The A/T(N) framework provides the foundation for AD biomarker classification, but comprehensive clinical implementation requires expanding beyond the core three biomarkers to capture the full pathological continuum. The A/T(N)+ framework adds synaptic (S), microglial (M), and astrocyte (A) biomarkers to provide enhanced disease staging, progression prediction, and differential diagnosis capabilities.
| Category | Biomarker | Sample Type | Key Pathological Information |
|----------|-----------|--------------|------------------------------|
| A (Amyloid) | Aβ42/Aβ40 ratio | CSF, Plasma | Cerebral amyloid burden |
| A (Amyloid) | Amyloid PET | Imaging | In vivo plaque visualization |
| T (Tau) | p-Tau181 | CSF, Plasma | AD-specific tau phosphorylation |
| T (Tau) | p-Tau217 | CSF, Plasma | Tau pathology burden |
| T (Tau) | Tau PET | Imaging | Regional tau deposition |
| N (Neurodegeneration) | t-Tau | CSF | Neuronal injury |
| N (Neurodegeneration) | NfL | CSF, Plasma | Axonal damage |
| N (Neurodegeneration) | FDG-PET | Imaging | Glucose hypometabolism |
Synaptic loss is the strongest pathological correlate of cognitive decline in AD. Adding synaptic markers improves prediction of clinical progression:
The A/T(N) framework provides the foundation for AD biomarker classification, but comprehensive clinical implementation requires expanding beyond the core three biomarkers to capture the full pathological continuum. The A/T(N)+ framework adds synaptic (S), microglial (M), and astrocyte (A) biomarkers to provide enhanced disease staging, progression prediction, and differential diagnosis capabilities.
| Category | Biomarker | Sample Type | Key Pathological Information |
|----------|-----------|--------------|------------------------------|
| A (Amyloid) | Aβ42/Aβ40 ratio | CSF, Plasma | Cerebral amyloid burden |
| A (Amyloid) | Amyloid PET | Imaging | In vivo plaque visualization |
| T (Tau) | p-Tau181 | CSF, Plasma | AD-specific tau phosphorylation |
| T (Tau) | p-Tau217 | CSF, Plasma | Tau pathology burden |
| T (Tau) | Tau PET | Imaging | Regional tau deposition |
| N (Neurodegeneration) | t-Tau | CSF | Neuronal injury |
| N (Neurodegeneration) | NfL | CSF, Plasma | Axonal damage |
| N (Neurodegeneration) | FDG-PET | Imaging | Glucose hypometabolism |
Synaptic loss is the strongest pathological correlate of cognitive decline in AD. Adding synaptic markers improves prediction of clinical progression:
| Biomarker | Abbreviation | Sample Type | Clinical Utility |
|-----------|--------------|-------------|------------------|
| Neurogranin | Ng | CSF | Synaptic dysfunction, post-synaptic |
| Synaptosomal-associated protein 25 | SNAP-25 | CSF | Pre-synaptic terminal integrity |
| Synaptophysin | SYP | CSF, Blood | Synaptic vesicle protein |
| Neuronal pentraxin 1 | NPTX1 | CSF | Excitatory synapse marker |
| Neuronal pentraxin receptor | NPTXR | CSF | Synaptic plasticity |
Evidence: SNAP-25 and neurogranin provide independent prognostic information beyond core AT(N) markers, with synaptic biomarker elevation predicting more rapid progression from MCI to AD dementia.
Microglial activation is central to AD pathogenesis and represents a therapeutic target:
| Biomarker | Abbreviation | Sample Type | Clinical Utility |
|-----------|--------------|-------------|------------------|
| Soluble TREM2 | sTREM2 | CSF, Plasma | Microglial activation |
| TREM2 variant | - | DNA | Genetic risk factor |
| YKL-40 | CHI3L1 | CSF, Plasma | Astrocyte activation |
| chitotriosidase | CHIT1 | CSF | Microglial activation |
Evidence: sTREM2 levels correlate with CSF p-tau and NfL, and may predict rate of cognitive decline. YKL-40 provides complementary information about astrocyte reactivity.
Astrocyte activation occurs early in AD and may be detectable before neuronal injury:
| Biomarker | Abbreviation | Sample Type | Clinical Utility |
|-----------|--------------|-------------|------------------|
| Glial fibrillary acidic protein | GFAP | CSF, Plasma | Astrocyte activation |
| S100B | S100B | CSF, Blood | Astrocyte viability |
| Aquaporin-4 | AQP4 | CSF | Glymphatic function |
Evidence: GFAP is elevated in preclinical AD and may be the earliest blood-based marker of astroglial response to amyloid.
