Vascular risk factors and cognitive decline: An integrated perspective from epidemiology to precision intervention

Abstract

Cognitive impairment and dementia have become a major global public health challenge. Traditionally attributed to Alzheimer’s disease pathology, cognitive decline is now recognized as being profoundly influenced and often driven by vascular factors, as evidenced by accumulating data over the past two decades. Based on recent high-quality evidence, this review systematically outlines the current epidemiological association between vascular risk factors and cognitive impairment. It delves deeply into the complex pathogenic mechanisms, ranging from macrovascular disease and cerebral small vessel disease to neurovascular unit dysfunction. The review critically evaluates the impact of traditional and novel management strategies for major vascular risk factors, such as hypertension, diabetes, and atrial fibrillation, on cognitive outcomes, and provides an in-depth analysis of multi-domain lifestyle intervention models represented by the Finnish FINGER study. Finally, this review critically points out the limitations of current research regarding population representativeness, biomarker translation, and intervention timing. It also looks forward to future directions integrating multi-omics data, developing precision risk stratification models, and conducting adaptive intervention trials. This review provides a comprehensive evidence-based synthesis, offering a forward-looking framework for a full-chain prevention system from risk screening to effective intervention centered on vascular health.

Key Words: Vascular risk factors; Cognitive decline; Vascular cognitive impairment; Cerebral small vessel disease; Mechanisms; Management

Core Tip: Vascular pathology is a core driver of cognitive decline (often coexisting with Alzheimer’s disease pathology). Midlife (40-65 years) is the critical prevention window. Key mechanisms include cerebral small vessel disease, blood-brain barrier disruption, neurovascular unit dysfunction, and neuroinflammation. Hypertension (including blood pressure variability) is the primary intervention target. Lifestyle interventions (e.g., FINGER model) are the most effective broad prevention strategy. Current challenges include diagnostic difficulties and insufficient personalized interventions. The core message is that maintaining vascular health maintains brain health.

INTRODUCTION

Global population aging has made cognitive impairment and dementia one of the most severe public health challenges of the 21^st century[1]. For a long time, attention has been focused on the neurodegenerative pathology of Alzheimer’s disease (AD), such as β-amyloid deposition and tau protein tangles. However, substantial neuropathological and epidemiological evidence indicates that vascular pathological processes play at least an equally important, and often deeply intertwined, role with neurodegenerative processes in the initiation, progression, and even clinical phenotypic shaping of cognitive impairment[2-4]. Pure dementia caused solely by AD pathology or solely by cerebrovascular disease is relatively uncommon. Most cases present as mixed pathology, where AD pathology coexists with varying degrees of cerebrovascular lesions[5,6].

The concept of “vascular cognitive impairment” (VCI) encompasses the entire disease spectrum from vascular mild cognitive impairment (MCI) to vascular dementia. Its fundamental etiology lies in various cerebrovascular diseases and their resulting brain tissue damage[7]. In the development of VCI, a series of modifiable vascular risk factors (VRFs) constitute critical intervention targets[8]. These factors, including hypertension, diabetes, dyslipidemia, obesity, smoking, physical inactivity, and cardiac diseases [such as coronary heart disease, heart failure, and atrial fibrillation (AF)], not only directly damage the structure and function of cerebral blood vessels, leading to cerebral infarction, hemorrhage, or cerebral small vessel disease (CSVD), but can also exacerbate or even drive the neurodegenerative process through multiple mechanisms, including inducing chronic cerebral hypoperfusion, blood-brain barrier (BBB) dysfunction, neuroinflammation, and oxidative stress[9-12].

Notably, the impact of VRFs on cognition is life-course dependent. Exposure and accumulation of VRFs during midlife (typically ages 40-65) have been confirmed as strong predictors of late-life cognitive decline and dementia risk[13,14]. This finding significantly shifts the window for maintaining cognitive health earlier, emphasizing the major preventive potential of vascular risk management in midlife. Therefore, a deep understanding of the association between VRFs and cognitive impairment, their intrinsic mechanisms, and the exploration of effective management strategies are of paramount importance for achieving primary and secondary prevention of dementia[15].

