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

Alzheimer's disease and related dementias are increasing globally, highlighting the urgent need to clarify disease mechanisms to improve diagnosis and treatment. Vascular alterations are a major pathological feature of Alzheimer's disease. Beyond the established contributions of small vessel disease and large artery atherosclerosis, our group has shown that dilatation of large cerebral arteries is associated with an increased risk of dementia and Alzheimer's pathology. The most severe manifestation of this non-atherosclerotic vascular phenotype is dolichoectasia, characterized by abnormal enlargement of large blood vessels. Despite consistent epidemiological evidence, the mechanisms linking arterial dilatation to Alzheimer's disease pathology remain poorly understood. To address this gap, we induced large artery dilatation in homozygous App^NL-G-F mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. Mice were euthanized at 9 months and brains were analyzed using biochemical and immunohistochemical approaches. Elastase-treated mice showed a significant increase in amyloid plaque burden in the hippocampus and cortex compared with vehicle-treated controls. Neuronal loss was observed in the CA1 region of the hippocampus, with a similar trend in CA3. Markers of impaired autophagic-lysosomal clearance were elevated in both hippocampal and cortical regions, while neuroinflammation and astrogliosis were unchanged. In contrast, matrix metalloproteinase-9 (MMP-9) levels were significantly increased. Overall, this study establishes a novel mixed vascular-neurodegenerative pathology model by inducing large artery dilatation in an amyloid mouse model. Our findings demonstrate that vascular dilatation accelerates Alzheimer's disease-related pathology and provide a platform to investigate underlying mechanisms and potential therapeutic targets for mixed dementia.