SUMMARY
# Vascular Contribution to Alzheimer's Disease — Beyond Amyloid
## Background and Rationale
Alzheimer's disease (AD) pathogenesis extends beyond amyloid-beta accumulation to include significant vascular dysfunction. The vascular hypothesis of AD posits that cerebrovascular abnormalities, including blood-brain barrier (BBB) breakdown, reduced cerebral blood flow, and endothelial dysfunction, contribute independently to cognitive decline and interact synergistically with amyloid pathology. This mu
METHODOLOGY NOTES
Phase 1 (Months 1-6): Recruit 300 participants across three groups: cognitively normal controls (n=100), MCI (n=100), and AD dementia (n=100). Inclusion criteria: ages 65-85, MMSE scores appropriate for group classification, stable medications. Exclusion: contraindications to MRI, significant psychiatric disorders, or other neurodegenerative diseases. Phase 2 (Months 7-18): Baseline assessments including comprehensive neuropsychological testing (CDR, ADAS-Cog, TMT), lumbar puncture for CSF collection, and retinal photography. Advanced MRI protocol: 3T scanner with dynamic contrast-enhanced sequences using gadolinium-DTPA (0.1 mmol/kg), arterial spin labeling for perfusion mapping, DTI with 64 directions, and structural T1/FLAIR imaging. Simultaneous amyloid PET using 18F-florbetapir. Phase 3 (Months 19-30): CSF analysis for traditional biomarkers (Aβ42, tau, p-tau) and novel vascular markers (PDGFR-β, sTREM2, VEGF) using ELISA and Luminex multiplex assays. Quantitative analysis of BBB