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A series of articles in Alzheimer’s & Dementia describe a new framework that uses biomarkers β-amyloid and tau, and neurodegeneration [AT(N)] to define Alzheimer’s disease (AD). In time, this biological approach may help decide which tests are most appropriate for clinical diagnosis.
A flurry of recent studies have linked biomarkers to mild cognitive impairment and progression to AD. Doctors currently give a clinical diagnosis based on symptoms, and a definitive AD diagnosis comes only after examining a patient’s brain in death, when classic plaques and tangles are present. The problem with this approach is it can’t pinpoint the neuropathologic changes that define AD, nor can it identify those patients who are otherwise asymptomatic but have biological evidence of disease.
Updating 2011 diagnostic recommendations from the National Institute on Aging and the Alzheimer’s Association (NIA-AA) on preclinical, mild cognitive impairment, and dementia stages of the disease, the new NIA-AA research framework proposes moving biomarkers forward, shifting the focus from symptoms to brain changes in living patients. “The research framework opens the door to examining known and potential new Alzheimer’s disease biomarkers for diagnostics and also to determine the sequence of brain changes and their affiliated proteins of interest to target,” Maria Carrillo, PhD, the AA’s chief science officer, told CLN Stat.
Under the new NIA-AA research framework, diagnosis would be based on the presence of β-amyloid, tau, and neurodegeneration. “This A(TN) classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures,” the authors explained. The AT(N) system is flexible in that it allows for the addition of new, evolving biomarkers to existing groups and new groups beyond the system. “We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures,” the authors indicated. In addition, they employed three traditional syndromal categories and a six-stage numeric scheme to help determine severity of cognitive impairment.
Enabling more precise staging of patients along the disease continuum should lead to more targeted clinical trials featuring biologically as well as clinically defined populations. In an accompanying article, a roundtable of scientists that met in 2017 to offer perspective on the framework mentioned the importance of diagnostic accuracy in crafting these interventional trials.
“Interventional clinical trials aimed to stop or slow the disease process by addressing the underlying pathophysiology of AD have been adjusting to this emerging science by moving to study patients at earlier stages of AD, thus requiring biomarkers to ensure diagnostic accuracy as well as confirming the presence of the pathophysiology being targeted,” they observed.
The framework will require further analysis and modifications before its adoption into routine clinical practice, said first author Clifford R. Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, in a statement. “Importantly, this framework should be examined in diverse populations.” The framework also shouldn’t be used to restrict nonbiomarker alternative testing approaches. “Biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia,” its authors added.
An accompanying editorial written by Ara S. Khachaturian, PhD, executive editor of Alzheimer’s & Dementia, and its staff praised the framework authors’ efforts to develop new pathways and a common language for testing of Alzheimer’s disease. “Such a language is a critical and essential element in addressing the ongoing challenge of developing more intricate and comprehensive models of Alzheimer’s disease ... for the identification of new interventions and diagnostics,” they offered. In other editorial comments on the research framework, NIA scientists offer that the framework will “allow more precise estimates of how many people are at risk [for or living with] Alzheimer’s disease, how best to monitor response to therapies, and how to distinguish the effects of Alzheimer’s disease from other similar pathologies.”