The etiology of Alzheimer's disease (AD) is complex and multifactorial. Multiple risk factors through still not well understood molecular mechanisms are known to influence the individual susceptibility for sporadic AD. One of the often-overlooked contributors to AD pathophysiology is Aβ accumulation in the cerebrovasculature (CAA), present in >90% of AD cases. CAA imposes restriction in cerebral blood flow resulting in ischemic white matter lesions, microhemorrhages, enhanced neuroinflammation, and synaptic dysfunction. Synaptic damage correlates with loss of cognitive function, is an early event in AD pathogenesis, and worsens with disease progression. Oligomeric Aβ (oligAβ) has emerged as the species capable to selectively disrupt synaptic transmission, triggering cascades of events that primarily affect mitochondrial function, disrupting ATP production, inducing caspase-3 activation, and affecting levels and distribution of synaptic components. Our own preliminary data in APP Tg lines demonstrate profound changes in pre-/post-synaptic markers, low ATP levels and reduced mitochondrial activity in isolated synaptosomes. Highlighting the relevance of interlinked metabolic pathways, we show that hypoxic conditions drastically potentiate the detrimental effects of oligAβ, exacerbating ROS production and inducing comparable toxicity by 500-fold lower Aβ doses than those required under normoxia. The affected mechanisms are in part related to the protective redox sensor Nrf2 – downregulated in AD – as small-molecule Nrf2 activators rescue the in vitro phenotype under normoxic conditions. Notably, hypoxia triggers activation of the oxygen sensitive HIF-1α pathway via upregulation of Siah2, a hypoxia-inducible molecule also capable of downregulating Nrf2. We hypothesize that progressive brain hypoperfusion as a result of CAA precipitate Aβ-induced mitochondrial dysfunction via dysregulation of the Nrf2–HIF-1α oxidative stress/hypoxia protective response resulting in increased synaptic alterations, neuroinflammation, and vascular susceptibility to microhemorrhages, events we postulate are amenable for translational interventions. We propose in vitro studies to identify the protective mechanisms exerted by small molecule Nrf2 activators under conditions mimicking hypoperfusion, assessing changes in global bioenergetics, functional impact in cell-specific biological parameters, and regulatory shifts in Nrf2–HIF-1α paths modulated by the hypoxia-sensor Siah2. Data will be validated in vivo in Tg models with progressive Aβ CAA using 1HMRS, conventional MRI, behavioral assessments, and LTP measurements, complemented by biochemical dissection of functional components of the mitochondrial machinery and Nrf2–HIF-1 paths, and their impact on synaptic changes and bioenergetics in isolated microvessels and synaptic mitochondria. Induction of hyperhomocysteinemia through a diet that results in cerebrovascular abnormalities, reduced oxygen delivery and cognitive defi...