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  • br Conclusion br Introduction The identification


    Introduction The identification of Alzheimer's disease (AD) biomarkers and their ability to measure pathology antemortem has led to a fundamental reconsideration of the pathogenesis of AD. The importance of biomarkers was already reflected in revised diagnostic criteria proposed by the National Institute on Aging and the Alzheimer's Association in 2011 [1–4] and the International Working Group in 2007 [5]. The International Working Group criteria were subsequently updated in 2010 [6] and 2014 [7]. With each of these iterations, the field has achieved greater sensitivity and specificity of AD diagnoses, which in turn has better enabled our ability in clinical trials to test hypotheses of treatment and ultimately prevention of AD. The National Institute on Aging and the Alzheimer's Association Workgroup's Research Framework uses a biomarker classification scheme proposed by Jack et al [8], which divides the current major AD biomarkers into three categories, based on the type of pathologic change each measures: β-amyloid (A), pathological tau (T), and neurodegeneration (N). The framework is intended to provide the research field with a common language for diagnostic purposes. Its scope is therefore focused on those aspects of research involving humans where specificity of the diagnosis of AD is important. Although the framework contains certain assumptions about diagnostic relevance to AD, it should not be conceived as a mechanistic Nile Red australia about the pathogenesis of AD. An important goal of this effort is to speed up and improve the development of disease-modifying treatments for AD. A draft of the framework was presented at the Alzheimer's Association International Conference in July 2017, and an updated draft was posted online in November 2017 [9], with the intent of collecting comments from the research community. Given the importance of this issue, the Alzheimer's Association's Research Roundtable convened scientists from academia, industry, and government in the of Fall 2017 to discuss the framework.
    The ATN system The ATN nomenclature represents a conceptual framework that is based on the past decade's empiric observations of relationships between markers of amyloid, tau, and neurodegeneration. “A” refers to amyloid β (Aβ) as measured either by amyloid positron emission tomography (PET) imaging of amyloid plaques or in the cerebrospinal fluid (CSF) as Aβ42 or the Aβ42 to Aβ40 ratio. “T” refers to tau pathology as measured by CSF phosphorylated tau or tau PET imaging of parenchymal neurofibrillary tangles. “N” refers to neurodegeneration or neuronal injury and dysfunction, as measured for example by hippocampal volume or cortical volume or thickness. While “A” and “T” are considered to have diagnostic specificity for AD, “N” is not specific for AD diagnoses because bud sports can reflect any number of etiologies in addition to AD. The roundtable discussion devoted several sessions to understand the details of each category of biomarkers, which is summarized below.
    Barriers to adopt ATN for clinical trials
    Challenges to the biological definition of AD A major motivation for the development of the ATN system was the recognition that biomarkers reflect the key diagnostic markers of AD. Whereas previously, clinical diagnoses were the sole basis for inclusion in clinical trials, the use of amyloid imaging in several recent large clinical trials of anti-amyloid agents showed that 20%–30% of participants did not have elevated amyloid biomarkers and therefore did not have the target required by many of the therapies. Because clinical trials are a multinational effort in the 21st century, developing a common language for biomarker designations in the AD spectrum is critical for harmonization across the international roster of clinical trial sites and investigators. Thus, even before there was a formal international consensus document, leaders in the AD clinical trial field have recognized that an abnormal amyloid imaging study or abnormal CSF Aβ42 is a necessary inclusion criterion for any clinical trial purporting to target AD pathology specifically. Much more work needs to be done to determine the proper diagnostic role in clinical trials for “T” and “N” biomarkers. However, to the extent that those who are A+, T+, and N+ appear to have a worse prognosis than those who lack abnormalities in all three categories, selecting participants for AD dementia or MCI trials based on the ATN scheme would enrich the trial with persons with the greatest likelihood of decline in the time frame of a clinical trial. Whether those individuals would have the greatest response to a treatment targeting the Aβ peptide or amyloid plaques is a testable hypothesis.