part of the Alzheimer’s disease phenotype,” wrote Dubois, Villain, and co-authors.
  11. Because AD is often associated with other neurologic diseases and AD lesions may exist as co-pathologies in patients with other neurodegenerative diseases, biomarker positivity is not enough for a diagnosis of AD. Rather, clinicians should rely on phenotyping and follow-up for a final diagnosis, knowing that in some cases, post-mortem evaluation may be the only definitive test.
  12. Clinicians must individualize biomarker testing in symptomatic patients objectively, considering risks of comorbidity, phenotype, life context, patients’ wishes, possible clinical trial enrolled, and many other clinical and personal factors.
  13. When biomarker testing is unavailable, clinicians can arrive at a clinical syndromic diagnosis to which staging can still be applied. “If a positive neurodegeneration biomarker (e.g., ¹⁸F-fluorodeoxyglucose-PET hypometabolism, T1-weighted MRI atrophy, elevated CSF neurofilament light chain) is associated with a common Alzheimer’s disease phenotype, the term neurodegenerative disease of Alzheimer type can be used,” wrote authors.

“Although the definition of Alzheimer’s disease based exclusively on biological markers has gained substantial traction in research settings, emerging studies suggest that the biomarker definition is not ready for application in clinical settings and for diagnosis of individuals without cognitive impairment,” wrote Dubois, Villain, et al.

“We recommend that Alzheimer’s disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer’s disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer’s disease,” they concluded.

In an accompanying editorial, William J. Jagust, MD, of the Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley, reviewed the discovery of biomarkers such as amyloid β and tau and how this was the catalyst that led to changes in the criteria and definitions of AD.

“Continued evolution of these criteria resulted in the term preclinical dementia, introduced by a US National Institute on Aging–Alzheimer’s Association (NIA–AA) workgroup and the IWG. This term was meant to describe individuals with no symptoms but who expressed biomarkers indicating the presence of amyloid β and tau pathology, with the goal of identifying those in the very earliest stages of Alzheimer’s disease who might benefit from therapeutic trials and, eventually, therapy. This description of asymptomatic individuals was controversial enough, but in 2018, the NIA–AA group introduced a research framework in which people with biomarkers indicating pathological accumulation of amyloid β and tau were categorized as having Alzheimer’s disease (no longer modified by the term preclinical or probable), regardless of the presence of symptoms,” Jagust wrote.

This is problematic for many reasons, according to Jagust, the least of which that studies have shown that both biomarkers often exist concomitantly with other neurologic pathologies, making clinical phenotyping difficult. Further, finding abnormal biomarkers in patients who are asymptomatic carries a host of problems that include prognostic uncertainty and ethical issues surrounding the communication of these findings to patients. “As Dubois and colleagues point out, expert evaluation is crucial in the clinic, but as more biomarkers for different pathological processes become available, the nature and importance of clinical evaluation might also evolve. Ultimately, the question of how best to diagnose Alzheimer’s disease will revolve around therapy: at what point, and in whom do we start it? The relative importance of clinical examination and biomarkers will depend on the answer,” Jagust concluded.

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  1. The International Working Group recommends that diagnoses of Alzheimer’s disease only be applied to patients with both positive biomarkers and specific AD phenotypes.

  2. Biomarker-positive individuals with no cognitive impairment should be considered only at-risk for progression to AD.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Dubois reports personal fees from Biogen and grants paid to his institution from Roche, Merck-Avenir Foundation, and Fondation Recherche sur Alzheimer, outside the submitted work.

Villain reports grants from Fondation Recherche Alzheimer, Département Médical Universitaire APHP– Sorbonne Université, and non-financial support from GE Healthcare, Merz Pharma, UCB Pharma, Medtronic, and Laboratoire Aguettant, outside the submitted work.

Jagust reports receiving personal fees for consulting from Roche and Genentech, Biogen, Bioclinica, and Grifols outside of the submitted work.

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Topic ID: 82,130,282,404,485,494,730,130,33,361,192,255,925