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.