Background: While aging is the primary risk factor for Alzheimer's disease (AD), emerging evidence suggests that vascular dysfunction, present in cerebral small vessel diseases (CSVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is also a major contributor for disease progression. Indeed, several studies have provided clinical evidence for a close synergistic relationship between AD and CSVD in cases where both diseases coexist. CSVD can elicit amyloid pathology, while Alzheimer's‐associated cerebral amyloid angiopathy (CAA) and Ab plaque deposition may lead to concomitant vascular damage. Mutations in genes such as APP, PSEN1, and PSEN2 are not limited to AD, as APP mutations can also cause CAA, while PSEN1 and PSEN2 are involved in Notch3 signaling, a process known to be dysregulated in CADASIL. Here, we aimed to investigate the additive or synergistic effects of amyloid pathology and CADASIL‐related vascular damage on disease progression. Method: To explore alterations in amyloid and vascular pathology when AD and CADASIL‐related CSVD coexist, we used PET/CT and histology to analyze over time the amyloid deposition in the form of plaques and CAA in a relevant mouse model of AD (5xFAD) carrying the Notch3 C456R mutation that causes CADASIL. Methoxy‐X04, Thioflavin‐S, or 6E10 were used to visualize amyloid accumulation in fixed brain tissues. The progression of microvascular dysfunction and neuroinflammation were assessed by immunofluorescence staining, Western blotting, RNA sequencing, and real‐time PCR. Result: Adult 5xFAD‐Notch3C456R mice showed accelerated parenchymal and vascular amyloid deposition compared to 5xFAD mice. Progressive gliosis and microvascular damage were concomitant to parenchymal and vascular amyloid accumulation. These changes were associated with blood‐brain barrier disruption and reduction in pericyte coverage of cerebral capillaries. Conclusion: We found accelerated amyloid plaque deposition, CAA, gliosis, and vascular damage in a mixed murine model of AD and CADASIL, suggesting that CSVD‐associated vascular changes directly contribute to AD pathology. This model offers novel opportunities to investigate the intricate interplay between CSVD and AD. This research was funded by NIH/NINDS grant RF1NS117486. [ABSTRACT FROM AUTHOR]