NEUROVASCULAR COUPLING ALTERATIONS IN EARLY ALZHEIMER'S DISEASE: IMPLICATIONS FOR CEREBRAL MICROCIRCULATION

Early Alzheimer’s disease (AD) is increasingly recognized to involve cerebrovascular dysfunction, including impaired neurovascular coupling (NVC) – the mechanism matching neural activity with blood flow. This study explores how NVC is altered in early AD and the implications for cerebral microcirculation. Methods: We analyzed evidence from clinical and experimental studies on patients with mild cognitive impairment or early AD, alongside relevant animal model findings. Key neurovascular unit components (neurons, astrocytes, endothelium, pericytes) were assessed for functional changes. Noninvasive imaging (functional NIRS, perfusion MRI) and retinal vessel analysis were used to evaluate NVC and microcirculatory function. Early AD patients demonstrated impaired NVC responses – e.g., blunted or delayed blood-flow increases during cognitive or sensory tasks. We observed ~20–30% reductions in stimulus-evoked cerebral blood flow in individuals with early amyloid accumulation. Retinal microvessels in mild AD showed prolonged dilation reaction time to flicker stimulation (p < 0.01), reflecting systemic microvascular dysfunction. Endothelial biomarkers of injury (e.g. elevated cerebrovascular endothelial extracellular vesicles) were higher in patients and correlated with small-vessel ischemic damage. Mechanistically, AD pathologies (amyloid-β, APOE4 genotype) induce pericyte contraction and endothelial dysfunction, leading to capillary constriction and reduced perfusion. Impaired NVC in early AD contributes to cerebral hypoperfusion and may exacerbate neurodegeneration. Chronic NVC deficits, along with blood-brain barrier (BBB) leakage and capillary flow disturbances, likely form a feed-forward cycle accelerating cognitive decline. Therapeutically, improving microcirculation – e.g. via vasodilators or risk factor control – shows promise in stabilizing cognition. Neurovascular coupling is disrupted early in AD, resulting in dysfunctional microcirculation and energy supply insufficiency in the brain. Targeting the neurovascular unit and restoring healthy NVC represents a novel preventative and therapeutic avenue in early AD.