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

Abstract

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.

Keywords: Alzheimer's disease diagnosis; Alzheimer's disease imaging; Amyloid PET; Biomarkers Alzheimer's disease; CSF biomarkers Alzheimer's disease; Preclinical Alzheimer's disease; Tau PET.

Fig. 1

Alzheimer’s disease with dementia. A 75-year-old woman with amnestic multidomain dementia. Participant in the Mayo Alzheimer’s Disease Research Center. Abnormal amyloid PET with Pittsburgh compound B (top left), tau PET with flortaucipir (top right and bottom left), and atrophy on MRI (bottom right). Biomarker profile A+T+(N)+.

Fig. 2

Preclinical Alzheimer’s pathologic change. A cognitively unimpaired 67-year-old man. Participant in the Mayo Clinic Study of Aging. Abnormal amyloid PET (Pittsburgh compound B, top row), no uptake on tau PET (with flortaucipir, middle row), no atrophy on MRI (bottom row). Biomarker profile A+T−(N)−.

Fig. 3

Alzheimer’s and concomitant suspected non-Alzheimer’s pathologic change with dementia. A 91-year-old male with severe amnestic dementia. Participant in the Mayo Alzheimer’s Disease Research Center. Abnormal amyloid PET with Pittsburgh compound B (top row), normal tau PET (flortaucipir, middle row), and severe medial temporal atrophy on MRI (bottom row). The biomarker profile (A +T−(N)+) suggests the patient has Alzheimer’s pathologic change (A+T−) plus an additional degenerative condition [(N)+], likely hippocampal sclerosis.

Fig. 4

Descriptive nomenclature Venn diagram. As an adjunct to Table 4, we illustrate how AT(N) biomarker grouping and cognitive status interact for classification of research participants in this Venn diagram. For simplicity, MCI and dementia are combined into a single (cognitively impaired) category and the A−T−(N)− groups are not shown. Also “Alzheimer’s and concomitant non-Alzheimer’s pathologic change” [A+T−(N)+] in cognitively impaired is not shown in this figure. Abbreviation: MCI, mild cognitive impairment.

Fig. 5

Non-Alzheimer’s pathologic change with dementia. An 86-year-old female with progressive amnestic dementia. The patient had been diagnosed clinically (i.e., without biomarkers) as “Alzheimer’s disease dementia” by several physicians before enrolling in the Mayo Alzheimer’s Disease Research Center. Imaging performed for research purposes revealed a normal amyloid PET (Pittsburgh compound B, left), normal tau PET with flortaucipir (middle), and severe medial temporal atrophy on MRI (right). The biomarker profile [A−T−(N)+] suggests the patient has non-Alzheimer’s pathologic change. Based on her biomarker profile, hippocampal sclerosis was suspected antemortem, and hippocampal sclerosis with TDP43 (and without Alzheimer’s disease) was later confirmed at autopsy.

Fig. 6

Hypothesis testing using the research framework. In this figure, we outline various possible mechanistic pathways that involve A, T, (N), and (C). We believe current evidence most strongly supports the “modified amyloid cascade hypothesis” pathway denoted in (A), and this is reflected in the terminology in Table 2. However, we illustrate several alternatives that could be tested using the research framework. These are discussed in the text. This is not intended to represent an exhaustive list of all possible pathways but rather an illustration of some possible mechanistic pathways where A and Tare and are not causal in AD pathogenesis. In each of these models, the final common pathway is (N) → (C), which is based on the assumption that in neurodegenerative diseases, neuronal/ synaptic damage is the histopathologic feature that is most proximate to cognitive impairment. Abbreviation: AD, Alzheimer disease.