📋 Research Plan
alzheimerTREM2$4,200,00024 monthsN = 200
Assay
Protocol: Intrathecal delivery of TREM2 agonistic antibody (mAb 4D9) or ZF-ZFN gene activator.
Reagents: TREM2 agonist mAb (4D9, 5mg/kg), ZF-ZFN plasmid (pJT-45), AAVrh10 capsid.
Cohort: Early AD (MMSE 20-26), ages 55-80, N=200, randomized 1:1 treatment:placebo.
Controls: Vehicle-treated AD mice (5xFAD model), TREM2 KO mice.
Readouts: (1) CSF Aβ42/Aβ40 ratio (primary), (2) PET amyloid SUVr (secondary), (3) CSF NfL, (4) cognitive battery (ADAS-Cog13), (5) microglial coverage by Iba1 PET.
Sample size rationale: Two-group comparison, effect size 0.45, α=0.05, power=0.80, gives n=80/group; inflate to 100/group for 20% dropout.
Primary endpoint
12-month change in CSF Aβ42/Aβ40 ratio from baseline
Kill criteria
- No significant microglial activation by 6-month PET imaging
- Aβ42/Aβ40 ratio worsening > 10% vs placebo
- Serious adverse events (SAEs) > 5% in treatment arm
- Anti-drug antibody formation in > 25% of subjects
Power: {'test': 'ANCOVA', 'alpha': 0.05, 'power': 0.8, 'covariates': ['baseline_cognition', 'age', 'APOE4_status'], 'effect_size': 0.45, 'expected_dropout': 0.2}