This review distinguishes itself from prior landmark statements, such as the 2011 American Heart Association/American Stroke Association scientific statement on vascular contributions to cognitive impairment[2] and the 2020 Lancet Commission report on dementia prevention[8], by offering three unique contributions. First, we integrate the most recent evidence from 2020-2025, including novel insights into blood pressure variability (BPV)[16], the heart[17-21] and heart-brain axis[22,23], and emerging mechanisms such as venous system dysfunction[24,25] and glymphatic impairment[26,27]. Second, we provide a critical synthesis of the translational gap between mechanistic understanding and clinical application, highlighting challenges in biomarker development[28-31] and animal model fidelity[32,33]. Third, and most importantly, we articulate a concrete roadmap toward precision prevention, moving beyond population-level recommendations to discuss how interventions might be tailored based on genetic background [e.g., apolipoprotein E (APOE) epsilon 4], sex differences, and dominant pathology - a vision now being tested in trials like MET-FINGER[34].

This review aims to systematically expound, based on recent (especially 2020-2025) high-quality evidence, the epidemiological contribution of VRFs to cognitive decline, core pathogenic mechanisms, evidence-based progress in management strategies, and to critically examine the limitations of current research, thereby pointing the way for future basic research, clinical practice, and public health policy.

EPIDEMIOLOGY OF COGNITIVE DECLINE AND THE WEIGHT OF VASCULAR FACTORS

Disease burden of vascular etiology and the prevalence of mixed pathology

In the global etiological composition of dementia, vascular dementia is the second most common type after AD, while mixed pathology is even more prevalent[5,35]. Community studies show that clinically diagnosed mixed dementia actually constitutes a large proportion, typically based on the coexistence of AD pathology and cerebrovascular disease. Autopsy-based studies have found that up to 80% of AD patients also have significant cerebrovascular pathology[6,36]. Among patients with MCI, a subgroup that remains cognitively stable (stable MCI) shows significantly less AD-related pathology but more cerebrovascular disease (especially cerebral microinfarcts) on neuropathological examination. This suggests that a “non-progressive” form of cognitive impairment characterized by microvascular disease may constitute an important subtype of VCI[36].

Post-stroke cognitive impairment is a classic manifestation of vascular cognitive injury[37]. Epidemiological data indicate that approximately 10% of first-ever stroke patients progress to dementia, while this proportion can be as high as 30% in recurrent stroke patients[38]. More importantly, in community-dwelling elderly populations without a history of clinical stroke, CSVD-related occult cerebrovascular pathology is a major vascular cause of cognitive decline and functional impairment[39,40]. Neuroimaging markers of CSVD, such as widely present white matter hyperintensities (WMH), lacunes, and cerebral microbleeds, are closely associated with declines in processing speed and executive function, and are strong predictors of cognitive decline[41]. Furthermore, WMH burden has been linked to neuropsychiatric symptoms in MCI and AD patients, suggesting a broader clinical impact of cerebrovascular pathology[42].

Prevalence, cumulative effects, and life course impact of VRFs

VRFs are highly prevalent in the population and often occur in clusters (e.g., metabolic syndrome), with their cumulative effect greatly increasing the risk of cognitive decline[43]. Data from large population cohorts consistently show that VRFs contribute substantially to the population-attributable risk for dementia. For example, an analysis of over 500000 individuals in the United Kingdom Biobank found that midlife cardio VRFs (e.g., hypertension, smoking, diabetes, obesity) were significantly associated with subsequent dementia events[44].

The impact of VRFs on brain health exhibits a time-cumulative effect. Long-term follow-up from studies like the Atherosclerosis Risk in Communities Study indicates that VRFs such as hypertension and diabetes in midlife are associated with a significantly increased risk of late-life cognitive impairment[45,46]. A 12-year follow-up in the Maastricht Aging Study further showed that both prevalent and incident cardiovascular disease can predict the trajectory of cognitive decline in middle-aged and older individuals. Incident cardiovascular events appear to be associated with an acceleration point in cognitive decline[47]. Even after excluding clinical stroke events, VRFs (such as frequent premature atrial contractions) remain independently associated with poorer executive function, global cognitive function, and a higher prevalence of MCI or dementia, suggesting their influence on cognition via subclinical cerebrovascular damage pathways[48].

