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Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular A\u03b2 lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular A\u03b2 fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar A\u03b2 load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar A\u03b2, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.<\/jats:p>","DOI":"10.64898\/2026.06.23.733858","type":"posted-content","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T10:00:12Z","timestamp":1782640812000},"source":"Crossref","is-referenced-by-count":0,"title":["mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimer\u2019s disease with cerebral amyloid angiopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-7771","authenticated-orcid":false,"given":"Candice E.","family":"Van Skike","sequence":"first","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0460-6774","authenticated-orcid":false,"given":"Lauren 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