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.