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      NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease


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          In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each 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. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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          Author and article information

          Alzheimers Dement
          Alzheimers Dement
          Alzheimer's & dementia : the journal of the Alzheimer's Association
          24 April 2018
          April 2018
          18 May 2018
          : 14
          : 4
          : 535-562
          [a ]Department of Radiology, Mayo Clinic, Rochester, MN, USA
          [b ]Department of Neurological Sciences, Rush University, Chicago, IL, USA
          [c ]Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden
          [d ]Medical & Scientific Relations, Alzheimer’s Association, Chicago, IL, USA
          [e ]Office of Drug Evaluation, FDA, Silver Spring, MD, USA
          [f ]Biogen, Cambridge, MA, USA
          [g ]Department of Neurology, Washington University, St. Louis, MO, USA
          [h ]Department of Public Health and Neuroscience, University of California Berkeley, Berkeley, CA, USA
          [i ]Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany
          [j ]Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
          [k ]Prothena Biosciences, Inc., San Francisco, CA, USA
          [l ]BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation and Hospital Clinic-IDIBAPS, Barcelona, Spain
          [m ]Department of Pathology, Stanford University, Standford, CA, USA
          [n ]Formerly at National Institute on Aging, Bethesda, MD, USA
          [o ]Department of Neurology, University of California San Francisco, San Francisco, CA, USA
          [p ]Department of Molecular Imaging, Austin Health, University of Melbourne, Melbourne, Australia
          [q ]Department of Neurology, VU University Medical Center, Amsterdam, Netherlands
          [r ]Formerly at Eli Lilly and Company, Indianapolis, IN, USA
          [s ]Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
          Author notes
          [* ]Corresponding author. Tel.: 507-284-9087; Fax: 507-293-2235. jack.clifford@ 123456mayo.edu

          Contributors : Cerise Elliott, Eliezer Masliah, Laurie Ryan, and Nina Silverberg


          The listed National Institute on Aging program staff are acknowledged for their key contributions in leadership and scientific guidance on this project.


          This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).


          alzheimer’s disease diagnosis,preclinical alzheimer’s disease,biomarkers alzheimer’s disease,csf biomarkers alzheimer’s disease,alzheimer’s disease imaging,amyloid pet,tau pet


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