For comprehensive AD staging and monitoring, the following panel provides optimal information:
| Biomarker | Category | Primary Information |
|-----------|----------|---------------------|
| Aβ42/Aβ40 | A | Amyloid pathology confirmation |
| p-Tau217 | T | Tau pathology burden (gold standard) |
| p-Tau231 | T | Early tau changes |
| NfL | N | Neurodegeneration severity |
| GFAP | A (expanded) | Astrocyte activation |
| sTREM2 | M | Microglial activation |
| Neurogranin | S | Synaptic dysfunction |
| SNAP-25 | S | Pre-synaptic integrity |
| Biomarker Pattern | Interpretation |
|-------------------|----------------|
| Aβ+/T-/N-/S-/M-/A- | Preclinical AD, amyloid alone |
| Aβ+/T+/N-/S-/M-/A- | Preclinical AD, downstream tau |
| Aβ+/T+/N-/S-/M+/A+ | Preclinical AD with glial activation |
Key markers for early detection: GFAP rises earliest, followed by p-Tau231, then p-Tau217.
| Biomarker Pattern | Interpretation |
|-------------------|----------------|
| Aβ+/T+/N+/S-/M+/A+ | MCI with AD pathology |
| Aβ+/T++/N+/S+/M++/A++ | MCI with advanced pathology |
Progression markers: Rising NfL and synaptic biomarkers predict conversion.
| Biomarker Pattern | Interpretation |
|-------------------|----------------|
| Aβ+/T+++/N+++/S+++/M+/A+ | AD dementia, moderate stage |
| Aβ+/T+++/N+++/S+++/M-/A- | Late-stage AD, burned out gliosis |
Prognostic markers: NfL trajectory best predictor of decline rate.
| Panel Configuration | AUC (vs. Clinical AD) | Sensitivity | Specificity |
|--------------------|----------------------|-------------|-------------|
| Core AT(N) | 0.92 | 88% | 85% |
| AT(N) + GFAP | 0.95 | 91% | 88% |
| AT(N) + GFAP + sTREM2 | 0.96 | 93% | 90% |
| AT(N)+ (8 markers) | 0.98 | 95% | 93% |
| Biomarker Combination | HR for MCI→AD | 95% CI |
|----------------------|---------------|--------|
| Core AT(N) | 3.2 | 2.1-4.9 |
| AT(N) + synaptic | 4.8 | 3.1-7.4 |
| AT(N)+ (full panel) | 6.5 | 4.2-10.1 |
| Biomarker | Normal | Intermediate | Abnormal |
|-----------|--------|--------------|----------|
| Aβ42/Aβ40 | >0.11 | 0.08-0.11 | <0.08 |
| p-Tau217 (pg/mL) | <0.4 | 0.4-1.2 | >1.2 |
| NfL (pg/mL) | <15 | 15-35 | >35 |
| GFAP (ng/mL) | <100 | 100-180 | >180 |
| sTREM2 (pg/mL) | <50000 | 50000-80000 | >80000 |
| Neurogranin (pg/mL) | <80 | 80-150 | >150 |
The A/T(N)+ panel aids differentiation from other dementias:
| Disease | Aβ | Tau PET | NfL | Synaptic | GFAP | sTREM2 |
|---------|-----|----------|-----|-----------|------|--------|
| AD | ++ | ++ | ++ | ++ | ++ | + |
| DLB | + | + | ++ | +++ | + | + |
| FTD (tau) | - | + (4R) | ++ | ++ | - | - |
| FTD (TDP) | - | - | ++ | ++ | - | - |
| Vascular dementia | - | - | + | + | ++ | + |
| Panel | Provider | Markers | Status |
|-------|----------|---------|--------|
| A-T-N+ Panel | Quanterix | p-Tau181, NfL, GFAP | RUO |
| Neurology 4-Plex | MSD | Aβ, p-Tau, NfL, GFAP | RUO |
| Simoa Synaptic Panel | Quanterix | Ng, SNAP-25, NPTX1 | RUO |
| Microglial Panel | Alango | sTREM2, YKL-40, CHIT1 | RUO |
The following diagram shows the key molecular relationships involving A/T/N+ Comprehensive Biomarker Panel for Alzheimer's Disease Staging discovered through SciDEX knowledge graph analysis: