New criteria for Alzheimer’s disease

More recently, the National Institute on Aging–Alzheimer’s Association (NIA–AA) (Jack CR et al. 2018) has proposed to define exclusively AD by its underlying neuropathologic changes that can be documented by the biomarkers in living people. The biomarker profile (pathologic process) and cognitive staging represent independent sources of information. The definition and the grading of disease severity is assessed by the biological construct of AD across its entire spectrum as a continuum.

 
AT(N) BIOMARKER GROUPING

• A: Aggregated Aβ amyloid peptides or associated pathologic state
  (CSF Aβ₄₂, or Aβ_42/40 ratio; Amyloid PET)
• T: Aggregated tau (neurofibrillary tangles) or associated pathologic state 
  (CSF phosphorylated tau; Tau PET)
• (N): Neurodegeneration or neuronal injury
  (Anatomic MRI; FDG PET; CSF total tau)

 
CSF VERSUS IMAGING BIOMARKERS

• The ongoing active pathologic state is denoted by CSF
• The accumulation of neuropathologic load and location in the brain is denoted by imaging

 
DEFINITION OF ALZHEIMER’S CONTINUUM

• A: Amyloid biomarkers (Aβ42 or Aβ42/40 ratio for CSF) determine whether or not an individual is potentially in the Alzheimer’s continuum.
• T: Pathologic tau biomarkers (P-tau for CSF) determine if someone who is in Alzheimer’s continuum has Alzheimer’s disease.

 
STAGING SEVERITY

• (N): Neurodegenerative/neuronal injury biomarkers (T-tau for CSF) provide powerful prediction of future cognitive decline.
• (C): Cognitive symptoms determine the syndromal categorical cognitive staging regardless the etiology.

Note: A and T are specific neuropathologic changes of AD, whereas (N) and (C) are not specific to AD and therefore placed in parentheses.

 
FLEXIBILITY OF THE AT(N) SYSTEM

• Each biomarker group is labeled (-) normal, (+) abnormal or (*) not determined

E.g. A+T+(N)+ to categorize AD-pathologic changes

• Alternatively to the binary approach, each biomarker group could be also labelled semi-quantitatively (0) clearly normal, (1) intermediate / marginally altered or (2) clearly abnormal.

E.g. A²T¹(N)¹ categorize AD profile or A²T⁰(N)⁰ if only the Amyloid biomarker is clearly abnormal

• New biomarker groups beyond AT(N) can be added when they will become available.

These guidelines would permit an important step toward harmonization of interpretation of biomarkers in a personalized medicine.

• A combination of an abnormal Aβ and a pathologic tau biomarker constitutes AD regardless of cognitive symptoms, and thus AD is a biologically defined entity.
• The staging of the severity of cognitive symptoms is independent of the underlined pathology. The syndromal categorical scheme preserves the tree clinical categories: cognitively unimpaired, mild cognitive impairment and dementia.