The AT(N) classification system is a research framework established by the National Institute on Aging and Alzheimer's Association (NIA-AA) to categorize Alzheimer's disease biomarkers based on three core pathological processes: Amyloid (A), Tau (T), and Neurodegeneration (N). This framework provides a standardized approach for biomarker-based diagnosis and staging of AD. [1]
These biomarkers detect the presence of amyloid-beta (Aβ) plaque pathology in the brain. [2]
| Biomarker | Fluid | Imaging | Key Features | [3]
|-----------|-------|---------|--------------| [4]
| Aβ42/40 ratio | CSF, Plasma | - | Decreased in AD; ratio more specific than Aβ42 alone | [5]
| Aβ42 | CSF | - | Decreased due to plaque deposition | [6]
| Amyloid PET | - | PET (PiB, Florbetapir, Florbetaben) | Visualizes cortical amyloid binding | [7]
Diagnostic Performance: [8]
References:
These biomarkers detect tau pathology, including neurofibrillary tangles (NFTs) and tau positivities.
| Subcategory | Biomarker | Fluid | Imaging | Key Features |
|---|---|---|---|---|
| T-tau (total) | t-Tau | CSF | - | Non-specific neuronal damage marker |
| T-tau (phosphorylated) | p-Tau181, p-Tau217, p-Tau231 | CSF, Plasma | - | AD-specific, correlates with NFT burden |
| Tau PET | - | - | PET (Flortaucipir, MK-6240, PI-2620) | Visualizes tau neurofibrillary tangles |
Diagnostic Performance:
References:
These biomarkers indicate neuronal injury, synaptic loss, and brain atrophy.
| Biomarker | Fluid | Imaging | Key Features |
|---|---|---|---|
| Total tau (t-Tau) | CSF | - | Non-specific, elevated in various dementias |
| Neurofilament Light (NfL) | CSF, Blood | - | Axonal injury marker, non-specific |
| Neurogranin | CSF | - | Synaptic marker, AD-specific |
| VILIP-1 | CSF | - | Neuronal injury marker |
| FDG-PET | - | PET | Hypometabolism in AD-vulnerable regions |
| MRI atrophy | - | MRI | Hippocampal, entorhinal cortical atrophy |
Diagnostic Performance:
References:
| Stage | A | T | N | Clinical Status |
|---|---|---|---|---|
| Preclinical AD | + | - | - | Cognitively normal |
| Preclinical AD | + | + | - | Cognitively normal, downstream tau |
| MCI due to AD | + | + | -/+ | Mild cognitive impairment |
| Dementia due to AD | + | + | + | Dementia with AD pathology |
| Clinical Syndrome | A | T | N | Interpretation |
|---|---|---|---|---|
| Typical AD | + | + | + | AD dementia |
| AD with Lewy bodies | + | + | + | + α-synuclein markers |
| FTLD | - | + (4R) | + | Tau PET negative, no amyloid |
| Vascular dementia | - | - | + | Neurodegeneration without AD |
Emerging blood-based biomarker panels are simplifying AT(N) profiling:
| Panel Components | Detection |
|---|---|
| Aβ42/40 + p-Tau217 | A+T profile |
| p-Tau181/NfL | T+N profile |
| p-Tau217 + NfL + GFAP | Full AT(N) approximation |
Cost Comparison:
Accessibility: Blood-based biomarkers offer the highest accessibility, particularly in primary care settings.
Japanese Cohorts:
Korean Cohorts:
Chinese Cohorts:
References:
| Biomarker | FDA Status | CE Mark |
|---|---|---|
| Amyloid PET (Florbetapir) | Approved | Yes |
| CSF Aβ42, t-Tau, p-Tau181 | Research use only | Yes (some) |
| Plasma p-Tau (Elecsys) | FDA breakthrough device | Under review |
| Blood NfL | Research use only | Yes (some) |
| Setting | First-line | Confirmatory |
|---|---|---|
| Memory clinic | Blood Aβ42/40 + p-Tau | CSF biomarkers or PET |
| Primary care | Blood p-Tau217 | Referral for confirmation |
| Research | Full AT(N) panel | N/A |
Hansson et al. CSF biomarkers for AD (2019). 2019. ↩︎
Palmqvist et al. Plasma p-Tau217 for AD (2020). 2020. ↩︎
Zetterberg et al. Neurofilament light chain (2019). 2019. ↩︎
Khalil et al. Neurogranin as AD biomarker (2018). 2018. ↩︎
Fleisher et al. Tau PET imaging (2020). 2020. ↩︎
Kanemaru et al. Japanese AD biomarkers (2020). 2020. ↩︎
Park et al. Korean AD biomarker validation (2021). 2021. ↩︎
Li et al. Chinese AD biomarker studies (2022). 2022. ↩︎