Blood–brain barrier (BBB) dysfunction is an early feature of Alzheimer’s disease (AD) and is particularly pronounced in individuals carrying the APOE ε4 allele, but the mechanisms linking APOE ε4 to BBB failure remain unclear. Here we show that astrocyte-derived fibronectin (FN1) is a key mediator of apolipoprotein E4 (APOE4)-driven BBB dysfunction in AD. Using postmortem human brain tissue, human three-dimensional vascular models and in vivo models, we demonstrate that APOE4, amyloid-β42 and inflammatory signals induce astrocytic FN1 upregulation and excessive perivascular deposition.
Fibronectin accumulation is sufficient to cause BBB leakage and disrupt VEGF/HB-EGF/IGF-1 signaling through integrin-mediated focal adhesion kinase activity. Reducing fibronectin or restoring growth factor signaling rescues BBB function in vitro and in vivo. Together, evidence from experimental models, human brain tissue and clinical datasets identifies fibronectin as a proximal mediator of APOE4-driven gliovascular dysfunction and highlights FN1 as a potential therapeutic target for vascular and BBB dysfunction in AD.
Blood–brain barrier (BBB) dysfunction is a hallmark of Alzheimer’s disease (AD)1,2,3,4,5,6 and is exacerbated in individuals carrying the APOE ε4 allele, the strongest genetic risk factor for late-onset AD7,8. Remodeling of the extracellular matrix (ECM) contributes to BBB dysfunction2,3,9,10,11, but the mechanisms linking apolipoprotein E4 (APOE4) and ECM remodeling remain unclear. We previously reported that APOE ε4 carriers with AD accumulate fibronectin at the gliovascular interface of the BBB, and that a protective loss-of-function fibronectin 1 (FN1) variant reduces AD risk by 71% (ref. 12).
These findings implicate fibronectin as a downstream mediator of APOE4 but leave its pathogenic mechanism unresolved. Here, we demonstrate that APOE4 and amyloid-β42 (Aβ42) drive the pathological accumulation of astrocyte-derived fibronectin at the gliovascular interface, disrupting astrocyte–endothelial communication and growth factor signaling essential for BBB integrity. Integrating human genetics, postmortem neuropathology, cerebrospinal fluid (CSF) analyses, single-cell transcriptomics, human induced pluripotent stem (iPS) cell-derived cerebrovascular models, and complementary zebrafish and mouse models, we establish fibronectin as a key mechanistic mediator of BBB dysfunction in AD.
Because AD and cerebrovascular pathology (CVP) frequently coexist4,13,14,15,16,17, we examined whether both conditions promote fibronectin deposition. We hypothesized that these conditions may induce fibronectin deposition and contribute to BBB dysfunction. To test this hypothesis, we examined fibronectin upregulation as a shared pathological feature in AD and CVP.
We performed immunolabeling for fibronectin and CD31 (a vascular endothelial marker) in the dorsolateral prefrontal cortex (Brodmann area 9) of 23 postmortem human brains divided into four groups based on postmortem neuropathological assessments (Fig. 1a–e and Supplementary Table 1): (1) no CVP or AD (control brains; Braak stage 0–I, no antemortem cognitive abnormalities, arteriolosclerosis score (ATS; indicating microvascular pathology) 0–1, n = 5); (2) CVP without AD (ATS 3–4, Braak stage 0–II or higher without antemortem cognitive abnormalities, n = 6); (3) AD without CVP (Braak stage IV–VI, ATS 0–1, n = 6); and (4) coincident CVP and AD (Braak stage IV–VI, ATS 3–4, n = 6)12. We observed significantly higher FN1 levels in CVP brains (+46.7%, generalized estimating equation (GEE) donor-level comparison: P = 1.8 × 10−4) and codirectionally elevated trends in AD and AD + CVP (+22.3% and +21.0%, respectively) under conservative donor-level inference (Fig. 1f–h). As a secondary analysis, when we combined all pathology groups and compared them to controls, we observed a significant overall effect on FN1 levels (+29.1%, GEE donor-level P = 8.0 × 10−3).
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