A cerebrospinal fluid blood-brain barrier dysfunction score is associated with progression from mild cognitive impairment to Alzheimer's disease.

BACKGROUND: Blood-brain barrier permeability-related alterations are increasingly recognised as an early process in Alzheimer's disease, but their prognostic value and candidate molecular markers remain unclear. METHODS: Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we derived a cerebrospinal fluid BBB permeability-related score and evaluated its association with progression from mild cognitive impairment (MCI) to clinically diagnosed Alzheimer's disease dementia using Kaplan-Meier and multivariable Cox analyses. We additionally performed two-sample Mendelian randomisation screening across 832 CSF proteins in FinnGen, with replication in Bellenguez et al. 2022. RESULTS: Among 134 MCI participants, the higher BBB permeability-related score group showed significantly faster progression to clinically diagnosed AD dementia (HR 1.73, 95% CI 1.10-2.74; p = 0.018), remaining significant after adjustment for CSF amyloid-beta, total-tau, and phosphorylated tau. CD226 (IVW OR 3.12; FDR = 0.018) and GFRα-1 (IVW OR 0.52; FDR = 0.009) were identified; CD226 showed directional consistency across datasets whereas GFRα-1 did not. CONCLUSIONS: A BBB permeability-related score is associated with longitudinal progression from MCI to clinically diagnosed AD dementia. CD226 is a biologically supported candidate signal; GFRα-1 is hypothesis-generating pending replication.