Targeting of the PI3K/AKT/mTOR signaling pathway in the neurovascular interface in both Alzheimer's disease and atherosclerosis: The potential nexus.

Alzheimer's disease (AD) and atherosclerosis (AS) are traditionally viewed as distinct neurodegenerative and vascular disorder respectively. However, emerging evidence reveals a profound molecular cross-talk and pathophysiological interplay between these two conditions. This review explores the molecular crossroads where AD and AS converge, identifying shared signaling pathways that offer novel therapeutic opportunities. At the center of this connection is amyloid-beta (Aβ), which serves as a systemic molecular nexus. While central Aβ accumulation is a hallmark of AD, peripheral Aβ, produced in tissues such as skeletal muscle and pancreas, can cross the blood-brain barrier (BBB) to induce endothelial dysfunction and neurovascular inflammation. This review highlights how common molecular hubs, including the PI3K/AKT/GSK3β, mTOR, PP2A, and PTEN signaling pathways, drive the pathogenesis of both diseases by regulating oxidative stress, inflammation, and autophagy. By addressing these shared mechanisms, the review proposes a paradigm shift toward dual-purpose therapies. Modulating Aβ clearance, inhibiting the over-activated GSK3β, or utilizing mTOR inhibitors and PP2A activators could concurrently mitigate neurodegeneration and stabilize atherosclerotic plaques. Ultimately, recognizing AD and AS as interconnected systemic disorders provides a compelling rationale for multidisciplinary clinical strategies and integrated pharmacological interventions to improve outcomes in an aging population.