This experiment investigates the fundamental question of why amyloid-clearing antibodies (lecanemab, donanemab) provide only ~27% slowing of cognitive decline despite achieving near-complete plaque removal. Understanding this mechanism is critical for developing more effective therapeutic strategies.
Need combination therapy — targeting both amyloid AND tau is required for meaningful disease modification
Experimental Design
Cohort
N=200: Participants from CLARITY-AD (lecanemab) or TRAILBLAZER-ALZ 2 (donanemab) with:
Complete amyloid PET clearance (Centiloid <10)
Baseline and 18-month tau PET (Braak I-III vs IV-VI)
CSF biomarkers at baseline, 6, 12, 18 months
Cognitive assessments (CDR-SB, MMSE, ADAS-Cog13)
Primary Endpoints
...
Amyloid Removal Mechanism Insufficient
Overview
Mermaid diagram (expand to render)
This experiment investigates the fundamental question of why amyloid-clearing antibodies (lecanemab, donanemab) provide only ~27% slowing of cognitive decline despite achieving near-complete plaque removal. Understanding this mechanism is critical for developing more effective therapeutic strategies.
Mechanistic insight: Determine whether tau spread continues after amyloid removal
Biomarker panel: Identify patients likely to benefit from amyloid therapy
Trial design: Propose combination therapy trial for non-responders
Timeline: Results within 24 months of study initiation
Model Systems
| System | Use | Strength | |--------|-----|----------| | Human clinical data | Primary analysis | Direct relevance to patients | | iPSC neurons | Mechanism validation | Patient-specific biology | | Mouse models (5xFAD x P301S) | Combination testing | In vivo proof-of-concept |
Feasibility Assessment
Data availability: CLARITY-AD and TRAILBLAZER-ALZ 2 datasets are public