Primary Hypothesis: Tau pathology becomes detectable via blood-based biomarkers 5-10 years before clinical onset in individuals with pathogenic MAPT mutations, enabling pre-symptomatic intervention trials.
Secondary Hypotheses:
- The sequence of biomarker abnormalities follows a predictable pattern: CSF p-tau217 → blood p-tau217 → CSF NfL → tau PET → clinical symptoms
- Regional vulnerability in the brainstem (subsequently spreading to cortical regions) determines the timing of symptom onset
- Genetic modifiers (other tauopathy risk alleles) modulate the age of onset in MAPT carriers
This experiment addresses the critical unknown identified in the CBS/PSP Cure Roadmap Phase 5:
- "When does tau pathology begin relative to symptoms? (5 years? 10 years? 20 years?)"
- "Is there a 'point of no return' after which intervention is too late?"
Also addresses AD Cure Roadmap prevention questions:
- Validated pre-symptomatic biomarkers for early detection
- Type: Multi-center prospective longitudinal biomarker study
- Cohort:
- MAPT mutation carriers (any pathogenic variant): n=150 (50 pre-symptomatic, 50 early-symptomatic, 50 moderate)
- Age-matched non-carrier family members: n=100 (controls)
- Sporadic PSP patients: n=50 (positive controls for biomarker validation)
- Follow-up: 5 years minimum, with optional extension to 10 years
- Age 18-75 years
- Either:
- Pathogenic MAPT mutation (confirmed by genetic testing) OR
- First-degree relative of MAPT mutation carrier
- Able to undergo MRI and PET imaging
- Willing to undergo genetic counseling
- Current diagnosis of PSP, CBD, AD, or other neurodegenerative disease
- Contraindications to MRI (pacemaker, metal implants)
- Contraindications to PET (recent chemotherapy, pregnancy)
- Active psychiatric condition requiring hospitalization
| Biomarker |
Baseline |
6mo |
12mo |
18mo |
24mo |
Year 3 |
Year 4 |
Year 5 |
| Blood p-tau217 |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
| Blood NfL |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
| Blood GFAP |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
| CSF p-tau181/217 |
✓ |
|
✓ |
|
✓ |
|
✓ |
✓ |
| CSF NfL |
✓ |
|
✓ |
|
✓ |
|
✓ |
✓ |
| CSF total tau |
✓ |
|
✓ |
|
✓ |
|
✓ |
✓ |
| Tau PET (flortaucipir) |
✓ |
|
|
|
✓ |
|
|
✓ |
| MRI (T1, SWI, DTI) |
✓ |
|
✓ |
|
✓ |
|
✓ |
✓ |
| Clinical assessment |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
✓ |
- Primary Outcome: Time to clinical conversion (PSP or CBS diagnosis)
- Secondary Outcomes:
- PSP Rating Scale (PSPRS)
- MDS-UPDRS
- Cognitive batteries (MoCA, FAB, Trail Making A/B)
- CSF biomarker trajectories
- Rationale: Blood p-tau217 has shown high accuracy for detecting tau pathology in AD; validate for 4R-tauopathies
- Methods:
- Compare sensitivity of blood p-tau217 vs CSF p-tau217 vs PET
- Establish cutoff values for pre-symptomatic detection
- Test correlation with tau PET regional uptake
- Rationale: Determine which biomarker becomes abnormal first
- Methods:
- Population-average biomarker trajectories
- Individual-level trajectory modeling (mixed-effects)
- Correlation with clinical conversion
- Rationale: Determine whether pre-symptomatic intervention is feasible
- Methods:
- Modeling of biomarker slopes pre-conversion
- Simulation of trial power at different intervention timepoints
- Identification of optimal inclusion criteria for prevention trials
- Biomarker detection window: p-tau217 detectable in blood at mean 7.2 years (95% CI: 4.2-10.1) before clinical conversion
- Biomarker sequence: Blood p-tau217 → CSF NfL → tau PET → clinical symptoms (in that order)
- Sensitivity/specificity: Blood p-tau217 for detecting pre-symptomatic tauopathy: 85% sensitivity, 90% specificity
- Age of onset prediction model: R² > 0.7 for age of onset prediction using biomarker panel + genetic modifiers
- Regional spread pattern: Tau PET identifies brainstem as initiation site in 80% of cases
- Point of no return: Identify biomarker threshold beyond which intervention shows no benefit
- Genetic modifiers: Identify novel variants that modify age of onset
- Environmental factors: Characterize lifestyle factors that modify biomarker trajectories
- Sex differences: Characterize sex-based differences in biomarker patterns
- Multi-center network (Cleveland Clinic, UCL, UCSF, Mayo Clinic) ensures adequate enrollment
- Existing MAPT family registries provide pre-identified participants
- Comprehensive biomarker panel enables detailed temporal mapping
- Integration with clinical trials infrastructure for future prevention studies
- Rarity of MAPT mutations (estimated prevalence 1:100,000)
- Long follow-up required to capture conversions (may need 10+ years)
- Ethical considerations around predictive genetic testing
- Variable penetrance of MAPT mutations complicates age of onset prediction
| Milestone |
Expected Date |
| Protocol finalization |
Month 1-3 |
| Site activation (4 sites) |
Month 4-6 |
| First participant enrolled |
Month 7 |
| 50% enrollment (100 total) |
Month 18 |
| Full enrollment (250 total) |
Month 30 |
| First clinical conversions expected |
Month 24 (variable) |
| Primary analysis (5-year data) |
Month 66 |
| Category |
Cost (USD) |
| Personnel (3 FTE coordinators, 2 PI, 1 biostatistician) |
$1,800,000 |
| Biomarker assays (blood, CSF) |
$1,000,000 |
| Imaging (MRI, PET) |
$800,000 |
| Clinical assessments |
$300,000 |
| Genetic testing and counseling |
$150,000 |
| Data management |
$200,000 |
| Indirect costs (20%) |
$850,000 |
| Total |
$5,100,000 |
This experiment provides infrastructure and biomarkers relevant for:
- AD prevention trials (blood p-tau217 already validated for AD)
- PSP sporadic cases (biomarker validation)
- Other tauopathies (FTD, CBD)
- General neurodegeneration (NfL as general neuronal injury marker)