New criteria for AD

New criteria for different stages of AD have been suggested by the International Working Group (IWG) and the National Institute on Aging–Alzheimer’s Association (NIA–AA) (Dubois et al. 2007; Albert et al. 2011; McKhann et al. 2011; Sperling et al. 2011; Dubois et al. 2014).

These criteria have been constructed to permit a diagnosis of AD in earlier stages of the disease, and are centered on the clinical identification of cognitive impairment subtypes together with one or more abnormal biomarkers, including MRI, PET, and CSF markers.

These criteria broaden the spectrum of the disease to include its preclinical states, in which Alzheimer’s pathology exists without clinical symptoms.

To increase diagnostic certainty, the criteria for Alzheimer’s disease incorporate biomarker evidence for pathology, which can be obtained by neuroimaging (MRI measures of atrophy, ¹⁸F-fluorodeoxyglucose PET measures of cerebral hypometabolism, and amyloid PET measures of β-amyloid deposition) and CSF testing (decreased β-amyloid concentrations and increased total tau or hyperphosphorylated tau concentrations).

AT(N)(C) system in 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 Alzheimer’s disease (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 Aβ42/Aβ40 ratio
Amyloid PET

T: Aggregated tau (neurofibrillary tangles) or associated pathologic state

CSF phosphorylated tau

(N): Neurodegeneration or neuronal injury

Anatomic MRI
CSF total tau

CSF (cerebrospinal fluid) 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 ‘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 (Phospho-tau for CSF) determine if someone who is in Alzheimer’s continuum has an Alzheimer’s disease.

Staging severity

(N): Neurodegenerative/neuronal injury biomarkers (Total 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

P.ex.  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.

P.ex.  A2T1(N)1   categorize AD profile or A2T0(N)0   if only 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.



  • NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.
    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R. Alzheimers Dement. 2018 Apr;14(4):535-562.
  • Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers.
    Frisoni GB, Boccardi M, Barkhof F, Blennow K, Cappa S, Chiotis K, Démonet JF, Garibotto V, Giannakopoulos P, Gietl A, Hansson O, Herholz K, Jack CR Jr, Nobili F, Nordberg A, Snyder HM, Ten Kate M, Varrone A, Albanese E, Becker S, Bossuyt P, Carrillo MC, Cerami C, Dubois B, Gallo V, Giacobini E, Gold G, Hurst S, Lönneborg A, Lovblad KO, Mattsson N, Molinuevo JL, Monsch AU, Mosimann U, Padovani A, Picco A, Porteri C, Ratib O, Saint-Aubert L, Scerri C, Scheltens P, Schott JM, Sonni I, Teipel S, Vineis P, Visser PJ, Yasui Y, Winblad B. Lancet Neurol. 2017 Aug;16(8):661-676.
  • Are CSF Biomarkers Useful as Prognostic Indicators in Diagnostically Unresolved Cognitively Impaired Patients in a Normal Clinical Setting.
    Schjønning Nielsen M, Simonsen AH, Siersma V, Hasselbalch SG, Høgh P.Dement Geriatr Cogn Dis Extra. 2016 Oct 7;6(3):465-476.
  • Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.
    Herukka SK, Simonsen AH, Andreasen N, Baldeiras I, Bjerke M, Blennow K, Engelborghs S, Frisoni GB, Gabryelewicz T, Galluzzi S, Handels R, Kramberger MG, Kulczyńska A, Molinuevo JL, Mroczko B, Nordberg A, Oliveira CR, Otto M, Rinne JO, Rot U, Saka E, Soininen H, Struyfs H, Suardi S, Visser PJ, Winblad B, Zetterberg H, Waldemar G. Alzheimers Dement. 2017 Mar;13(3):285-295
  • Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.
    Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL. Lancet Neurol. 2014 Jun;13(6):614-29.