The hypertension-NVU-cognition Axis: Mechanisms and interventions.

Introduction

The burden of AD and the emergence of vascular risk factors

Alzheimer's disease (AD) has become the leading neurodegenerative disorder causing cognitive impairment and functional loss in the elderly globally [1].It is estimated that over 50 million people worldwide are affected by this disease, and with the accelerating pace of population aging, the total number of patients is projected to rise to nearly 150 million by 2050 [2].This disease not only imposes a heavy caregiving burden and emotional stress on patients' families but also presents a severe socioeconomic challenge [3].Annual global expenditures on medical and care costs for AD and related dementias have surpassed one trillion US dollars, constituting a significant burden on public health systems.

Global epidemiological burden and economic costs of AD

The epidemiological burden of AD shows significant geographical and population disparities. High-income countries exhibit higher age-standardized incidence rates due to their aging population structures, while low- and middle-income countries experience rapid growth in the absolute number of patients due to their large population bases. In the middle to late stages of the disease, patients often lose basic self-care abilities, requiring long-term professional care, which further exacerbates the consumption of family and societal resources [4].Economic cost analyses reveal that direct medical expenses constitute only a portion of the total cost; indirect costs such as productivity loss and the burden on informal caregivers often account for a larger proportion, creating a multi-layered and persistent socioeconomic impact [5].

Limitations of anti-aβ therapies driving the need for new targets

The amyloid-beta (Aβ) hypothesis has long dominated the direction of AD drug development [6].However, most monoclonal antibodies or secretase inhibitors targeting Aβ have failed to significantly improve patients' cognitive function in clinical trials or have shown only limited clinical significance. While some drugs can clear Aβ plaques in the brain, they have not effectively slowed the cognitive decline process and have even caused adverse effects such as vasogenic edema or microhemorrhages [7].These outcomes suggest that the pathological mechanisms of AD are highly complex, and targeting Aβ alone may be insufficient to halt disease progression. Therefore, there is an urgent need to re-examine disease mechanisms from multi-system and multi-pathological perspectives and explore new intervention targets [8].

Positioning of vascular risk factors in the latest diagnostic criteria

With the deepening understanding of disease mechanisms, the role of vascular factors in the pathophysiology of AD has gained increasing attention. The 2018 research framework updated by the National Institute on Aging and the Alzheimer's Association explicitly lists vascular brain injury as an important comorbid pathology influencing the continuous disease spectrum of AD [9].This framework emphasizes the systematic assessment of vascular risk factors and their resulting imaging manifestations, such as cerebral small vessel disease and white matter hyperintensities, during diagnosis and disease subtyping [10].This shift marks the integration of the vascular component into the overall pathological assessment system of AD, providing a theoretical basis and clinical guidance for preventing and intervening in the disease from a vascular perspective.

The vascular contribution of midlife hypertension to cognitive decline: Positioning within established VCID and CSVD frameworks

Although hypertension is widely recognized as a significant risk factor for Alzheimer's disease (AD), the extent to which hypertension in midlife drives cognitive decline through mechanisms that are partially independent of, yet interacting with, traditional Aβ/tau pathology has not been fully elucidated [11].Existing studies often treat hypertension as a confounding variable or a comorbidity, failing to systematically reveal its early, partially independent mechanistic role in the temporal progression of the disease.There is a particular lack of in-depth exploration into the crucial mediating role of the neurovascular unit (NVU) between hypertension and cognitive decline. This limitation hinders our ability to develop precise prevention strategies from a vascular perspective.

Temporal differences in the impact of midlife versus late-life blood pressure on cognition

Growing epidemiological evidence suggests a significant temporal heterogeneity in the impact of blood pressure on cognitive function. Elevated blood pressure in midlife (typically ages 40–60), especially a sustained rise in systolic blood pressure, has been confirmed as a strong predictor of late-life cognitive impairment and the onset of AD [12].For instance, multiple long-term cohort studies show that midlife hypertension is significantly associated with brain structural changes, white matter lesions, and cognitive decline 20–30 years later. Conversely, the relationship between late-life blood pressure (especially systolic) and cognition is more complex.

Some studies even observe an association between lower blood pressure and cognitive worsening in later life, which may be related to impaired cerebral autoregulation and increased risk of hypoperfusion [13].This temporal difference strongly suggests that midlife hypertension inflicts early and potentially irreversible damage on the brain through pathophysiological mechanisms distinct from those in late life, thereby laying the groundwork for future cognitive decline.

Current research lacks focus on the NVU as a mediating mechanism

Current research on the association between hypertension and cognition largely remains at the level of epidemiological links or terminal neuropathology, failing to deeply dissect the mediating mechanisms involved. Most studies focus on the correlation between hypertension and late-stage pathological features like brain atrophy, amyloid plaques, or neurofibrillary tangles, while overlooking potential microcirculation and NVU dysfunction that may occur earlier in the disease process [14].The NVU, as the first line of defense in maintaining brain homeostasis, is highly sensitive to hypertensive injury. However, systematic research on how midlife hypertension leads to early NVU damage—such as blood-brain barrier disruption, pericyte loss, and neurovascular uncoupling—and how these damages further trigger neuronal dysfunction and network connectivity abnormalities, ultimately resulting in cognitive decline, is still insufficient [15].Clarifying the core mediating role of the NVU in this process represents a key theoretical gap connecting hypertensive exposure to long-term cognitive outcomes and is a crucial foundation for developing early vascular-targeted intervention strategies.

It is important to position this framework precisely within the existing literature. The amyloid-β (Aβ) cascade and tau propagation remain central to current Alzheimer's disease pathogenesis models. This review does not present the Hypertension-NVU-Cognition axis as a standalone, mutually exclusive alternative to these classical hypotheses.

Rather, we integrate midlife hypertension and NVU dysfunction into the broader AD continuum, recognizing that vascular pathology and neurodegenerative proteinopathy likely coexist, interact, and synergistically drive cognitive decline in many individuals. The contribution of this review lies in its systematic emphasis on midlife blood pressure trajectories as actionable predictors, its detailed mechanistic linkage of NVU injury to cognitive decline, and its translation toward biomarker-guided precision prevention—rather than in claiming a fully independent pathogenic pathway.

To facilitate critical appraisal of the evidence presented, this review distinguishes between levels of certainty. High-level evidence derives from large-scale prospective cohort studies and randomized controlled trials in humans. Moderate-level evidence includes cross-sectional neuroimaging and fluid biomarker studies, which establish associations but require longitudinal validation.

Mechanistic claims—such as specific phosphorylation events, eNOS uncoupling, or microglial activation states—are primarily inferred from preclinical models (e.g., spontaneously hypertensive rodents, in vitro endothelial or glial cultures) and are explicitly labeled as mechanistic hypotheses requiring translational confirmation. Table 5 summarizes the evidence grading for key claims across this review. In positioning this framework within the established literature, we emphasize that the Hypertension–NVU–Cognition axis builds upon, rather than replaces, well-characterized constructs—including vascular cognitive impairment, cerebral small vessel disease, and neurovascular dysfunction—and that its relationship to amyloid and tau pathology is one of coexistence and interaction rather than exclusivity.

Overview of the structure and function of the neurovascular unit (NVU)

The neurovascular unit (NVU) is the fundamental functional and structural unit that maintains the internal environment stability of the central nervous system. It extends beyond the traditional singular concept of the blood-brain barrier (BBB), integrating brain microvascular endothelial cells, pericytes, astrocytic endfeet, microglia, and the extracellular matrix basement membrane into a dynamic, synergistic functional complex [16].This unit not only constitutes and rigorously regulates the BBB but is also the key structural foundation for achieving precise coupling between neural activity and local cerebral blood flow, ensuring brain tissue energy metabolism and the timely clearance of metabolic waste [17].A deep understanding of the NVU's composition and function is a prerequisite for elucidating how it becomes an early disease target under pathological conditions and mediates cognitive dysfunction (Fig. 1).Fig.

1Schematic of Central Nervous System Multi-Barrier Architecture: Anatomical and Functional Relationships Among the Meningeal Barrier, Blood–Brain Barrier, and Blood–CSF Barrier This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig. 1

Cellular composition and molecular markers

Brain microvascular endothelial cells

Brain microvascular endothelial cells (BMECs) constitute the physical and biochemical core of the blood-brain barrier (BBB). Their most distinctive feature compared to peripheral endothelial cells is the formation of highly complex tight junctions and adherens junctions, creating an almost impermeable continuous barrier [18].Tight junctions are primarily composed of transmembrane proteins such as claudin-5 and occludin, along with cytoplasmic scaffolding proteins like zonula occludens-1 (ZO-1). Claudin-5 is the key protein determining barrier tightness and selective pore size, while occludin is more involved in junctional stability and signal transduction [19].The expression, phosphorylation status of these junctional proteins, and their anchoring to the cytoskeleton collectively and dynamically regulate the permeability of the BBB.

The core components, molecular markers, and primary functions are detailed in Table 1.Table 1Core Components, Molecular Markers, and Primary Functions of the Neurovascular Unit (NVU).ComponentKey Molecular MarkersPrimary FunctionsPositional RelationshipReferencesBrain Microvascular Endothelial CellsClaudin-5, Occludin, ZO-1 (Tight junction proteins)Form the main structure of the BBB; regulate selective permeability; express various transporters, mediating nutrient uptake and metabolite efflux.Form the capillary lumen; connected to each other via tight junctions.[20], [21]PericytesPDGFRβ (Platelet-Derived Growth Factor Receptor β) signaling axisMaintain microvascular stability; regulate capillary blood flow; support endothelial cell function; participate in BBB development and maintenance.嵌入在基底膜中；细胞体和突起环绕内皮细胞。[22], [23]星形胶质细胞末端AQP4（水通道蛋白-4，分布于端足膜上）调节脑部水分和离子稳态；参与神经血管耦合；通过淋巴脑系统清除代谢废物；释放血管活性物质。覆盖约85%的毛细血管表面，形成胶质界限。[24]小胶质细胞各种模式识别受体，细胞因子受体免疫监视与防御；清除细胞碎片和异常蛋白质；调节突触可塑性；参与神经炎症反应。Located in the perivascular space, with processes extending into the NVU microenvironment.[25], [26]Basement MembraneLaminin, Collagen IVProvide structural support and cell anchoring sites; participate in cell signaling; regulate cell migration and differentiation; influence barrier selectivity.Located between endothelial cells/pericytes and astrocytic endfeet.[27]

Pericytes

Pericytes are embedded within the basement membrane of cerebral capillaries, with their cell body extensions wrapping around endothelial cells. They are not only structural supporters of the microvasculature but also key participants in cerebrovascular development, stability, contraction, and the regulation of barrier function [28]血小板源性生长因子受体β（PDGFRβ）信号轴是调节周细胞募集、增殖、存活及其与内皮细胞相互作用的核心通路。周细胞通过分泌多种因子、感知血流动力学变化以及参与毛细血管水平的血流调节，维持内皮细胞的静息状态。它们的丢失或功能障碍是多种神经退行性疾病早期微血管病理学的标志。[29].

