It’s time for researchers to change how they think about Alzheimer’s disease (AD), says a panel of scientists convened by the National Institute on Aging (NIA). The panel proposes that for research purposes, AD should be defined according to a biomarker-based framework instead of the disease’s clinical consequences. A biomarker-based framework, the panel suggests, would give researchers a common language to use in clinical trials, enable a more accurate understanding of the events that culminate in cognitive impairment, and accelerate the testing of drugs and other interventions.

The new framework was issued on April 10 by the NIA and the Alzheimer’s Association (AA), in the form of an article (“NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease”) that appeared in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. The article acknowledges that a biomarker-based research framework has the potential to be misused. The article also recognizes that common biomarkers, such as beta-amyloid plaques and neurofibrillary tau deposits, may not be causal in Alzheimer’s pathogenesis. Nonetheless, the article emphasizes that it is these abnormal protein deposits that define Alzheimer’s as a unique neurodegenerative disease among different disorders that can lead to dementia.

“[This] framework…shifts the definition of AD in living people from a syndromal to a biological construct [and] focuses on the diagnosis of AD with biomarkers in living persons,” states the NIA-AA. “Biomarkers are grouped into those of beta-amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each biomarker measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available.”

Researchers can use measures from a study participant and identify A, T, or N to characterize that person's combination of biomarkers in one of eight profiles. For example, if a person has a positive beta-amyloid (A+) biomarker but no tau (T-), they would be categorized as having “Alzheimer's pathologic change.” Only those with both A and T biomarkers would be considered to have AD, along a continuum. The N biomarker group provides important pathologic staging information about factors often associated with AD development or worsening of symptoms.

This framework reflects the latest thinking in how AD begins perhaps decades before outward signs of memory loss and decline may appear in an individual. In 2011, NIA-AA began to recognize this with the creation of separate sets of diagnostic guidelines that incorporated recognition of a preclinical stage of AD and the need to develop interventions as early in the process as possible. The research framework offered today builds from the 2011 idea of three stages—preclinical, mild cognitive impairment, and dementia—to a biomarker-based disease continuum.

“In the context of continuing evolution of Alzheimer's research and technologies, the proposed research framework is a logical next step to help the scientific community advance in the fight against Alzheimer's,” said NIA Director Richard J. Hodes, M.D. “The more accurately we can characterize the specific disease process pathologically defined as Alzheimer's disease, the better our chances of intervening at any point in this continuum, from preventing Alzheimer's to delaying progression.”

The NIA-AA research framework authors, which included 20 academic, advocacy, government, and industry experts, noted that the distinction between clinical symptoms and measurable changes in the brain has blurred. The new research framework focuses on biomarkers grouped into different pathologic processes of AD which can be measured in living people with imaging technology and analysis of cerebral spinal fluid samples. It also incorporates measures of severity using biomarkers and a grading system for cognitive impairment.

“We have to focus on biological or physical targets to zero in on potential treatments for Alzheimer's,” explained Eliezer Masliah, M.D., director of the Division of Neuroscience at the NIA. “By shifting the discussion to neuropathologic changes detected in biomarkers to define Alzheimer's, as we look at symptoms and the range of influences on development of Alzheimer's, I think we have a better shot at finding therapies, and sooner.”

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