SUMMARY
# Mechanism: Why Does Amyloid Removal Only Slow Decline 27%?
## Background and Rationale
The recent clinical approval of amyloid-clearing antibodies lecanemab and donanemab represents a significant milestone in Alzheimer's disease therapeutics, yet their modest clinical efficacy—approximately 27% slowing of cognitive decline despite achieving near-complete plaque removal—reveals a fundamental gap in our understanding of AD pathogenesis. This paradox suggests that while amyloid-beta accumulation
METHODOLOGY NOTES
**Study Design and Patient Cohort Recruitment**
A prospective, longitudinal observational study enrolling 500 early-stage Alzheimer's disease patients (CDR 0.5-1.0, MMSE 20-26) receiving FDA-approved amyloid-clearing monoclonal antibodies (lecanemab or donanemab) across 15 tertiary medical centers. Stratification occurs by: (1) APOE4 genotype (ε4+/ε4-), (2) age quartiles (55-65, 65-75, 75-85, >85 years), (3) baseline cognitive scores (ADAS-Cog13 tertiles), and (4) amyloid PET burden (SUVr >1.3 or ≤1.3). Baseline assessment includes neuropsychological testing (ADAS-Cog13, CDR-SB, MMSE), genetic profiling (whole genome sequencing), structural and functional neuroimaging (3T MRI with DTI, resting-state fMRI), and blood/CSF biomarker collection within 2 weeks pre-treatment initiation.
**Multi-Omics Biofluid and Tissue Analysis Pipeline**
Longitudinal CSF sampling occurs at baseline, 6, 12, 24, and 36 months post-treatment initiation via lumbar puncture. Each 12-mL CSF aliquot undergoes: (