星形胶质细胞末端

星形胶质细胞通过其被称为“末端足”的特化末端结构，广泛覆盖在脑毛细血管的表面，形成胶质界限。[30].The endfeet not only provide physical and trophic support to endothelial cells and pericytes, but the polarized distribution of aquaporin-4 (AQP4) on their membrane is particularly critical [31].AQP4 is predominantly clustered in the membrane regions where endfeet contact blood vessels. By efficiently transporting water molecules, it plays a central role in brain water homeostasis, cerebrospinal fluid circulation, and interstitial solute clearance. Astrocytic endfeet also directly participate in neurovascular coupling by releasing vasoactive substances [32].

Microglia and the basement membrane layer

Microglia, as the brain's resident immune cells, exist in a state of dynamic surveillance within the NVU microenvironment. Their branched processes continuously scan the perivascular space, participating in debris clearance, synaptic function modulation, and responding to microenvironmental changes.

The basement membrane is a specialized extracellular matrix layer situated between the endothelial cells/pericytes and the astrocytic endfeet. It is primarily composed of laminin, type IV collagen, proteoglycans, among other components [33]. (Table 2)It provides a structural anchoring and signal transduction platform for all NVU components.

Its integrity and compositional changes directly affect barrier stability and intercellular communication [33].Table 2Molecular Composition and Functions of Microglia and Basement Membrane.ComponentStructural FeaturesKey Molecular MarkersMain FunctionsPathological AssociationsMicrogliaResident immune cells with highly dynamic, branched processes.•Pattern Recognition Receptors (e.g., TLR4, TREM2)•Cytokine Receptors (e.g., CSF1R)•Phagocytosis-associated proteins (e.g., CD68)•Immune Surveillance: Continuously scan the microenvironment, identifying pathogens and damage signals.•Synaptic Pruning: Remove redundant synapses during development and plasticity.•Inflammation Modulation: Regulate neuroinflammation via context-dependent activation states.•Phagocytic Clearance: Engulf cellular debris and abnormal protein aggregates.•Neurotrophic Support: Release growth factors (e.g., BDNF).•Overactivation: A pro-inflammatory activation state exacerbates neurodegeneration.•Dysfunction: Impaired clearance capacity leads to Aβ/tau accumulation.•Activation-state imbalance: Associated with disease progression in AD, PD, etc.Basement MembraneSpecialized extracellular matrix layer located between endothelial cells/pericytes and astrocytic endfeet.•Structural Proteins: Laminin, Collagen IV•Proteoglycans: Perlecan, Agrin•Glycoproteins: Nidogen, Fibronectin•Structural Anchoring: Provide adhesion and support for NVU cells.•Signaling Platform: Integrate growth factors and extracellular signals.•Permeability Barrier: Assist in regulating macromolecule permeability.•Cell Migration Guidance: Influence migration of immune cells and progenitor cells.•Thickening/Degradation: Associated with cerebral small vessel disease and BBB leakage.•Altered Composition: Affects cell signaling and barrier integrity.•Abnormal Deposits: Observed in cerebral amyloid angiopathy.

The Core role of the NVU in cerebral blood flow regulation and metabolic homeostasis

Neurovascular coupling

Neurovascular coupling refers to the rapid and precise increase in local cerebral blood flow mediated by the NVU in response to increased neuronal activity, which is the physiological basis of functional brain imaging [34].Astrocytes play a central signal transduction role in this process: glutamate released from neurons activates metabotropic receptors on astrocytes, leading to an increase in intracellular calcium concentration. This, in turn, prompts endfeet to release vasoactive substances, such as arachidonic acid metabolites, causing vasodilation [35].The blood oxygen level-dependent (BOLD) signal in functional magnetic resonance imaging is precisely based on the local blood oxygenation changes resulting from this coupling process. High spatiotemporal resolution optical imaging techniques have further confirmed in vivo the tight temporal relationship between neuronal activation, astrocytic calcium signaling, and vasomotor responses.

Selective transport at the blood-brain barrier

The blood-brain barrier (BBB) is not an absolute seal but rather a highly selective interface for substance exchange. Apart from the passive diffusion of lipid-soluble small molecules, essential nutrients such as glucose and amino acids primarily cross via specific transendothelial transporters [36].Furthermore, receptor-mediated transcytosis is a crucial mechanism for the passage of various macromolecules, such as insulin, transferrin, and their ligands, across the BBB. This process involves the binding of ligands to specific receptors on the luminal surface of endothelial cells, endocytosis to form vesicles, transit across the cytoplasm, and subsequent release at the abluminal membrane.

This pathway not only helps maintain nutrient and hormonal homeostasis in the brain but can also become a potential route for harmful substances or therapeutic macromolecular drugs to enter the brain under pathological conditions [37](Table 3).Table 3Selective Transport Mechanisms of the Blood-Brain Barrier.Transport MechanismTransport Carrier/ReceptorRepresentative SubstratesTransport DirectionFunctional SignificancePathological/Therapeutic RelevanceReferencesPassive DiffusionNone (lipophilic substances diffuse directly)•O₂, CO₂•Ethanol, Nicotine•Some anestheticsBidirectional, following concentration gradientRapid exchange of small, lipophilic molecules.Some neurotoxic substances (e.g., organic solvents) may enter the brain via this route.[36]Transmembrane TransportersSolute Carrier (SLC) superfamily•LUT1 (Glucose)•LAT1 (Large neutral amino acids)•MCT1 (Lactate/short-chain fatty acids)•CAT1 (Cationic amino acids)Primarily inward transportUptake of nutrients and energy substrates; exchange of metabolites.GLUT1 deficiency causes epilepsy and developmental delay; LAT1 is a target for amino acid analog drug delivery.[38]Receptor-Mediated Transcytosis (RMT)Endothelial luminal membrane receptors•Transferrin Receptor (TfR)•Insulin Receptor (InsR)•Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1)•Transferrin Receptor 2, CD98hc, etc.Primarily inward (some outward)Selective uptake of macromolecules (hormones, carrier proteins, growth factors); clearance of some pathological proteins (e.g., Aβ via LRP1).Therapeutic antibodies (anti-TfR, anti-InsR) designed for brain-targeted delivery strategies; impaired Aβ clearance is associated with AD.[39]Adsorptive-Mediated Transcytosis (AMT)Depends on cationic charge adsorption•Cationic albumin•Cell-penetrating peptides (e.g., TAT)•Cationic lipid nanoparticlesPrimarily inwardCharge-dependent, non-specific transport of macromolecules/nanocarriers.Used for gene/nucleic acid drug delivery; may exacerbate brain entry toxicity of certain cationic proteins.[40]Efflux TransportATP-binding Cassette (ABC) transporters•P-glycoprotein (MDR1)•Breast Cancer Resistance Protein (BCRP)•Multidrug Resistance-associated Proteins (MRPs)Outward (brain → blood)Protective efflux, limiting toxic/foreign substance accumulation; regulating clearance of endogenous metabolites.Overexpression limits chemotherapy drug brain entry; inhibiting efflux pumps can enhance CNS drug exposure.[41], [42]Paracellular DiffusionTight junctions (when pathologically opened)•Small ions (Na+, K+)•Small molecules (<500 Da)•Some inflammatory mediatorsBidirectional, enhanced under pathological conditionsExtremely limited under normal conditions; permeability increases during inflammation, ischemia, leading to vasogenic edema.BBB disruption observed in stroke, neuroinflammation, brain tumors, early neurodegenerative disease.[43]

Clearance of brain metabolic waste

The effective clearance of metabolic waste from the brain, including protein aggregates such as beta-amyloid (Aβ), is crucial for maintaining brain health. The recently discovered glymphatic system has elucidated the central role of the NVU in waste clearance. This model posits that cerebrospinal fluid (CSF) flows along periarterial spaces into the brain parenchyma, where it mixes with interstitial fluid (ISF).

Driven by convection, mediated by astrocytic endfeet via aquaporin-4 (AQP4), this mixture carries solutes and waste from the interstitium into perivenous spaces, eventually draining out of the brain via the extracranial lymphatic system (Fig. 2). The efficiency of this “brain cleansing” process is highly dependent on the functional integrity of all NVU components, particularly the polarized distribution of AQP4 on astrocytic endfeet and vascular pulsatility.Fig.

2Schematic of Brain Metabolic Clearance Pathways This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig. 2

Early biomarkers and imaging features of NVU injury

Plasma biomarkers

Specific molecules detectable in peripheral blood have emerged as potential windows into NVU injury. Elevated levels of soluble platelet-derived growth factor receptor β (sPDGFRβ) have been confirmed to correlate with cerebral pericyte damage and serve as a predictive marker for cerebral small vessel disease and cognitive decline [44].Intercellular adhesion molecule-1 (ICAM-1), an indicator of endothelial activation and inflammation, shows elevated levels suggesting blood-brain barrier (BBB) dysfunction. Glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) are markers of astrocyte activation or injury.

These plasma biomarkers offer the possibility of non-invasively assessing NVU status [45], [46].

Imaging biomarkers

Advanced neuroimaging techniques enable the non-invasive quantification of structural and functional NVU injury. Diffusion tensor imaging (DTI) combined with free water imaging models can sensitively detect white matter microstructural damage, enlargement of perivascular spaces, and increased interstitial free water content. It is important to emphasize that free water imaging does not directly quantify blood–brain barrier (BBB) permeability; rather, it captures tissue microstructural disorganization that may arise from multiple, overlapping pathological processes, including axonal loss, demyelination, neuroinflammation, and vasogenic edema secondary to BBB disruption.

Therefore, an elevated free water fraction serves as an indirect indicator of NVU injury and related pathologies, not as a specific biomarker of focal BBB leakage [47].Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), through pharmacokinetic modeling, can quantitatively calculate the permeability of the BBB to contrast agents, i.e., the Ktrans value. This is considered the in vivo gold standard method for assessing BBB integrity. Techniques such as high-resolution magnetic resonance vessel wall imaging can visualize microvascular morphological abnormalities [48].Furthermore, arterial spin labeling (ASL) can be used to assess cerebral blood flow and neurovascular coupling function.

In addition, functional ultrasound (fUS) imaging has emerged as a high-spatiotemporal-resolution tool for quantifying resting cerebral blood flow, microvascular density, and neurovascular coupling responses in rodents; combining focused ultrasound-mediated BBB opening with fUS has revealed an age-dependent dissociation between resting perfusion and evoked neurovascular responses, underscoring the value of assessing neurovascular function rather than perfusion alone.

