The National Institute on Aging and Alzheimer’s Association (NIA-AA) has proposed updates to the 2011 guidelines for symptomatic or clinical stages of Alzheimer’s disease (AD) to include the concept that certain imaging and cerebrospinal fluid (CSF) biomarkers are valid proxies for neuropathologic changes of AD, according to a study published in Alzheimer’s & Dementia.

Clifford R. Jack Jr, MD, from the Department of Radiology at the Mayo Clinic in Rochester, MN, and colleagues, determined that these recommendations should be cast as a “research framework,” not as diagnostic criteria or guidelines and not intended for general clinical practice. The committee followed an unbiased, descriptive classification scheme (labeled AT(N)] for biomarkers used in AD and brain aging research.

The scheme recognized 3 general groups of biomarkers based on the nature of the pathologic process that each measures:

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  • Biomarkers of Aβ plaques (labeled “A”) are cortical amyloid positron emission tomography (PET) ligand binding or low CSF Aβ42.
  • Biomarkers of fibrillar tau (labeled “T”) are elevated CSF phosphorylated tau (P-tau) and cortical tau PET ligand binding.
  • Biomarkers of neurodegeneration or neuronal injury [labeled “(N)”] are CSF T-tau.

The committee also outlined staging severity. Two types of information about the research participant are staged independently from each other: (1) grading disease severity using biomarkers and (2) grading the severity of cognitive impairment. Aβ biomarkers determine whether an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has AD because both Aβ and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which are specific for AD, are used only to stage severity and not to define the presence of the Alzheimer’s continuum.

The committee outlined 2 different categorical cognitive schemes for staging the severity of cognitive impairment. The syndromal cognitive staging scheme divides the cognitive continuum into 3 traditional categories: cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia, with dementia further subdivided into mild, moderate, and severe stages.

The “numeric clinical staging scheme” avoids traditional syndromal labels and reflects the sequential evolution of AD from an initial stage characterized by the appearance of abnormal AD biomarkers in asymptomatic individuals.

  • Stage 1 is defined by biomarker evidence of the Alzheimer’s continuum in asymptomatic individuals.
  • Stage 2 describes the earliest detectable clinical consequence of the Alzheimer’s continuum.
  • Stage 3 describes cognitive impairment that is not severe enough to result in significant functional loss.
  • Stages 4 through 6 describe progressively worse functional loss.

“The NIA-AA research framework defines AD biologically, by neuropathologic change or biomarkers, and treats cognitive impairment as a symptom/sign of the disease rather than the definition of the disease,” the researchers concluded. “This approach should enhance efforts to understand both the biology of AD and the multifactorial etiology of dementia, which has been obscured to some extent in the past by equating amnestic multidomain dementia with the presence of AD neuropathologic changes, and by equating the absence of the prototypical dementia syndrome with the absence of AD neuropathologic changes.”

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In a second, related study, a research roundtable led by David S. Knopman, MD, stated that “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 hypothesis 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.”


  1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. April 2018. DOI:
  2. Knopman DS, Haeberlein SB, Carrillo MC, et al. The National Institute on Aging and the Alzheimer’s Association Research Framework for Alzheimer’s disease: Perspectives from the Research Roundtable. Alzheimers Dement. April 2018. DOI: