1 NIAAA Research Framework : Towards a Biological Definition of Alzheimer ’ s Disease 1 2 draft 11-2 7-17 3 4

21 In 2011 the National Institute on Aging and Alzheimer’s Association (NIA-AA) created 22 separate diagnostic recommendations for the preclinical, mild cognitive impairment, and 23 dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by 24 the NIA-AA to update and unify the 2011 guidelines. This unifying update is labeled a “research 25 framework”, because its intended use is for observational and interventional research, not routine 26 clinical care. In the NIA AA research framework Alzheimer’s disease (AD) is defined by its 27 underlying pathologic processes which can be documented by post-mortem examination or in 28 vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e. 29 symptoms/signs) in this research framework which shifts the diagnosis of AD in living people 30 from a syndromal to a biological construct. The research framework focuses on the diagnosis of 31 AD with biomarkers in living persons. Biomarkers are grouped into those of β-amyloid 32 deposition, pathologic tau, and neurodegeneration. Although we focus on AD as a continuum, 33 the severity of cognitive impairment is denoted using two different categorical cognitive staging 34 schemes: a scheme employing 3 traditional syndromal categories, and a 6 stage numeric scheme. 35 We envision that defining AD as a biological construct will enable a more accurate 36 characterization and understanding of the sequence of events that lead to cognitive impairment as 37 well as the multi factorial etiology of dementia. This approach also will enable a more precise 38 approach to interventional trials where specific pathways can be targeted in the disease process 39 and in the appropriate people. Importantly, this construct should be examined in more diverse 40 populations. 41 Finally we emphasize, that this report does not outline a rigid set of diagnostic criteria or 42 guidelines. Rather, this framework is a flexible tool to generate and test hypotheses about the 43 interactions among different pathologic processes (denoted by biomarkers) and cognitive 44 symptoms. 45 46 DRAFT as of 11/27/2017 DO NOT DISTRIBUTE DRAFT