Cerebrospinal fluid (CSF) biomarkers

Cerebrospinal fluid (CSF) analysis offers a more direct basis for assessing NVU function. The CSF-to-serum albumin ratio is a classic clinical indicator for evaluating the overall permeability of the blood-brain barrier (BBB). An elevated ratio indicates increased passage of macromolecules such as albumin from the blood into the CSF, serving as reliable evidence of BBB dysfunction [49].Abnormal changes in this ratio can be observed in the early stages of neurodegenerative diseases such as Alzheimer's disease, suggesting that NVU injury may be an early event in the disease process(Table 4).Table 4Early Biomarkers and Imaging Features of NVU Injury.Marker CategorySpecific MarkerDetection MethodPathological Process ReflectedClinical/Research SignificanceReferencesPlasma BiomarkersSoluble PDGFRβ (sPDGFRβ)ELISA / SIMOAPericyte injury and lossEarly predictive marker for cerebral small vessel disease and cognitive decline; positively correlates with white matter hyperintensity volume.[50]Intercellular Adhesion Molecule-1 (ICAM-1)ELISA / Multiplex immunoassayEndothelial cell activation and inflammationIndicator of systemic inflammatory state; indirect marker of BBB dysfunction; risk factor for cardiovascular events.[51]S100 Calcium-Binding Protein B (S100B)ELISA / ElectrochemiluminescenceAstrocyte activation/injuryIndicator of neuroinflammation and glial response; used for severity assessment after traumatic brain injury and stroke.[52]Glial Fibrillary Acidic Protein (GFAP)SIMOA / Single-molecule detectionAstrocyte injury and reactive astrogliosisMarker of neurodegenerative disease progression; significantly elevated in AD, CJD, etc.[53], [54]Imaging BiomarkersDTI Free Water ImagingDiffusion Tensor MRI + Free water correctionIncreased interstitial free water; white matter microstructural disorganization; enlarged perivascular spacesSensitive marker of tissue microstructural damage; elevated free water may indirectly reflect vasogenic edema among other pathologies; correlates with executive function.[55], [56], [57]Dynamic Contrast-Enhanced KtransDCE-MRI Pharmacokinetic modelingFocal blood-brain barrier leakageQuantitative assessment of BBB permeability; abnormal in early AD, cerebral small vessel disease, inflammatory diseases.[58]Arterial Spin Labeling CBFASL-MRIDecreased cerebral blood flow perfusion; impaired neurovascular couplingNon-invasive assessment of cerebral blood flow; perfusion abnormalities present early in hypertension and AD.[59]High-Resolution Vessel Wall Imaging3D Black-Blood MRI / 7 T MRIMicrovascular morphological abnormalities; vascular wall remodelingVisualization of “beaded” microvascular lesions, capillary rarefaction.[60], [61]CSF BiomarkersCSF/Serum Albumin RatioImmunoturbidimetry / ELISAOverall blood-brain barrier permeabilityClassic BBB function index; elevated ratio indicates barrier integrity disruption.[62], [63]CSF sPDGFRβELISA / Mass spectrometryDirect evidence of cerebral pericyte injuryMore CNS-specific than plasma; associated with vascular cognitive impairment.[64]CSF Matrix Metalloproteinases (MMPs)Zymography / Multiplex assayExtracellular matrix degradation; BBB structural damageMMP-9, etc., closely associated with ischemia-reperfusion injury and neuroinflammation.[65], [66]

Limitations and standardization challenges of NVU biomarkers

While the biomarkers described above hold considerable promise, several methodological limitations must be acknowledged. Plasma sPDGFRβ, although correlated with pericyte injury, lacks brain-specificity; elevations may reflect systemic microvascular pathology or reduced renal clearance, and age- and renal-function-adjusted normative thresholds are not yet established. Similarly, plasma GFAP and S100B are sensitive to peripheral astrocyte populations and systemic inflammation, complicating interpretation in individuals with comorbidities.

On the imaging front, DCE-MRI Ktrans values are highly dependent on acquisition protocols (temporal resolution, contrast agent dose), pharmacokinetic models, and post-processing pipelines, making cross-study comparison and meta-analysis challenging; international standardization efforts are urgently needed. ASL-derived cerebral blood flow measurements can be confounded by hematocrit, transit time, and arterial transit delay variations, while free water imaging, as detailed above, reflects tissue microstructural disorganization rather than direct BBB permeability. Finally, the absence of universally accepted, clinically validated cut-off points for any NVU biomarker limits their immediate deployment in routine diagnostic or risk-stratification workflows.

These constraints underscore that NVU biomarkers currently remain powerful research tools and adjunctive measures, rather than standalone diagnostic standards.

Damage pathways of midlife hypertension on the NVU

Midlife hypertension, as a persistent pathological factor affecting brain health, inflicts progressive and cumulative damage on the neurovascular unit through multiple interconnected mechanisms. These mechanisms do not operate in isolation but form a cascading network ranging from hemodynamic alterations to cellular dysfunction, and further to chronic inflammation and interaction with aging processes. Together, they undermine the NVU's core capacity to maintain brain homeostasis.

Chronic Hypoperfusion and abnormal shear stress

The sustained hypertensive state leads to fundamental changes in the hemodynamic environment of the cerebral microcirculation, inducing chronic hypoperfusion and abnormal vascular wall shear stress. This serves as the initiating step for NVU damage.

Increased pulse pressure impairs endothelial NO synthesis

Midlife hypertension often presents with elevated systolic blood pressure while diastolic pressure remains relatively normal or even decreases, resulting in a significantly widened pulse pressure. This increased pulse pressure translates into abnormally high pulsatile shear stress acting on the walls of cerebral microvessels. This abnormal mechanical stimulus impairs the normal function of endothelial nitric oxide synthase (eNOS) in endothelial cells, leading to a decrease in the bioavailability of the vasodilator nitric oxide (NO) [67], [68], [69].

(Fig. 3)The reduction of NO not only weakens vasodilation capacity but also diminishes its protective roles in anti-inflammation, anti-platelet aggregation, and maintaining barrier integrity. This early impairment of endothelial function lays the groundwork for subsequent barrier disruption and inflammation activation.

These mechanistic details derive primarily from preclinical vascular biology and ex vivo cerebral artery studies; direct in vivo evidence in midlife hypertensive humans remains limited, and they should be regarded as mechanistic hypotheses pending translational confirmation (Table 5).Fig. 3Pathophysiological Cascade of Pulse Pressure-Induced Endothelial Nitric Oxide Synthase Dysfunction This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig. 3Table 5Evidence Grading for Key Claims in the Hypertension-NVU-Cognition Axis.Claim / MechanismPrimary Evidence SourceEvidence LevelNotesMidlife hypertension predicts late-life cognitive decline and dementiaProspective cohort studies (ARIC, Whitehall II, Framingham)High (epidemiological)Consistent across multiple independent cohortsHypertension disrupts BBB tight junction integrityAnimal models (SHR, Ang-II infusion), in vitro endothelial shear-stress modelsModerate (mechanistic)Requires direct human validation in midlife cohortsPericyte loss correlates with cognitive decline and small vessel diseaseHuman neuropathology, plasma/CSF sPDGFRβ studies, DCE-MRIModerate to HighCorrelational; causal sequence not fully establishedeNOS uncoupling and endothelial oxidative stress in hypertensionPreclinical vascular biology, ex vivo cerebral artery studiesModerate (mechanistic)Direct human brain endothelial data limitedGLT-1 downregulation and glutamate excitotoxicityTransgenic mouse models, cell culture, human postmortem protein studiesModerate (mechanistic inference)Human in vivo evidence indirectsPDGFRβ as a plasma biomarker for NVU injuryCross-sectional and longitudinal observational studiesModerate (requires standardization)Lacks brain-specificity and age/renal-adjusted thresholdsDCE-MRI Ktrans quantifies BBB permeabilityNeuroimaging methodological studies, small clinical cohortsModerate to High (technical)High inter-center variability in acquisition and modelingIntensive BP lowering reduces MCI riskSPRINT-MIND randomized controlled trialHigh (clinical)Effect on dementia alone not significant; age heterogeneity observedGLP-1 RAs improve BBB integrity in hypertensive modelsPreclinical studies; early-phase clinical biomarker trialsLow to Moderate (emerging)No completed large RCT with cognitive endpoint

This flowchart delineates the molecular and cellular mechanisms by which increased pulse pressure in midlife hypertension leads to impaired endothelial nitric oxide synthesis, forming a vicious cycle that exacerbates vascular dysfunction. The core pathology involves: (1) Excessive pulsatile shear stress activating mechanosensors; (2) Subsequent induction of oxidative stress (via NOX) and upregulation of vasoconstrictors (ET-1, Ang II); (3) Critical post-translational modifications (dephosphorylation at S1177, phosphorylation at T495) and cofactor depletion (BH4 oxidation) that cause eNOS uncoupling—shifting its enzymatic activity from producing protective NO to generating harmful superoxide; (4) Resulting reduction in bioavailable NO impairs vasodilation, increases arterial stiffness, and further elevates pulse pressure, thereby perpetuating the cycle. This impaired endothelial function contributes directly to a pro-inflammatory, pro-thrombotic state that accelerates neurovascular unit damage and cognitive decline.

Rightward shift of the autoregulation curve increases sensitivity of cerebral blood flow to blood pressure fluctuations

Chronic hypertension induces remodeling of cerebral autoregulation, characterized by a rightward and upward shift of the autoregulation curve. This indicates that the blood pressure range required to maintain stable cerebral blood flow is elevated, and the plateau phase of regulation is shortened. The pathophysiological basis involves vascular smooth muscle hyperplasia, wall thickening, and enhanced myogenic reactivity.

The direct consequence of impaired autoregulation is the loss of the brain's effective buffering capacity against daily or pathological blood pressure fluctuations. During blood pressure drops (e.g., at night or after antihypertensive medication), the brain becomes more susceptible to hypoperfusion and ischemic risk. During blood pressure surges, excessive pressure can be directly transmitted to the fragile capillary bed, increasing the risk of blood-brain barrier leakage and vasculogenic injury.

This loss of blood flow regulatory capacity leaves brain tissue in a state of chronic perfusion instability.

Endothelial mitochondrial dysfunction and capillary rarefaction

Beyond hemodynamic shear stress, hypertension directly impairs endothelial mitochondrial homeostasis. Elevated transmural pressure and pulsatile stretch increase mitochondrial reactive oxygen species (mtROS) production in brain microvascular endothelial cells. This oxidative burden promotes mitochondrial DNA damage, opening of the mitochondrial permeability transition pore (mPTP), and reduced ATP generation, compromising the energy-dependent maintenance of tight junctions and transporter function.

Concurrently, age-related declines in mitophagy efficiency exacerbate the accumulation of dysfunctional mitochondria. The resulting redox imbalance not only directly oxidizes tight junction proteins and basement membrane components but also activates redox-sensitive transcription factors such as NF-κB, amplifying pro-inflammatory and matrix-degrading signaling.

Chronic hypertension also induces structural microvascular remodeling in the form of capillary rarefaction—a progressive loss of capillary density that reduces the total exchange surface area and impairs cerebral blood flow reserve. This rarefaction is compounded by basement membrane thickening and hyalinization, which increase diffusion distances and further impair neurovascular coupling. In hypertensive animal models, capillary rarefaction precedes overt white matter lesions and renders downstream neural tissue vulnerable to subsequent hypotensive episodes, creating a state of chronic “borderline perfusion” that promotes ischemic axonopathy and oligodendrocyte injury.

Oxidative modification of circulating lipids provides an additional, systemic source of endothelial injury. Oxidized LDL and related lipid peroxidation products promote cerebrovascular endothelial dysfunction, amplify neuroinflammation, and compromise BBB integrity, linking metabolic dysregulation to vascular cognitive impairment and dementia [70], [71]. This lipid oxidation-driven endothelial injury interacts synergistically with hypertension-induced mechanical and oxidative stress, suggesting that lipid-targeted strategies may complement blood pressure control in NVU protection.

Blood-brain barrier disruption

The blood-brain barrier is the core structure of the NVU, and its integrity is particularly vulnerable to hypertensive insult. Damage primarily manifests as dysregulation of structural proteins and loss of cellular components.

Downregulation of tight junction protein phosphorylation

The expression, phosphorylation status, and cytoskeletal anchoring of tight junction proteins are molecular determinants of BBB permeability. Under hypertensive conditions, Rho-associated protein kinase (ROCK) is activated in brain microvascular endothelial cells. ROCK phosphorylates myosin phosphatase target subunit 1 (MYPT1), thereby inhibiting myosin light-chain phosphatase (MLCP); the resulting accumulation of phosphorylated myosin light chain (MLC) enhances actomyosin contractility and produces centripetal tension on the cortical actin ring.

This mechanical force pulls transmembrane tight junction proteins—claudin-5 and occludin—away from their zonula occludens-1 (ZO-1)-mediated anchoring, destabilizing the junctional complex and increasing paracellular permeability (Fig. 4). MLCK can further amplify this process by directly phosphorylating MLC.

Importantly, tight junction phosphorylation is site-specific rather than uniformly barrier-disruptive: for example, claudin-5 phosphorylation at Thr207 strengthens junctional assembly, whereas phosphorylation at other residues weakens it, so the net effect of hypertension reflects a shift in the balance among site-specific phosphorylation events rather than a uniform “downregulation of phosphorylation.” These mechanisms are derived primarily from preclinical endothelial culture and animal models and should therefore be regarded as mechanistic hypotheses that require confirmation in human hypertension (Table 5) [72], [73], [74].Fig. 4Molecular Mechanism of MLCK/ROCK Signaling Pathway in Regulating Endothelial Tight Junction and Barrier Permeability This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig. 4

Pericyte loss leads to microvascular “beaded” deformities

Pericytes are highly sensitive to hypertension-induced oxidative stress and inflammatory damage. Under hypertensive conditions, pericytes undergo contraction, apoptosis, and detach from the capillary wall. The loss of pericytes removes their paracrine inhibitory control over endothelial cell proliferation and morphology, leading to abnormal endothelial hyperplasia and segmental dilation of microvessels.

This manifests radiologically as characteristic “beaded” or “fusiform” deformities. Ultra-high-field 7 Tesla magnetic resonance imaging can now clearly visualize these morphological abnormalities of cortical microvessels in vivo, with their severity significantly correlating with declines in cognitive test scores. This provides direct visual evidence linking hypertensive microangiopathy to brain functional impairment [75], [76], [77].

Neuroinflammatory Cascade

The cellular components of the NVU are not only targets of hypertensive damage but also amplifiers of neuroinflammation. The sustained activation of immune cells transforms hemodynamic injury into a chronic, destructive inflammatory microenvironment.

Microglial pro-inflammatory activation: A context-dependent continuum

Disruption of the BBB allows plasma-derived inflammatory factors (such as fibrinogen) to infiltrate the brain parenchyma. Simultaneously, hypoperfusion and cellular injury release damage-associated molecular patterns (DAMPs), which together activate the brain's resident immune cells—microglia. These microglia shift from a resting surveillance state toward a pro-inflammatory, activated phenotype (historically referred to as “M1-like,” though contemporary single-cell transcriptomic evidence supports a broad spectrum of activation states rather than a strict binary M1/M2 dichotomy).

Pro-inflammatory activated microglia release large quantities of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), as well as reactive oxygen and nitrogen species. These factors not only directly damage neurons and oligodendrocytes but also further disrupt the BBB, creating a self-perpetuating vicious cycle of inflammation [78].(Table 6).Table 6Core Cytokines Released by Pro-inflammatory Activated Microglia and Their Pathological Roles.CytokinePrimary ReceptorMain Pathological EffectsSpecific Impact in Hypertensive NVU InjuryReferencesTNF-αTNFR1/2Induces endothelial cell apoptosis; upregulates adhesion molecule expression; disrupts tight junction structure; directly damages neurons.Acute elevation can exacerbate BBB permeability; chronic low levels promote chronic neuroinflammation and synaptic loss.[79], [80]IL-1βIL-1R1Activates endothelial NF-κB pathway; induces astrocytic A1 transformation; enhances MMP expression; exacerbates excitotoxicity.Synergizes with hypertensive stress to significantly amplify inflammatory cascade; a key driver of glial reactivity.[80]IL-6IL-6R/gp130Stimulates acute-phase protein synthesis; induces Th17 differentiation; promotes B cell proliferation; inhibits Treg function.Facilitates transmission of systemic inflammation to the CNS; associated with endothelial dysfunction and insulin resistance.[81]IL-12IL-12Rβ1/2Promotes Th1 cell differentiation; enhances IFN-γ production; activates cytotoxic T cells and NK cells.Links innate immune response to adaptive immunity, potentially leading to autoimmune-like damage.[82], [83]IL-23IL-23RStabilizes Th17 cell phenotype; synergizes with IL-1β to induce GM-CSF production.Sustains and amplifies pro-inflammatory T cell responses, prolonging inflammation duration.[84]IFN-γIFNGR1/2Upregulates MHC-II expression; enhances antigen presentation; activates STAT1 pathway; induces iNOS expression.Synergizes with the hypertensive environment to strongly drive microglia toward a pro-inflammatory activation state.[85]CCL2 (MCP-1)CCR2Chemoattracts monocytes/macrophages to the CNS; activates endothelial cells.Recruits peripheral immune cells across the damaged BBB, amplifying central inflammatory infiltration.[86], [87]CXCL1 (GRO-α)CXCR2Chemoattracts neutrophils; promotes angiogenesis.May be involved in neutrophil recruitment following acute hypertensive crises.[88], [89]CXCL10 (IP-10)CXCR3Chemoattracts Th1 cells; inhibits endothelial cell proliferation.Links innate immunity to T cell-mediated immune responses, potentially exacerbating chronic inflammation.[90]Reactive Oxygen/Nitrogen SpeciesDirect oxidative damageCauses lipid peroxidation, protein nitration, DNA damage; activates the NLRP3 inflammasome.Directly damages neurons and oligodendrocytes; synergizes with hypertension-induced ROS production, exacerbating oxidative stress.[91]MMP-9Substrate degradationDegrades basement membrane collagen IV and laminin; disrupts BBB structural integrity.Directly causes structural BBB damage, promoting vasogenic edema and neurotoxic substance entry into the brain.[92], [93], [94]

Reactive Astrogliosis and disrupted synaptic support: A context-dependent continuum

Driven by inflammatory cytokines, astrocytes also undergo a detrimental reactive transformation toward a pro-inflammatory state (historically termed the “A1” phenotype; however, single-cell transcriptomic studies indicate that reactive astrocytes exist along a context-dependent continuum of states rather than conforming to a strict binary A1/A2 dichotomy). These reactive astrocytes lose their normal functions in synaptic support, nutrient provision, and ion homeostasis regulation [95], [96].

.Synergistic amplification through interaction with aging

Midlife hypertension synergizes with physiological aging processes, jointly accelerating NVU functional decline and amplifying injury outcomes.

Senescence-associated secretory phenotype (SASP) exacerbates endothelial senescence

Aging vascular cells (including endothelial cells and pericytes) develop a senescence-associated secretory phenotype (SASP), characterized by persistent DNA damage response and the substantial secretion of bioactive molecules such as pro-inflammatory factors and matrix-degrading enzymes. Hypertension-induced oxidative stress and mechanical damage, as potent drivers of senescence, significantly accelerate this process. SASP factors (e.g., interleukin-6, plasminogen activator inhibitor-1) not only impair the normal function of neighboring cells but also create a chronic pro-inflammatory and pro-fibrotic background within the entire NVU microenvironment.

This reduces vascular repair capacity and increases susceptibility to further damage [97], [98].(Fig. 5).Fig. 5Self-Perpetuating Cycle of SASP in Hypertensive Endothelial Injury This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig.

5

Mitochondrial dysfunction

Mitochondria are organelles commonly targeted by both hypertension and aging. Hypertension-induced calcium overload and energy demand imbalance, compounded by age-related declines in mitophagy (selective autophagy of mitochondria), lead to mitochondrial structural damage and functional impairment [99].Damaged mitochondria produce excessive reactive oxygen species (ROS). This excessive ROS not only directly oxidatively damages biological macromolecules but also persistently activates key transcription factors such as nuclear factor-kappa B (NF-κB).

Activated NF-κB translocates to the nucleus, driving the expression of more pro-inflammatory genes. These inflammatory factors, in turn, further impair mitochondrial function, establishing a difficult-to-break positive feedback loop of “ROS—NF-κB—Inflammation—ROS” [100].This cycle constitutes the core molecular hub through which hypertension and aging synergistically damage the NVU, driving the pathological transition from reversible functional disturbance to irreversible structural damage [101].(Fig. 6).Fig.

6ROS–NF-κB Self-Amplifying Feedback Loop in Hypertensive NVU Injury This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig. 6

This streamlined diagram illustrates the core self-reinforcing cycle between mitochondrial dysfunction and neuroinflammation. Key pathways include: (1) ROS overproduction from damaged mitochondria; (2) NF-κB activation leading to pro-inflammatory cytokine release; (3) cytokine signaling further impairing mitochondria via mPTP opening; (4) immune cell activation amplifying oxidative and inflammatory stress.

Endothelial senescence and neurovascular uncoupling

Hypertension accelerates endothelial senescence beyond chronological aging. Senescent brain microvascular endothelial cells exhibit shortened telomeres, persistent DNA damage response foci, and a senescence-associated secretory phenotype (SASP) characterized by release of interleukin-6, plasminogen activator inhibitor-1, and matrix metalloproteinases. These SASP factors create a paracrine pro-inflammatory and pro-fibrotic milieu that impairs pericyte coverage and astrocytic endfoot polarization.

Functionally, senescent endothelium shows blunted responses to vasoactive stimuli and impaired propagation of vasodilatory signals along the vessel wall, manifesting as neurovascular uncoupling—the failure to increase local cerebral blood flow in response to neuronal activation. This uncoupling is detectable in vivo as reduced BOLD signal responsiveness and impaired functional hyperemia, and it represents a critical functional bridge between microvascular disease and network-level cognitive impairment.

Causally, clearance of senescent endothelial cells in aged mice restores microvascular density, BBB integrity, and neurovascular coupling responses and improves cognitive performance, supporting a direct pathogenic role of endothelial senescence in NVU dysfunction [91], [97], [102]; midlife metabolic stress similarly accelerates this senescence-associated phenotype, identifying midlife as a critical window for senescence-targeted intervention.

Molecular mechanisms by which NVU injury mediates cognitive decline

Neurovascular unit (NVU) dysfunction is both a pathological endpoint resulting from vascular risk factors such as hypertension and a key intermediary that contributes to progressive cognitive decline through partially independent mechanisms.NVU injury disrupts the microenvironmental homeostasis necessary for synaptic transmission, compromises energy supply to key neurotransmitter systems, impairs the efficiency of metabolic waste clearance in the brain, and ultimately leads to structural and functional disconnection of large-scale brain networks. These processes constitute the core pathological pathway linking microcirculatory disturbances to macroscopic cognitive impairment [70].

Downregulation of glutamate-astrocyte transporters and excitotoxicity

Glutamate is the primary excitatory neurotransmitter in the central nervous system. The precise regulation of its concentration in the synaptic cleft is crucial for maintaining normal neuronal signaling and plasticity. This regulation heavily depends on the glutamate transporter GLT-1 (also known as EAAT2), which is highly expressed on astrocytic endfeet [103], [104].

This flowchart illustrates the pathogenic sequence linking neurovascular unit dysfunction in hypertension to synaptic failure and neuronal damage via astrocytic glutamate transporter impairment. The core mechanism involves: (1) NVU damage creating a neuroinflammatory and energetically compromised microenvironment that downregulates astrocytic GLT-1 expression and function; (2) Resulting failure to clear synaptic glutamate leads to its pathological accumulation; (3) Excessive activation of extrasynaptic NMDA receptors triggers catastrophic calcium influx; (4) Calcium overload activates multiple degradative pathways that dismantle synaptic structures, induce oxidative stress, disrupt mitochondrial function, and initiate apoptosis; (5) This culminates in synaptic loss and neuronal death, directly underpinning cognitive impairment. Critically, secondary oxidative stress and inflammation create a positive feedback loop that further suppresses GLT-1 function, establishing a self-perpetuating cycle of excitotoxic damage.

Reduced GLT-1/EAAT2 expression leads to accumulation of Extrasynaptic glutamate

Within the NVU-damaged environment induced by hypertension, activated pro-inflammatory cytokines (particularly TNF-α and IL-1β) can significantly downregulate the expression and function of GLT-1 in astrocytes [105].Oxidative stress can directly damage the transporter protein, and ATP deficiency resulting from impaired energy metabolism also weakens its active transport capacity, which relies on the sodium‑potassium gradient. The downregulation of GLT-1 function leads to inefficient and delayed uptake of glutamate released at synapses, causing its abnormal accumulation in the extrasynaptic space. This sustained elevation of extracellular glutamate concentration disrupts the balance between excitation and inhibition, creating conditions for excitotoxicity [106], [107].

Overactivation of Extrasynaptic NMDA receptors and calcium-dependent synaptic degradation

Excess glutamate overactivates N-methyl-d-aspartate (NMDA) receptors on the postsynaptic membrane, leading to abnormal, prolonged opening of their ion channels. This triggers massive calcium ion influx, resulting in intracellular calcium overload in neurons [108].The sharp rise in intracellular calcium concentration activates a series of calcium-dependent proteases (e.g., calpains), phospholipases, and endonucleases. Activated calpain, for instance, can degrade key scaffolding proteins in the postsynaptic density (PSD), such as PSD-95, leading to the physical disintegration and functional loss of synaptic structures [109].This process is the core mechanism by which excitotoxicity causes synaptic loss and neuronal death, directly impairing the cellular foundation of learning and memory [110].(Fig.

7) The linkage of GLT-1 downregulation to excitotoxic synaptic loss is supported mainly by transgenic mouse models, cell-culture experiments, and human postmortem protein studies; in vivo human evidence remains indirect (Table 5).Fig. 7Molecular Cascade of Glutamate Excitotoxicity Driven by GLT-1/EAAT2 Downregulation This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig. 7

Impaired neurovascular coupling in cholinergic axons

Cholinergic neurons in the basal forebrain project extensively to the cortex, and the acetylcholine they release is crucial for maintaining arousal, attention, learning, and memory. These projection axons possess unique metabolic properties that make them particularly vulnerable to NVU dysfunction.

High demand for cerebral blood flow (CBF) by basal forebrain cholinergic neurons

Basal forebrain cholinergic neurons are a key neuromodulatory system for maintaining higher cognitive functions, especially attention, learning, and memory. These neurons are primarily located in the medial septum, diagonal band of Broca, and nucleus basalis, and their axons project widely to regions such as the cerebral cortex, hippocampus, and amygdala, forming the ascending pathway of the central cholinergic system [111]. A distinctive anatomical and physiological feature of this pathway is the exceptionally high density of mitochondria within its axons, a structural characteristic that dictates their extremely high energy metabolic demands [112].

As the “powerhouses” of the cell, the dense distribution of mitochondria indicates that cholinergic axons are continuously engaged in active oxidative phosphorylation to produce substantial amounts of adenosine triphosphate (ATP) to fuel energy-consuming processes such as acetylcholine synthesis, packaging, release, and axonal transport [113].This hypermetabolic state makes cholinergic axons acutely sensitive to the immediate supply of oxygen and glucose, resulting in an extraordinary physiological dependence on stable and adequate local cerebral blood flow. Any reduction or fluctuation in cerebral blood flow, regardless of cause, can rapidly induce an energy crisis in these axons [114].

Given the long projection routes of cholinergic axons—traveling from the basal forebrain through deep white matter regions to reach distant cortical targets—the perfusion level of the microvascular network along these pathways directly determines the sufficiency of energy substrate supply along the axons. Under pathological conditions such as hypertension, cerebral small vessel disease, microcirculatory disturbances, and impaired neurovascular coupling primarily affect the vascular supply territories of these long penetrating arteries. Therefore, due to its inherent hypermetabolic nature and vulnerable vascular supply pattern, the cholinergic system becomes an early and susceptible target for NVU dysfunction.

Its impairment constitutes one of the core mechanisms underlying executive dysfunction and attentional deficits in vascular cognitive impairment.

NVU injury leads to ischemic Axonopathy in cholinergic axons

Chronic cerebral hypoperfusion, microvascular rarefaction, and neurovascular coupling dysfunction induced by hypertension cause subcortical white matter regions (where cholinergic axons traverse) to exist in a state of chronic “borderline perfusion” [115], [116].This chronic ischemia-hypoxia first damages axonal mitochondrial function, triggering impaired axonal transport, abnormal phosphorylation and accumulation of cytoskeletal proteins, and ultimately leading to progressive axonal degeneration. This “ischemic axonopathy” selectively damages cholinergic pathways, resulting in reduced cortical acetylcholine input. The deficiency of acetylcholine directly impacts executive functions such as attention set-shifting and working memory, which are early and core features of vascular cognitive impairment [117].

It should be noted that direct evidence for ischemic axonopathy of cholinergic projections in hypertensive humans remains limited; much of this pathway is inferred from animal models of chronic cerebral hypoperfusion and from human neuroimaging and postmortem studies.

Impaired insulin receptor signaling and reduced aβ clearance

Brain insulin signaling not only regulates energy metabolism but also profoundly influences synaptic plasticity and Aβ clearance. The NVU is a critical interface for both insulin action and Aβ clearance.

Abnormal phosphorylation of insulin receptor Substrate-1 (IRS-1)

Hypertension-associated inflammatory factors (e.g., TNF-α) and oxidative stress can activate specific kinases that promote abnormal serine phosphorylation of IRS-1. This aberrant phosphorylation inhibits the normal tyrosine phosphorylation of IRS-1, blocking its signal transmission to the downstream PI3K/Akt pathway [118].Impairment of the brain's insulin signaling pathway weakens its promotive effects on neuronal survival, synaptogenesis, and glucose uptake. Concurrently, it diminishes the pathway's inhibition of glycogen synthase kinase-3β (GSK-3β), which in turn promotes the hyperphosphorylation of tau protein [119].

Reduced activity of insulin-degrading enzyme (IDE)

Insulin-degrading enzyme (IDE) is a key enzyme responsible for degrading both Aβ and insulin. Downregulation of the IRS-1/PI3K/Akt pathway reduces the expression and activity of IDE [120].Furthermore, the oxidative stress environment resulting from NVU injury can directly inhibit IDE's enzymatic function. Reduced IDE activity decreases the clearance efficiency of Aβ in the brain, particularly the more toxic Aβ42 species.

Since impaired insulin signaling can also affect β-secretase activity, it may lead to increased Aβ production [121], [122].The combined effect of diminished clearance and increased production results in elevated levels of Aβ42 and an increased Aβ42/Aβ40 ratio in the brain. This ratio is an important biomarker for AD pathological progression and cognitive impairment. Through this mechanism, NVU dysfunction directly exacerbates Aβ-related toxicity even in the absence of typical amyloid plaques [123], [124].

The evidence supporting this IRS-1/IDE–Aβ axis derives predominantly from preclinical and in vitro studies; longitudinal human data confirming its quantitative contribution to hypertension-related cognitive decline are still needed.

Structural brain network disconnection

Cognitive function relies on efficient and coordinated information exchange between different brain regions, which is built upon intact white matter structural connections and synchronized brain activity. NVU injury disrupts white matter microstructure and blood supply, ultimately leading to the disintegration of large-scale brain networks.