SOCIODEMOGRAPHIC FACTORS, HEALTH DISPARITIES, AND COGNITIVE RESERVE

The impact of VRFs on cognition varies significantly across racial, ethnic, and socioeconomic groups, constituting an important aspect of health inequity[49]. Studies consistently show that, after adjusting for age and education, Black and Hispanic older adults have higher prevalence rates of MCI and dementia compared to non-Hispanic white older adults[50]. This disparity cannot be fully explained by differences in the burden of traditional VRFs. Psychosocial factors such as perceived discrimination, depressive symptoms, and an external locus of control have been shown to lead to worse cognitive trajectories through specific pathways, with a pronounced effect on minority groups[51].

Emerging research in globally underrepresented populations reveals unique risk factor profiles and resilience patterns. For instance, the Tsimane indigenous population in Bolivia, who maintain a pre-industrial lifestyle with high physical activity and low cardiovascular risk, exhibit remarkably slow brain aging despite high systemic inflammation, suggesting that lifestyle factors may override inflammatory risk[52]. Conversely, Latin American populations face a growing burden of VRFs alongside limited healthcare infrastructure, creating distinct challenges for dementia prevention[5]. These observations underscore that risk factor-cognition relationships are population-specific and that global prevention strategies must be culturally adapted.

Cognitive reserve (often proxied by education level, occupational achievement, etc.) has been shown to buffer the negative impact of cerebrovascular lesions on cognitive function and to promote post-stroke cognitive recovery[53]. Educational attainment has been found to mediate racial differences in cognition. For instance, among older adults with schizophrenia, differences in global cognitive scores between Black and non-Black groups can be largely explained by differences in years of education[54]. The concept of cognitive reserve has important implications for both clinical trials and public health. In trial design, educational attainment and occupational complexity should be considered as potential effect modifiers or stratification variables, as they may influence both baseline cognitive performance and response to interventions[53]. For public health messaging, these findings support policies that promote early-life education and cognitively stimulating activities throughout life as investments in brain health capital that can buffer against future vascular insults[54]. These findings emphasize the necessity of considering broader social determinants and individual psychological resources when investigating the relationship between VRFs and cognition.

VRFS ASSOCIATED WITH COGNITIVE DECLINE AND THEIR PATHOGENIC MECHANISMS

Hypertension

Hypertension is the most well-established and modifiable VRF for VCI to date. Recent research has moved beyond focusing solely on mean systolic/diastolic blood pressure values to investigate BPV, circadian rhythm, and specific antihypertensive regimens.

BPV: Post-hoc analyses from the SPRINT trial showed that increased visit-to-visit systolic BPV was independently associated with an increased risk of MCI and dementia, even after controlling for mean blood pressure[16]. In the standard treatment group, increased BPV was associated with a 21% higher MCI risk; in the intensive treatment group, it was associated with a 17% higher dementia risk[16]. This suggests that even with well-controlled average blood pressure, significant blood pressure fluctuations may harm the cerebral vasculature.

Complex blood pressure-cognition relationship and sex differences: The relationship between blood pressure and dementia risk may follow a “U-shaped” or “J-shaped” curve, where excessively low blood pressure may also be harmful due to cerebral hypoperfusion, especially in the elderly[44,46]. United Kingdom Biobank data indicate sex differences in this association: A U-shaped relationship in men vs a dose-response relationship (higher blood pressure, higher risk) in women[44]. These differences may stem from variations in vascular physiology, hormonal environment, or susceptibility to brain pathology.

Mechanistic insights: Chronic hypertension impairs brain health through multiple pathways: (1) Increased large artery stiffness: Leads to elevated systolic blood pressure and widened pulse pressure, impairing cerebral perfusion and enhancing pulse wave impact on cerebral microvessels, causing cerebrovascular dysfunction and neuroinflammation[55,56]; (2) CSVD: Hypertension is a primary driver of CSVD, causing hyalinosis and fibrinoid necrosis of vessel walls, leading to WMH, lacunar infarcts, and microbleeds[57]; (3) BBB disruption: Hypertension can damage endothelial cells and tight junctions, increasing BBB permeability. Studies show that increased BBB permeability to small molecules (water) in MCI patients correlates with AD biomarkers, while increased permeability to large molecules (albumin) is more associated with VRFs[28]; and (4) Oxidative stress and neuroinflammation: Hypertension promotes reactive oxygen species generation, activates microglia and astrocytes, releasing pro-inflammatory cytokines, creating a chronic neuroinflammatory environment that accelerates neuronal damage[58].

