Rare FN1 Mutation Limits Fibronectin Buildup to Preserve Blood-Brain Barrier in APOE ε4 Carriers

The team integrated human postmortem tissue, CSF proteomics, single-cell RNA-seq, spatial transcriptomics, iPSC-derived vessel models, and zebrafish/mouse APOE ε4 knock-ins. APOE ε4 mice showed 1.9-fold higher perivascular fibronectin than APOE ε3 controls, with corresponding 40% increase in IgG leakage indicating barrier permeability. Human carriers of the rare FN1 variant displayed reduced fibronectin deposition and preserved claudin-5 expression despite APOE ε4 status. These orthogonal datasets converge on a mechanism where excess fibronectin disrupts tight junctions via integrin-mediated signaling rather than simple mechanical stiffening.

Prior observational cohorts linked APOE ε4 to accelerated barrier breakdown but could not isolate the fibronectin node. The current multi-model design supplies causal ordering: genetic reduction of fibronectin rescues barrier function downstream of APOE ε4, a step missing from earlier GWAS or purely epidemiological work. This also reframes fibronectin not as structural scaffold but as modifiable driver of neuroinflammation.

Translation hinges on whether pharmacologic FN1 suppression or integrin blockade can recapitulate the protective haplotype without impairing wound healing elsewhere. Planned phase-1 safety trials of antisense oligonucleotides targeting vascular fibronectin are slated for 2027 in biomarker-positive APOE ε4 individuals.