Microstructural damage in long-range white matter tracts

Ischemia and BBB leakage caused by hypertension chronically damage oligodendrocytes and their precursor cells within the white matter, leading to impaired myelination and demyelination. Diffusion tensor imaging (DTI) reveals that key white matter tracts connecting higher-order cognitive regions, such as the prefrontal and parietal cortices (e.g., the cingulum bundle and superior longitudinal fasciculus), show decreased fractional anisotropy and increased mean diffusivity, indicating compromised white matter microstructural integrity [125].The cingulum bundle connects the limbic system with association cortices, participating in episodic memory and emotional regulation, while the superior longitudinal fasciculus links the frontal lobe with temporoparietal regions and is a core pathway for language and working memory. Disruption of these tracts directly interrupts the information transmission pathways of cognitive networks [126].

Resting-state fMRI: Impaired functional connectivity in large-scale networks

The default mode network (DMN) and the executive control network (ECN) are two core large-scale brain networks underpinning higher human cognitive functions. The DMN primarily includes the medial prefrontal cortex, posterior cingulate cortex/precuneus, angular gyrus, and hippocampus, and is highly active during rest, introspection, episodic memory retrieval, and future planning [127].The ECN mainly encompasses the dorsolateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule, and is responsible for allocating attentional resources, exerting cognitive control, and operating working memory during goal-directed tasks. These two networks typically exhibit an “anti-correlated” dynamic balance in function, meaning that when executing external tasks, the ECN activates while the DMN is suppressed, and vice versa.

This dynamic interaction and switching is fundamental for the brain's flexible cognitive adaptation [128].

Resting-state functional magnetic resonance imaging (rs-fMRI) measures the temporal correlation of low-frequency fluctuations in spontaneous blood oxygen level-dependent (BOLD) signals across different brain regions, enabling the non-invasive quantification of functional connectivity strength within and between networks. In individuals with midlife hypertension and cerebral small vessel disease, studies have found a significant decrease in the coherence of functional connectivity among nodes within the DMN, manifested as weakened synchrony between core hubs like the posterior cingulate cortex and the medial prefrontal cortex [129].More importantly, functional connectivity between the DMN and the ECN also shows abnormal reduction, disrupting their normal anti-correlated or dynamic synergistic pattern. This weakening of inter-network connectivity reflects impaired large-scale brain system integration and segregation capabilities, beyond mere changes in activity levels.

The underlying neurovascular mechanism is deeply linked to widespread NVU dysfunction. Chronic hypertension-induced cerebral hypoperfusion and microangiopathy place cortical and subcortical regions housing network key nodes in a chronic state of borderline energy supply. Synaptic loss and imbalances in neurotransmitter systems (e.g., cholinergic, glutamatergic) further weaken the ability of neuronal assemblies to generate synchronous oscillations [130].Essentially, decreased functional connectivity signifies reduced efficiency of information transfer between different brain regions and a loss of the brain's flexible switching capability between “introspective” and “externally directed” cognitive modes.

This large-scale network disconnection manifests behaviorally as slowed thinking speed, difficulty in task switching, reduced working memory capacity, and comprehensive decline in executive functions. It thereby constitutes a significant neuroimaging substrate for hypertension-related cognitive impairment at the systems level [131], [132], [133].

Population evidence: Cohort and imaging studies

Population-level evidence from large-scale prospective cohort studies and advanced neuroimaging techniques provides strong empirical support for the hypothesis that midlife hypertension leads to cognitive decline via neurovascular unit (NVU) injury. These studies not only reveal temporal associations between blood pressure trajectories and long-term cognitive outcomes but also directly link macro-level blood pressure exposure with micro-level NVU damage and macro-level cognitive decline through in vivo biomarkers. Furthermore, they clarify the complex relationship between vascular pathology and classic AD pathology, which is both independent and synergistic.

Midlife blood pressure trajectories and cognitive endpoints 10–20 years later

Long-term epidemiological studies consistently indicate that blood pressure levels in midlife, rather than in late life, represent a critical time window for predicting cognitive function and dementia risk decades later.

The ARIC study case

The Atherosclerosis Risk in Communities (ARIC) Study is a community-based prospective cohort study. Following over 15,000 midlife participants (baseline age 45–64) for up to 25 years, analyses showed that individuals with systolic blood pressure ≥ 130 mmHg in midlife (average age 50) had a significantly increased risk of developing dementia in late life compared to those with normal blood pressure [12].More importantly, midlife hypertension was closely associated with reduced total brain volume, hippocampal atrophy, and increased white matter hyperintensity volume in later life. This study underscores midlife as a critical “window of opportunity” for blood pressure intervention to prevent long-term brain injury and cognitive decline [134].

The Whitehall II study

The UK Whitehall II cohort study, with repeated measurements over 30 years, meticulously mapped blood pressure life-course trajectories. Research identified patterns such as “stable-normal,”“midlife-rising-late-life-falling,” and “persistently-high.” Among these, the “midlife-rising” trajectory was associated with the worst late-life cognitive performance (particularly processing speed and executive function) and a higher risk of all-cause dementia. This study highlights the importance of dynamic blood pressure change patterns and suggests that late-life blood pressure decline may not be a protective factor but rather a consequence of impaired cerebral autoregulation, chronic hypoperfusion, or even neurodegeneration [135].

NVU imaging markers and the rate of cognitive decline

Advances in neuroimaging have enabled researchers to quantitatively assess early markers of NVU injury in vivo and confirm their direct association with the rate of cognitive decline.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can quantitatively calculate the permeability of the blood-brain barrier (BBB) to contrast agents. Studies indicate that elevated Ktrans values (suggestive of BBB leakage) in key brain regions such as the hippocampus and cortex in cognitively normal middle-aged and elderly individuals can independently predict faster memory decline and global cognitive decline over the next 3–5 years [136].Similarly, enlarged perivascular spaces and white matter microstructural damage detected by free water imaging based on diffusion tensor imaging (DTI) are also significantly associated with progressive decline in executive function and processing speed. These findings directly link microscopic NVU dysfunction to macroscopic cognitive trajectories, establishing NVU injury as an intermediate phenotype for cognitive decline.

A recent synthesis of neuroimaging evidence further indicates that the spatial distribution of blood-brain barrier and perivascular space abnormalities tracks the topography of cognitive impairment across small vessel and neurodegenerative diseases [137].

Comparison of independent effects relative to amyloid/tau burden

A core scientific question addressed in this review is: Does NVU injury drive cognitive decline independently of Aβ/tau pathology? Multiple multimodal imaging studies have investigated this in depth.

Interaction analysis

Studies find that NVU injury (e.g., increased BBB permeability, cerebral small vessel disease burden) often coexists with Aβ pathology as shown by CSF or amyloid PET, but their patterns of influence on cognition differ. More importantly, there is a significant synergistic interaction between them [138].For example, individuals with both high BBB permeability and high brain amyloid burden experience cognitive decline much faster than those with only one pathology, demonstrating a “1 + 1 > 2” effect. This synergy may arise through several mechanisms: BBB damage may facilitate Aβ entry into the brain or hinder its clearance; ischemia-hypoxia may upregulate β-secretase activity; an inflammatory environment may exacerbate tau hyperphosphorylation.

(Fig. 8)This suggests that in the AD continuum, vascular pathology and Aβ/tau pathology are mutually promoting, co-evolving partners.Fig. 8Synergistic Mechanisms Between NVU Dysfunction and Amyloid Pathology in Driving Cognitive Decline This figure was generated with AI assistance and has been carefully reviewed by the author for scientific accuracy, in compliance with the journal's editorial policies on AI-assisted content.Fig.

8

This flowchart illustrates the reciprocal and amplifying interactions between neurovascular unit damage and amyloid-β pathology, which together accelerate cognitive decline beyond the sum of their individual effects. Key synergistic mechanisms include: (1) BBB leakage allows blood-derived toxins to enter the brain, exacerbating neuronal stress in areas of Aβ accumulation; (2) Chronic hypoperfusion induces an energy crisis that upregulates BACE1 (increasing Aβ production) and impairs IDE (reducing Aβ degradation); (3) Neuroinflammation triggered by NVU dysfunction promotes astrocytic Aβ release and compromises microglial clearance function. Conversely, Aβ pathology induces secondary NVU injury through capillary compression and amplifying neuroinflammation, creating a vicious cycle.

This bidirectional crosstalk explains why individuals with both high NVU damage and high amyloid burden exhibit dramatically faster cognitive decline than those with either pathology alone.

Structural equation modeling

To quantify the relative contributions of different pathological pathways, researchers have employed methods such as structural equation modeling for path analysis. Model results indicate that, after controlling for factors like age, sex, and education, the “vascular pathway” represented by NVU injury (e.g., white matter hyperintensity volume, BBB-Ktrans values) and the “amyloid pathway” represented by amyloid PET burden can both independently and significantly predict cognitive variation, with standardized path coefficients of comparable magnitude. In some cohorts, particularly among younger individuals or those with non-demented mild cognitive impairment, the contribution of the vascular pathway may even exceed that of the amyloid pathway.

These models provide statistical support consistent with the proposed causal chain“midlife hypertension → NVU injury → cognitive decline,” independent of traditional AD pathology, supporting the central role of vascular factors in the spectrum of cognitive impairment. However, such path models are associative in nature and cannot by themselves establish causality; interventional evidence is required.

Intervention studies: Blood pressure lowering and NVU-targeted strategies

Intervention strategies targeting midlife hypertension and associated neurovascular unit damage are evolving from traditional, singular blood pressure control toward early, intensive, multi-targeted, and individualized precision models. Existing evidence not only affirms the foundational role of antihypertensive therapy in cognitive protection but also highlights the critical impact of intervention timing and strategy selection on efficacy, while opening prospects for novel therapies aimed directly at repairing NVU dysfunction. Importantly, with the exception of blood pressure lowering itself, the strategies discussed in this section are investigational: they are presented as promising research directions rather than clinically actionable recommendations, given the current lack of robust randomized evidence with cognitive endpoints.

Impact of intensive blood pressure lowering RCTs on cognitive outcomes

Randomized controlled trials (RCTs) targeting blood pressure values provide the highest level of evidence for preventing vascular cognitive impairment, while also underscoring the complexity of intervention.

Insights from the SPRINT-MIND study

The Systolic Blood Pressure Intervention Trial (SPRINT) and its cognitive ancillary study, SPRINT-MIND, constitute a landmark investigation. It randomized 9361 hypertensive patients to either an intensive blood pressure lowering group (target systolic BP <120 mmHg) or a standard group (target <140 mmHg). After a median follow-up of 3.3 years, the intensive group showed a significant 19% reduction in the combined risk of developing mild cognitive impairment or probable dementia [139].However, over longer follow-up or when analyzing the hard endpoint of “dementia” alone, no statistically significant difference was observed between the groups.

