Edwards, Natalie C.Lao, Patrick J.Alshikho, Mohamad J.Mazen, JessicaHuber, BenjaminHale, ChristianeBerroa, JoncarlosMorel, NataliePacheco, AliciaWalker, SaraHerman, MathieuGutierrez, JoséWilcock, Donna M.Simoes, SabrinaManly, Jennifer J.Brickman, Adam M.2025-12-022025-12-022025Edwards NC, Lao P, Alshikho MJ, et al. Alzheimer Disease, Vascular Disease, and Blood-Brain Barrier Permeability Biomarkers in Middle-Aged Adults. Neurology. 2025;105(9):e214220. doi:10.1212/WNL.0000000000214220https://hdl.handle.net/1805/52392Background and objectives: Cerebrovascular disease (CVD) influences Alzheimer disease (AD) risk and progression, but the link between vascular disease and AD pathophysiology remains unclear, particularly in midlife when the impact of CVD on AD risk may be strongest. This study examined the relationship of recently validated vascular cognitive impairment (VCI) plasma biomarker concentrations that reflect aspects of blood-brain barrier dysfunction with MRI markers of CVD and AD plasma biomarker concentrations. Methods: The study included middle-aged participants from the Offspring Study of Racial and Ethnic Disparities in AD who had MRI and plasma biomarker data available. Biomarker concentrations of vascular endothelial growth factor (VEGF) family members (VEGF-D, placental growth factor [PlGF], and basic fibroblast growth factor [bFGF]) were measured using the Meso Scale Discovery platform. β-Amyloid (Aβ42, Aβ40), phosphorylated tau 181 (p-tau181), astrocytosis (glial fibrillary acidic protein [GFAP]), and neurodegeneration (neurofilament light chain [NfL]) biomarkers were measured with Simoa immunoassays. White matter hyperintensity (WMH) volumes were derived from T2-weighted MRI scans. Bivariate relationships of WMH, Aβ42/Aβ40 ratio, p-tau181, GFAP, and NfL with VEGF biomarkers were tested, and path analyses examined potential causal pathways linking each VEGF biomarker concentration to WMH and GFAP, as well as their downstream associations with tau pathology and neurodegeneration. Results: We analyzed data from 488 participants (mean [SD] age = 54.3 [10.5]; 66.8% women). Higher PlGF levels were associated with older age (R [CI] = 0.25 [0.17-0.33]); greater WMH volume (R [CI] = 0.2 [0.11-0.29]); and higher levels of GFAP (R [CI] = 0.11 [0.02-0.2]), p-tau181 (R [CI] = 0.12 [0.03-0.21]), and NfL (R [CI] = 0.19 [0.1-0.27]). Higher VEGF-D was associated with increased GFAP (R [CI] = 0.11 [0.02-0.19]) and NfL (R [CI] = 0.16 [0.07-0.25]) levels. bFGF concentration was associated with a lower Aβ42/40 ratio (R [CI] = -0.1 [-0.19 to -0.02]) and higher p-tau181 levels (R [CI] = 0.13 [0.04-0.21]). The best fitting path model showed that PlGF had an indirect effect on GFAP levels mediated by WMH. GFAP subsequently had a direct positive effect on p-tau181, which in turn had a positive effect on NfL levels. VEGF-D and bFGF levels also had a positive direct effect on NfL. Discussion: The findings suggest that permeability of the blood-brain barrier is linked to AD pathophysiology, contributes to cerebrovascular lesions observed on MRI, and is associated with neuroinflammation in middle age.en-USPublisher PolicyAlzheimer diseaseBlood-brain barrierNeurofilament proteinsCerebrovascular disordersArticle