In Tg2576 mice modeling Alzheimer's disease with cerebral amyloid angiopathy (CAA), mTOR hyperactivation drives fibrillar amyloid-β accumulation within cerebrovascular walls, impairs endothelium-dependent vasodilation, disrupts tight junction proteins, increases cerebral microhemorrhages, and uncouples neurovascular signaling via nNOS dysfunction. Rapamycin treatment reversed all of these deficits — reducing vascular Aβ fibril load, restoring blood-brain barrier integrity, attenuating microhemorrhage, normalizing neurovascular coupling, and rescuing contextual memory in both male and female mice.
CAA affects roughly 50–80% of Alzheimer's patients and is a leading cause of intracerebral hemorrhage in older adults, yet it has no approved disease-modifying treatment. This study is notable for mechanistically linking mTOR — already implicated in tau pathology, neuroinflammation, and cognitive aging — directly to vascular amyloid deposition, a pathway previously underexplored. The nNOS-mediated neurovascular uncoupling angle is particularly important: it connects mTOR to impaired cerebral blood flow regulation, a finding with implications beyond Alzheimer's for vascular dementia broadly.
Critical caveats apply. This is a preprint, not yet peer-reviewed, and all findings are in a transgenic mouse model. Rapamycin's immunosuppressive profile complicates direct clinical translation, though rapalogs with better tolerability are in development. The study is nonetheless paradigm-advancing: it positions mTOR as a unifying driver of both parenchymal and vascular amyloid pathology, strengthening the case for vascular-targeted rapamycin trials in CAA and mixed-pathology dementia.