This result carries a dual implication: on one hand, it strongly demonstrates that intensive blood pressure lowering can effectively delay the transition from normal cognition to early cognitive impairment, emphasizing the importance of preventing “upstream” events; on the other hand, it suggests that once a clear dementia stage is reached, blood pressure lowering alone may be insufficient to reverse widespread established neurodegeneration, highlighting the crucial importance of intervening earlier.

Subgroup analyses

In-depth analyses of data from trials like SPRINT reveal significant age heterogeneity in the cognitive protective effects of blood pressure lowering. Middle-aged participants between 50 and 60 years old derived the most substantial cognitive benefit from intensive blood pressure lowering. In contrast, benefits were attenuated in very elderly patients (over 75 years), potentially even offset by risks such as orthostatic hypotension.

This finding, from a clinical intervention perspective, provides corroborating evidence that midlife represents a “critical period of plasticity” for hypertensive brain injury [140].Active management during this window may maximize protection of NVU function, prevent or delay irreversible structural damage, and thereby lay the foundation for cognitive health in later life [141].

Multimodal trials targeting the NVU

Moving beyond simple blood pressure value management, therapeutic strategies directly targeting NVU injury mechanisms are under exploration, representing the next generation of vascular cognitive protection.

GLP-1 receptor agonists and their effects on improving blood-brain barrier permeability

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have garnered attention for their neuroprotective signs in diabetes treatment. Preclinical studies show that GLP-1RAs like liraglutide can significantly improve BBB integrity and reduce permeability in hypertensive animal models by mitigating neuroinflammation and inhibiting oxidative stress [142].Preliminary clinical imaging studies have also found that GLP-1RA treatment is associated with decreased plasma levels of BBB damage markers (e.g., S100β). These drugs may exert direct NVU protective effects by acting on GLP-1 receptors on endothelial cells and astrocytes.

Several clinical trials are currently underway investigating their use in early Alzheimer's disease or vascular mild cognitive impairment [143]. It must be emphasized that no completed large-scale randomized controlled trial has demonstrated cognitive benefit of GLP-1RAs in hypertensive or normoglycemic individuals; their application for NVU protection therefore remains investigational.

Endothelium-targeted antioxidants and reduction of plasma ICAM-1

Given that oxidative stress is a core driver of NVU injury, antioxidant therapies targeting the vascular endothelium are of significant interest. For instance, certain antioxidants with endothelial affinity or Nrf2 pathway activators have been shown in clinical trials to effectively reduce circulating levels of the endothelial activation marker ICAM-1. Downregulation of ICAM-1 signifies alleviation of endothelial inflammatory status, which is expected to indirectly improve BBB function and neurovascular coupling.

This class of therapies aims to interrupt the chain of hypertension-induced endothelial dysfunction at the molecular level [144], [145]. However, no large randomized controlled trial has yet shown that reducing circulating ICAM-1 through endothelium-targeted antioxidants translates into preserved cognition or reduced NVU injury, and these agents remain investigational.

Exploratory analysis of multicomponent lifestyle interventions on NVU markers

Multidomain lifestyle interventions centered on diet, exercise, and cognitive training demonstrate potential for improving NVU biomarkers. For example, studies show that individuals adhering to a Mediterranean diet combined with regular aerobic exercise have lower plasma levels of markers reflecting pericyte injury and endothelial inflammation [146].Exercise is believed to enhance NVU resilience through multiple mechanisms, including increasing cerebral blood flow shear stress, upregulating endothelial nitric oxide synthase expression, and promoting angiogenesis. These non-pharmacological approaches offer safe and feasible strategies for protecting the NVU by improving overall vascular health.

The cautious optimism surrounding the aforementioned emerging strategies must be tempered by several important considerations. The SPRINT-MIND trial demonstrated that intensive blood pressure lowering reduces the risk of mild cognitive impairment, but the effect on hard dementia endpoints did not reach statistical significance, and benefits were attenuated in individuals older than 75 years due to risks of orthostatic hypotension and cerebral hypoperfusion. Excessive blood pressure reduction may even produce a “J-curve” effect—in individuals with pre-existing severe cerebral small vessel disease or impaired cerebral autoregulation, lowering blood pressure below the ischemic threshold may paradoxically worsen rather than preserve cognitive function, and more lenient targets should be considered in frail, poly-medicated, or autonomically dysfunctional patients.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown encouraging preclinical data on blood-brain barrier integrity, but human trials in cognitive impairment are ongoing and lack long-term cognitive outcomes; their neuroprotective effects have been primarily demonstrated in diabetic or obese populations, and whether these benefits extend to normoglycemic, lean hypertensive individuals remains uncertain. Sex differences in efficacy, gastrointestinal side effects, and cost represent additional practical barriers. Endothelium-targeted antioxidants have reduced plasma ICAM-1 in some studies, yet no large randomized controlled trial has confirmed that this translates into preserved cognition or reduced NVU injury.

Although the rationale for combining intensive blood pressure lowering with NVU-protective agents (e.g., GLP-1RAs) is biologically plausible, potential drug-drug interactions, additive side effects, optimal dosing, and sequencing of therapies remain entirely unknown, and the cost-effectiveness of such multi-target strategies requires formal evaluation. Multicomponent lifestyle interventions are safe and feasible, but their specific effects on NVU biomarkers versus general vascular health are difficult to disentangle. Furthermore, treatment response is likely modulated by age, sex, baseline cognitive status, diabetes and obesity status, burden of cerebral small vessel disease, genetic background (e.g., APOE ε4 carrier status), frailty, and concomitant medications, necessitating individualized rather than uniform approaches.

Future trials must therefore incorporate NVU biomarkers as intermediate endpoints and stratify participants by age, genetic risk, baseline BBB integrity, and comorbidity profiles to define which subgroups derive the greatest cognitive protection.

Intervention timing and individualization

The success of future interventions will depend on the precise determination of “when to intervene” and “in whom to intervene.”

Blood pressure thresholds

The traditional hypertension diagnostic threshold (≥140/90 mmHg) may no longer be optimal for brain protection. Studies like SPRINT suggest that moving the intervention threshold forward to a systolic blood pressure of 130 mmHg or even lower may yield greater cognitive benefits. Future guidelines may need to establish separate, more aggressive blood pressure management targets specifically for “brain health protection,” particularly in middle-aged populations.

Prospective validation in dedicated trials is required before any brain-health-specific blood pressure target can be recommended for clinical practice.

Stratified intervention design guided by genetic-imaging risk scores

Given the vast individual differences in susceptibility and response to hypertensive brain injury, risk stratification based on biomarkers is crucial. An ideal strategy involves integrating genetic risk (e.g., APOE ε4, vascular function-related gene loci), NVU imaging markers (e.g., baseline BBB-Ktrans values, white matter lesion burden), and traditional risk factors to construct an individualized “brain-vascular risk score.” High-risk individuals (e.g., those with midlife hypertension and early BBB leakage) could be selected for intensive multi-target intervention groups (e.g., intensive blood pressure lowering + GLP-1RA), while low-risk individuals receive standard management. This “stratified medicine” model aims to concentrate limited medical resources on those most likely to benefit, maximizing the benefit-risk ratio of interventions.

It represents an essential pathway toward achieving precise brain health protection.

Current controversies and knowledge gaps

Despite the increasingly clear role of midlife hypertension and neurovascular unit (NVU) injury in cognitive decline, significant controversies and knowledge gaps remain in areas such as clinical translation, biomarker standardization, and individual variability. Addressing these issues is key to translating current scientific understanding into effective clinical practice.

Blood pressure control targets

Significant disagreement persists regarding the optimal blood pressure target for preventing cognitive decline, especially in the elderly population.

Conflicting results from SPRINT and the EVA study

The positive findings of the Systolic Blood Pressure Intervention Trial (SPRINT) established the benefit of intensive blood pressure lowering (<120 mmHg) in reducing the risk of mild cognitive impairment. However, the Elderly Vascular Ambulatory (EVA) blood pressure and cognition study found no benefit of intensive blood pressure lowering (target <130/80 mmHg) compared to usual care (target <145/80 mmHg) in slowing the progression of white matter lesions or cognitive decline. This discrepancy may stem from heterogeneity in study populations (e.g., possibly more severe baseline vascular pathology in the EVA cohort), differences in intervention duration or follow-up endpoints, or may suggest a “J-curve” relationship where excessively low blood pressure could offset protective effects by impairing cerebral perfusion, particularly in individuals with pre-existing severe cerebral small vessel disease.

This has prompted profound reflection on whether a “one-size-fits-all” blood pressure target is appropriate for all populations.

Orthostatic hypotension and ventricular enlargement

An unavoidable risk of intensive blood pressure lowering, especially in the elderly, is the induction or exacerbation of orthostatic hypotension (OH). Transient cerebral hypoperfusion caused by OH may directly damage ischemia-sensitive regions such as the hippocampus. Furthermore, imaging studies suggest that OH is independently associated with ventricular enlargement, which may reflect brain atrophy.

Therefore, the pursuit of lower blood pressure values presents a major clinical challenge: how to dynamically monitor and avoid cerebral hypoperfusion events. For patients with autonomic dysfunction or significant existing brain atrophy, individualized, more lenient blood pressure targets may be safer.

Standardization challenges for NVU biomarkers

Using NVU injury as a measurable intermediate phenotype for early diagnosis and treatment efficacy assessment faces significant methodological standardization hurdles.

Inconsistency in DCE-MRI acquisition protocols and Ktrans post-processing parameters

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is the gold standard for quantitatively assessing blood-brain barrier permeability. However, the reproducibility and comparability of Ktrans values are influenced by numerous factors. Differences exist across centers in scanning sequences (e.g., temporal resolution, scan duration), contrast agent dose, administration methods, and, most critically, the choice of pharmacokinetic models for post-processing.

This makes it difficult to directly compare results and conduct meta-analyses across studies, hindering the establishment of Ktrans as a universal biomarker. There is an urgent need for international consensus to develop standardized scanning and post-processing protocols.

Lack of age/renal function-adjusted cut-off points for plasma biomarkers

Peripheral blood NVU-related markers, while convenient to obtain, are complex to interpret. Their levels are significantly influenced by various factors including age, renal function, and systemic inflammatory status. For instance, reduced renal clearance can lead to sPDGFRβ accumulation in the blood, which is difficult to distinguish from elevation caused by brain-derived pericyte injury.

Currently, the vast majority of studies do not provide specific cut-off values adjusted for age and renal function, and there is a lack of longitudinal reference range data from large samples of normal populations. This limits their direct application in clinical diagnosis and risk stratification.

