Brain large artery dilatation increases the risk for Alzheimer's disease pathology

Alzheimer's disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in App ^NL-G-F mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus ( p = 0.021 ) and cortex ( p = 0.029 ) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus ( p = 0.036 ), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex ( p = 0.009 and p = 0.001 , respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in App ^NL-G-F mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimer's disease progression.