🧫
Cognitive impact of TDP-43 pathology in AD patients
active
experiment
Created: 2026-04-06T12:29:12
By: etl-v1-backfill
Quality:
50%
✓ SciDEX
ID: exp-1f297f00-3d27-4c16-bfb2-d68eae4e3108
🧫 Experiment Protocol
ClinicalAlzheimer's diseaseTARDBPhuman patientscompleted
Clinical assessment comparing cognitive impairment severity between Alzheimer's disease patients with and without TDP-43 pathology. The study demonstrated that AD patients who have concurrent TDP-43 pathology exhibit increased severity of cognitive impairment compared to AD patients without TDP-43 pathology. This suggests that TDP-43 pathology contributes additively or synergistically to the cognitive decline observed in AD, beyond what is caused by amyloid and tau pathologies alone.
PRIMARY OUTCOME
cognitive impairment severity
EXPECTED OUTCOMES
## Primary Outcomes
**Baseline Cognitive Impairment**: AD patients with high CSF phospho-TDP-43 show worse baseline cognition: ADAS-Cog score ≥3 points higher (p < 0.01), CDR sum of boxes ≥0.5 higher (p < 0.05) vs. TDP-43 low AD group.
**Accelerated Decline**: Over 24 months, TDP-43 high AD group shows faster cognitive decline: ADAS-Cog increase +2.1 points/year vs. +1.0 point/year in TDP-43 low group (p < 0.001). Hazard ratio for cognitive decline = 1.8 (95% CI: 1.3-2.5).
## Secondary Outcomes
**Neuroimaging Correlation**: TDP-43 high AD patients show greater hippocampal atrophy rate (+0.08 mL/year, p < 0.05) and higher cortical thinning rate (+0.03 mm/year, p < 0.05) vs. TDP-43 low group, consistent with TDP-43 driving neurodegeneration independent of amyloid.
**Interaction with APOE4**: APOE4 carriers with high TDP-43 show the fastest decline, suggesting synergistic effects of amyloid (APOE4-driven) and TDP-43 pathologies.
SUCCESS CRITERIA
## Primary Success Criteria
**Association with Cognition**: CSF phospho-TDP-43 levels must correlate with baseline cognitive performance (ADAS-Cog or CDR, Spearman |ρ| ≥ 0.30, p < 0.01) in AD patients.
**Predictive Value**: High phospho-TDP-43 (above median) must predict ≥1.5-fold increased risk of 24-month cognitive decline (composite endpoint) with HR significantly >1.0 (p < 0.05) in Cox regression.
## Secondary Success Criteria
**Specificity**: Association must remain significant after adjusting for amyloid pathology (CSF Aβ42 or tau PET status) and neurodegeneration markers (total CSF tau), suggesting TDP-43 adds independent prognostic value.
**Replication**: Results must replicate in held-out validation cohort (30% random split) with consistent direction and magnitude within 35% of discovery effect.
PROTOCOL
# Cognitive Impact of TDP-43 Pathology in Alzheimer's Disease Patients Protocol
## Phase 1: Patient Enrollment and Baseline Assessment (Days 1-30)
**Participant Recruitment**: Recruit AD patients (n=100, ages 55-85, NINCDS-ADRDA criteria) and cognitively normal age-matched controls (n=50) from memory clinics. Obtain written informed consent, IRB approval.
**APOE Genotyping**: Extract DNA from peripheral blood (saliva kit or blood draw). Genotype APOE (ε2/ε3/ε4) via PCR-RFLP or TaqMan assay. Stratify for APOE4 carrier status as covariant.
**Baseline Cognitive Testing**: Administer comprehensive neuropsychological battery: (a) ADAS-Cog (Alzheimer's Disease Assessment Scale, cognitive subscale), (b) CDR (Clinical Dementia Rating sum of boxes), (c) MMSE (Mini-Mental State Examination), (d) Trail Making Test A/B, (e) Digit Span, (f) Logical Memory (WMS-R). Score locally and centralize for blind analysis.
## Phase 2: TDP-43 Biomarker Assessment (Days 31-60)
**CSF Collection**: Perform lumbar puncture (25G Sprotte, 12 mL CSF) per standard protocol. Centrifuge within 1 hour (800×g, 10 min, 4°C). Aliquot 0.5 mL fractions, store at -80°C. Exclude sanguinolent samples (>500 RBC/μL).
**TDP-43 Measurement**: Assay total TDP-43 and phospho-TDP-43 (pS409/410) via ELISA (Fujirebio). Run in duplicate with QC standards. Technicians blinded to diagnosis and cognitive scores.
**Statistical Stratification**: Using median CSF phospho-TDP-43 as cutoff, stratify AD patients into TDP-43 high (n~50) and TDP-43 low (n~50) groups. Compare cognitive performance between groups controlling for age, education, and APOE4 status.
## Phase 3: Longitudinal Cognitive Decline Assessment (Days 61-180)
**Follow-up Testing**: Repeat full neuropsychological battery at 12 and 24 months. Track change from baseline (ADAS-Cog, CDR sum of boxes, MMSE). Define decline endpoint as: (a) ≥4 point increase in ADAS-Cog, (b) ≥1 point increase in CDR, or (c) ≥3 point decrease in MMSE.
**Neuroimaging**: At 24-month endpoint, obtain 3T MRI (T1 MPRAGE, T2 FLAIR, tau-PET if available). Process via FreeSurfer for hippocampal volume, cortical thickness. Rate white matter hyperintensities.
**Time-to-Event Analysis**: Compare time to cognitive decline endpoint between TDP-43 high vs. low groups via Kaplan-Meier analysis and Cox proportional hazards regression (covariates: age, baseline cognition, APOE4, total tau).
LINKED HYPOTHESES
Source: PMID 34930382 ↗
🧫 Experiment Extras
PATHWAY
neurodegeneration and cognitive function
MARKET PRICE
$0.50
STATUS
completed
Prediction Markets (1 direct, 0 via hypothesis — 1 total)
Cognitive impact of TDP-43 pathology in AD patients — will this experiment confirm the hypYES 74% · Liq $100 · activeExperiment Results (1)
INCONCLUSIVEConfidence: 50%
Triggering stromal NOTCH-MYC by breast cancer cells increases RN7SL1 RNA, creating unshielded RNA that is packaged into exosomes. When transferred to immune cells, unshielded RN7SL1 triggers inflammatory responses. When
Recorded 2026-04-26T18:19 by llm
▸Metadataorigin_type: v1_polymorphic_backfill
| origin_type | v1_polymorphic_backfill |
| source_table | experiments |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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