The modifying role of genetic background

Genetic factors profoundly influence individual susceptibility to hypertensive brain injury and response to treatment, yet current understanding remains very limited.

Antihypertensive effects in APOE ε4 carriers

Apolipoprotein E ε4 (APOE ε4) is the strongest genetic risk factor for Alzheimer's disease and also influences lipid metabolism and vascular function. Some observational studies suggest that APOE ε4 carriers may derive greater cognitive protective benefit from antihypertensive treatment; however, others show no effect or even adverse effects. This inconsistency may arise from the complex interaction between APOE ε4 and hypertensive pathological mechanisms: it may simultaneously exacerbate both amyloid pathology and vascular injury, thereby altering the “substrate” for intervention.

Elucidating the influence of APOE genotype on the efficacy of antihypertensive treatment is crucial for achieving precision therapy.

PDGFRβ gene polymorphisms and susceptibility to NVU injury

The platelet-derived growth factor receptor beta (PDGFRβ) signaling pathway is crucial for pericyte development and function maintenance. Theoretically, functional polymorphisms in the PDGFRβ gene could affect an individual's pericyte resistance to hypertensive stress, thereby determining susceptibility to NVU injury. However, current population genetic research evidence on the association between common PDGFRβ gene variants and human cerebral small vessel disease or cognitive decline is insufficient and inconsistent.

Larger-scale genetic association studies with precisely defined phenotypes are needed to uncover the role of these modifier genes, thereby identifying high-risk subgroups at the genetic level.

Future research directions

Advancing the precision prevention and treatment of midlife hypertension-related cognitive decline requires innovations in research paradigms, trial design, and analytical tools. Future research should focus on integrating multi-dimensional data to build predictive models, conducting pathology mechanism-oriented precision clinical trials, and leveraging artificial intelligence (AI) technologies to simulate and optimize individualized intervention strategies.

Constructing a multi-omics neurovascular unit risk score

Moving beyond single biomarkers, a core direction for future research is to integrate multimodal and multi-omics data to build a quantitative scoring system capable of comprehensively and dynamically reflecting NVU health status and disease risk.

Multimodal data fusion models

An ideal NVU risk score should fuse information from diverse dimensions: radiomics can high-throughput extract hundreds of quantitative features from conventional or advanced MRI sequences (e.g., T1, T2-FLAIR, DWI), capturing subtle texture and morphological changes invisible to the naked eye and reflecting alterations in the brain tissue microenvironment; plasma proteomics and metabolomics can provide real-time information on circulating endothelial, pericyte, and glial cell damage, as well as systemic metabolic and inflammatory status; methylation or fragmentation patterns of cell-free DNA may serve as novel liquid biopsy markers for epigenetic aging and tissue-specific injury. By developing advanced statistical models to deeply integrate these heterogeneous data, it is possible to generate an NVU overall function index that is more sensitive and specific than any single metric.

Machine learning-driven feature selection and model optimization

Confronted with high-dimensional, small-sample biomedical data, traditional statistical methods face challenges. Machine learning, particularly embedded or wrapper feature selection algorithms (e.g., LASSO, random forest feature importance ranking, recursive feature elimination), can automatically screen the vast array of radiomic features, plasma proteins, or metabolites to identify the key feature subsets most relevant to NVU injury and cognitive prognosis. Subsequently, training on these selected features using ensemble learning models or deep learning architectures can construct a risk scoring model with high predictive performance while avoiding overfitting.

The goal of this model is not only to predict the risk of cognitive decline but also to differentiate the dominant underlying risk mechanisms (e.g., vascular-dominant vs. amyloid-dominant), thereby providing a basis for subsequent stratified interventions.

Conducting precision secondary prevention randomized controlled trials targeting pathological mechanisms

Future clinical trials need to shift from a “general population” model to a “precision enrichment” model, i.e., recruiting targeted populations with clearly defined pathological mechanisms who are most likely to benefit from a specific intervention.

Precise participant inclusion criteria

An ideal secondary prevention RCT should strictly define participant characteristics to ensure population homogeneity and intervention targeting. Core inclusion criteria may include: age 45–60 years (the golden window for intervention); blood pressure within stage 1 hypertension range (e.g., systolic BP 130–159 mmHg), indicating clear risk without yet causing irreversible damage; evidence of NVU injury, measured via standardized DCE-MRI, with region-specific Ktrans values above the 95th percentile of age-matched healthy individuals. Additionally, consideration could be given to excluding individuals with significant amyloid positivity (via PET or CSF) to focus on evaluating the intervention effect on “pure” vascular pathology.

Multi-target combination intervention strategy

Given the multifactorial nature of NVU injury, single interventions may have limited efficacy. Trials could employ a multi-target combination intervention arm, for example: “intensive blood pressure lowering” (target systolic BP <120 mmHg) combined with a “GLP-1 receptor agonist.” Intensive BP lowering aims to eliminate the primary hemodynamic stressor, while the GLP-1RA targets improving endothelial function and reducing neuroinflammation, theoretically having a synergistic effect. The control arm would be “standard blood pressure lowering” (target systolic BP <140 mmHg) combined with placebo.

The primary endpoint should not be limited to traditional cognitive scale score changes but should incorporate objective imaging biomarkers of NVU function (e.g., reduction in Ktrans, improvement in ASL-CBF) as surrogate or intermediate endpoints, to directly validate in humans the intervention's modifying effect on the target pathology.

Utilizing artificial intelligence for dynamic prediction of individualized intervention windows

Dynamic trajectory prediction based on deep learning

Leveraging large longitudinal cohort data, deep learning models (e.g., recurrent neural networks, Transformer time-series models) can be trained to simulate an individual's dynamic trajectory of “blood pressure exposure - NVU status - cognitive function” over time. Model inputs include the individual's time-series blood pressure data, intermittent NVU imaging markers, genetic background, and lifestyle, with outputs being probabilistic predictions of cognitive status or NVU injury degree at specific future time points. Such models can identify which individuals are approaching a “tipping point” toward cognitive decline, thereby dynamically determining the optimal time window to initiate intervention—the “golden moment” before irreversible damage occurs but when risk is already significantly elevated.

Digital twin models for intervention timing sensitivity testing

To overcome the high cost of clinical trial-and-error, a “digital twin” of an individual's brain NVU system can be constructed. This is a computational model initialized based on the individual's multi-omics data, encompassing multi-scale physiological mechanisms. Researchers can then test, without risk, the long-term effects of different intervention strategieson this virtual twin, performing “intervention timing sensitivity testing.” By comparing outcomes across different virtual intervention pathways, an optimal, personalized prevention plan can be recommended for the individual in advance.

This elevates clinical decision-making from experience-driven to model-optimization-driven, truly realizing the precision and proactivity of preventive medicine.

Conclusion

Summary of major findings

Midlife hypertension, as a significant modifiable risk factor for Alzheimer's disease and related cognitive impairment, has a pathogenic mechanism that extends beyond traditional cardio-cerebrovascular domains to the neurovascular unit (NVU)—the core functional interface for maintaining brain homeostasis. This review systematically delineates the complete pathological cascade through which midlife hypertension induces chronic hypoperfusion, disrupts blood-brain barrier (BBB) integrity, and triggers neuroinflammatory cascades, leading to progressive structural and functional damage of the NVU. NVU dysfunction not only manifests as impaired cerebral blood flow regulation and reduced efficiency of metabolic waste clearance but also directly drives cognitive decline through a series of molecular and system-level events, including glutamate excitotoxicity, energy crisis in cholinergic axons, impaired insulin signaling, and large-scale brain network disconnection.

Notably, evidence from large-scale cohorts and multimodal neuroimaging studies indicates that midlife blood pressure trajectories have significantly greater predictive value for long-term cognitive outcomes than late-life blood pressure, and NVU injury markers are closely associated with the rate of cognitive decline. These findings collectively establish the ‘hypertension-NVU injury-cognitive decline’ axis as a key vascular pathogenic pathway that can operate partially independently of, yet frequently interacts synergistically with, Aβ/tau pathology. The novelty of this framework lies not in claiming independence from amyloid pathology, but in integrating midlife blood pressure trajectories, NVU-specific injury mechanisms, emerging biomarkers, and early prevention strategies into a single actionable paradigm.

It should be acknowledged that the evidence base for different components of this axis varies considerably. The epidemiological link between midlife hypertension and late-life cognitive decline, as well as the benefits of intensive blood pressure control, are supported by strong evidence from large-scale cohort studies and randomized trials. Imaging markers of NVU injury (e.g., BBB leakage on DCE-MRI, white matter microstructural damage on DTI) represent moderate-to-strong evidence from human studies.

However, many of the detailed molecular mechanisms—particularly those involving glutamate excitotoxicity, cholinergic axonal energy failure, and insulin signaling impairment—are primarily supported by animal and in vitro studies and should be regarded as plausible mechanistic inferences requiring further human validation.

Clinical translation implications

The findings of this review have clear implications for clinical translation. First, they strongly support establishing midlife as the “critical time window” for intervening in hypertension to protect brain health. In clinical practice, blood pressure management for individuals aged 45–60 should adopt a more proactive approach, considering cognitive protection as an integral goal of antihypertensive therapy.

Second, NVU dysfunction should be regarded as an important intervention target. Future therapeutic research should move beyond mere numerical blood pressure control to investigate multi-target drugs (e.g., GLP-1 receptor agonists) and combination therapies that directly improve BBB function, reduce neuroinflammation, and enhance neurovascular coupling; at present, however, these approaches remain investigational and require validation in adequately powered randomized trials before clinical implementation. Finally, promoting the application of precision medicine models in preventing vascular cognitive impairment is crucial.

By integrating genetic risk, NVU imaging markers, and traditional risk factors to construct individualized risk scores, early identification and stratified management of high-risk populations can be achieved, making preventive measures more targeted and cost-effective.

Implications for public health policy

The aforementioned scientific insights have profound implications for public health policy formulation. Against the backdrop of an aging population, cognitive decline has become a major societal health burden. Public health strategies should shift from a focus on treating late-stage dementia to a brain health promotion model centered on risk factor control during midlife.

This includes: promoting regular blood pressure screening and cognitive risk education for middle-aged populations at the community level; explicitly incorporating brain health protection as a key consideration in hypertension management guidelines; supporting multidisciplinary collaboration to integrate neurology, cardiology, and geriatrics; and increasing investment in the development of NVU-targeted therapies and biomarker-guided precision prevention clinical trials. Only through synergistic innovation in science and policy can the rising trend of hypertension-related cognitive decline be effectively curbed, alleviating the increasingly heavy disease burden on individuals, families, and society.

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CRediT authorship contribution statement

Zhengde Tao: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

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Not applicable. This article is a narrative review and does not involve original research with human participants or animals.

Funding

This research received no external funding.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.