Diabetes and glucose metabolism abnormalities

Type 2 diabetes mellitus (T2DM) is an independent risk factor for cognitive decline and dementia, with harms beginning in the pre-disease stage (prediabetes).

Impact of prediabetes: The AD Neuroimaging Initiative cohort study showed that in non-demented older adults, a prediabetic state was associated with reduced cerebral glucose metabolic rate (cerebral hypometabolism). Furthermore, in women, prediabetes was associated with executive function decline and earlier dementia onset age[59]. United Kingdom Biobank data further found that a prediabetic state was associated with a higher risk of vascular dementia, faster cognitive decline, greater WMH volume, and smaller hippocampal volume[60].

Sex differences: The CAROLINA-COGNITION study found that female diabetics had a 27% higher risk of accelerated cognitive decline compared to males, with depressive symptoms mediating approximately 20% of this excess risk[61].

Mechanistic insights: (1) Insulin resistance and cerebral energy metabolism dysfunction: The brain is an insulin-sensitive organ. Insulin resistance affects neuronal glucose uptake, synaptic plasticity, and β-amyloid clearance[62]; (2) Advanced glycation end products: Hyperglycemia promotes advanced glycation end products formation, damaging vascular elasticity and increasing oxidative stress and inflammation; and (3) Microvascular complications: Diabetes directly damages microvessels in the retina and kidneys, which can similarly affect cerebral vessels, leading to CSVD[32]. Neuroimaging studies reveal a specific neural trajectory for episodic memory decline in T2DM patients: Abnormalities in functional connectivity between brain regions appear first, followed by behavioral changes, abnormal spontaneous neural activity, and finally, gray matter volume reduction[63].

Cardiac disease and the tight link of the “heart-brain axis”

AF: Beyond causing cardioembolic stroke leading to vascular dementia, AF may also directly impact cognition through chronic cerebral hypoperfusion, microembolism, and systemic inflammation. The REGARDS study confirmed that AF patients performed worse on multidomain cognitive tests at baseline and showed faster decline in verbal learning over follow-up. This association persisted, in part, even after adjusting for cardiovascular risks and stroke events[17]. Silent cerebral WMH are common in paroxysmal AF patients, with severity correlating with age, CHA₂DS₂-VASc score, and comorbidities like patent foramen ovale and coronary heart disease[18]. There is a growing consensus that AF should be viewed as a systemic vascular disease, and its management should extend beyond mere stroke prevention[19].

Chronic heart failure and coronary heart disease: Heart failure leads to reduced cardiac output, causing chronic global cerebral hypoperfusion. This is a key pathophysiological basis for cognitive impairment in approximately 25%-50% of heart failure patients[20]. Coronary heart disease is a well-established risk factor for cognitive impairment and dementia (especially vascular dementia)[21]. Elevated levels of blood-based cardiac biomarkers like N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T (hs-cTnT) are not only associated with cognitive decline but also predict future vascular events and mortality risk[22]. In stroke patients without dementia, higher hs-cTnT levels were associated with greater overall CSVD burden and poorer attention and executive function, suggesting that subclinical myocardial injury may serve as a biological window reflecting systemic vascular endothelial dysfunction and cerebral microangiopathy[23].

Atherosclerosis, dyslipidemia, and obesity

Subclinical atherosclerosis: Carotid intima-media thickness is a common marker of subclinical atherosclerosis. A meta-analysis showed higher carotid intima-media thickness in dementia and MCI groups compared to cognitively normal groups[64]. Fluorodeoxyglucose positron emission tomography studies found that carotid plaque burden in middle-aged asymptomatic individuals was significantly associated with reduced glucose metabolism in the whole brain and specific regions (e.g., angular gyrus, middle temporal gyrus), areas vulnerable in early dementia[65]. Intracranial atherosclerosis, a common cause of stroke in Asian populations, is closely associated with impaired executive function, memory decline, and cerebral hemodynamic compromise[66,67].

