Cerebral hypoperfusion and the vascular-metabolic-immune-glymphatic network in Alzheimer's disease: mechanisms, diagnosis, and therapy.

Abstract

Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strategies have dominated this field for over three decades. Although recent anti-Aβ antibodies have shown modest promise, their limited clinical benefits coupled with safety concerns underscore the necessity of re-evaluating the pathological mechanisms underlying AD. Cerebral hypoperfusion (CH), a detectable alteration emerging in the preclinical stage of AD, has garnered increasing attention for its potential driving role in disease pathogenesis. This review proposes a "vascular-metabolic-immune-glymphatic" (VMIG) pathological network model originating from CH: CH induces pericyte damage, astrocyte end-feet impairment, and extracellular matrix degradation, thereby resulting in neurovascular unit dysfunction; reduces oxygen and glucose delivery, precipitating mitochondrial energy failure and reactive oxygen species overproduction, which in turn initiates neuroinflammatory cascades; and attenuates arterial pulsation-driven flow while disrupting perivascular space architecture, culminating in glymphatic system clearance dysfunction. These mechanisms are intricately interconnected, establishing a self-perpetuating pathological loop. Building upon the VMIG framework, this review integrates multimodal neuroimaging techniques (ASL-MRI, Aβ/tau-PET, DTI-ALPS) with peripheral biomarkers (VEGF/Ang-2, sTREM2/GFAP, sPDGFRβ/Aβ42 ratio) to establish a comprehensive system for early diagnosis and stratified assessment of AD. Furthermore, we advocate for temporally sequenced combinatorial therapeutic strategies targeting the pathological network and discuss the translational potential of nanoparticle-based co-delivery systems. The VMIG model offers an integrative framework for understanding the multi-system dysregulation inherent to AD, facilitating a paradigm shift from single-target intervention toward network-based restoration.