Early Amyloid-beta-driven cerebrovascular dysfunction is associated with altered CSF Aβ dynamics and precedes prominent neuronal apoptosis in Alzheimer’s disease

Early vascular dysfunction is increasingly recognized as a key contributor to altered Amyloid-beta (Aβ) dynamics in Alzheimer’s disease (AD). Here, we combined in vitro cell culture assays with longitudinal in vivo analyses of APP/PS1 mice from 1 to 12 months, profiling cortical vascular density, VEGFR2 expression, cerebrospinal fluid (CSF) and cortical Aβ₁₋₄₂ levels, perivascular glial activation, and neuronal apoptosis. In vitro, Aβ₁₋₄₂ oligomers impaired pericyte-mediated tube-like network formation and induced endothelial apoptosis; effects on VEGFA mRNA varied with dose and cell type and were not strictly monotonic. In vivo, APP/PS1 mice with innate Aβ exhibited reduced VEGFR2 protein expression in cortex and capillary rarefaction starting at 1 month. These vascular deficits coincided with declining CSF Aβ₁₋₄₂ levels and preceded prominent cortical Aβ₁₋₄₂ deposition from 6 months. Perivascular GFAP-positive astrocytes and Iba1-positive microglia were chronically activated around cortical capillaries. Transcriptomic profiling of cortical capillaries isolated from 1-month-old APP/PS1 mice revealed early suppression of oxidative phosphorylation and mitochondrial pathways, indicating intrinsic metabolic vulnerability of the microvasculature. Reduced NeuN immunoreactivity was detectable from 1 month, whereas prominent TUNEL⁺/NeuN⁺ co-localization emerged only at 6 to 9 months, after prolonged vascular dysfunction and altered CSF Aβ dynamics. These findings suggest that congenitally expressed Aβ₁₋₄₂ may drive cerebrovascular dysfunction, alter CSF Aβ₁₋₄₂ dynamics, and contribute to cortical amyloid accumulation and neuronal apoptosis. Enhancing vascular function and capillary energy metabolism may represent a complementary therapeutic strategy in AD. Aβ₁₋₄₂ oligomers inhibited pericyte-mediated tube-like network formation and induced endothelial cell apoptosis in vitro. Congenital Aβ in APP/PS1 mice was associated with early cerebrovascular dysfunction with reduced cortical VEGFR2 protein, capillary rarefaction, and increased perivascular inflammation. Early vascular deficits coincided with altered CSF Aβ₁₋₄₂ dynamics and preceded prominent cortical Aβ₁₋₄₂ accumulation. Sustained microvascular energy-metabolism deficiency, capillary rarefaction, and Aβ accumulation preceded prominent neuronal apoptosis in AD progression.