The complex role of lipids: The relationship between lipids and cognition varies by specific lipid components and disease context. In the general population, high cholesterol is a risk factor. However, in advanced Parkinson’s disease patients, no strong or consistent association was found between lipid levels and motor or cognitive decline, suggesting that the pathophysiological significance of lipids may differ across neurodegenerative disease backgrounds[68]. The APOE ε4 allele not only increases AD risk but also contributes to vascular contributions to cognitive impairment and dementia pathogenesis by disrupting lipid homeostasis in astrocytes and microglia, promoting neuroinflammation, and exacerbating atherosclerosis[69].

Obesity and metabolic syndrome: Midlife obesity is a well-established risk factor for late-life dementia. Its mechanisms extend beyond simple cardiometabolic comorbidities to involve complex microvascular mechanisms, including impaired endothelium-dependent vasodilation, attenuated neurovascular coupling (NVC) response, microvascular rarefaction, and BBB disruption[70]. Adipokines and pro-inflammatory cytokines released from adipose tissue create a chronic low-grade inflammatory state, affecting cerebrovascular function and neuronal health[70]. Metabolic syndrome, a cluster of hypertension, hyperglycemia, central obesity, and dyslipidemia, is associated with impaired executive function[71].

AN INTEGRATIVE MODEL OF PATHOGENIC MECHANISMS

The mechanisms by which VRFs lead to cognitive impairment constitute a multi-layered, intertwined network, ultimately converging on common final pathways: White matter damage, synaptic loss, and neuronal death (Figure 1). As illustrated in Figure 1, VRFs initiate a multi-layered pathogenic cascade: Large artery stiffness impairs cerebral perfusion[55,56], while CSVD directly damages white matter tracts[57,72]. BBB dysfunction allows toxic blood components into the brain parenchyma[28,73], and neurovascular unit coupling failure deprives active neurons of energy[74,75]. Neuroinflammation and oxidative stress amplify all preceding mechanisms[76,77], and emerging evidence implicates venous system dysfunction in increasing cerebral venous pressure[24,25]. Genetic factors, particularly APOE ε4, modulate susceptibility across multiple pathways[69].

Figure 1 Integrated Pathomechanistic Network of Vascular Contributions to Cognitive Decline. This figure illustrates the multi-layered pathogenic cascade through which vascular risk factors lead to cognitive impairment. Numbered pathways [(1)-(7)] represent key mechanistic nodes: (1) Large artery stiffness: Hypertension and atherosclerosis increase arterial stiffness, elevating systolic blood pressure and pulse pressure, which impairs cerebral perfusion and transmits damaging pulsatile stress to cerebral microvessels[55,56]; (2) Cerebral small vessel disease (CSVD): Vascular risk factors cause lipohyalinosis and fibrinoid necrosis of small arteries, leading to white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and enlarged perivascular spaces, disrupting white matter tract integrity[39,41,57,72]; (3) Blood-brain barrier function and glymphatic impairment: Endothelial tight junction disruption increases permeability, allowing toxic blood components into brain parenchyma and impairing glymphatic clearance of neurotoxic proteins like β-amyloid[26-28,73]; (4) Neurovascular unit coupling failure: Endothelial dysfunction impairs neurovascular coupling, reducing cerebral blood flow response to neural activity and creating energy supply-demand mismatch[74,75,79]; (5) Neuroinflammation and oxidative stress: Microglial activation releases pro-inflammatory cytokines and generates reactive oxygen species, causing cellular damage and creating a self-perpetuating feedback loop that amplifies all mechanisms[58,76,77,80]; (6) Venous system dysfunction (emerging): Internal jugular vein reflux increases cerebral venous pressure, promoting vasogenic edema and Blood-brain barrier leakage, contributing to white matter damage[24,25]; and (7) Genetic susceptibility: Genetic factors, particularly apolipoprotein E epsilon 4 carriage, modulate vulnerability across all pathways by disrupting lipid homeostasis, promoting neuroinflammation, and exacerbating atherosclerosis[69]. These interconnected mechanisms converge to produce characteristic cognitive deficits including slowed processing speed, executive dysfunction, and memory impairment, culminating in vascular cognitive impairment, mixed dementia (Alzheimer’s disease + CSVD), or post-stroke cognitive impairment[5,7,35-38]. Furthermore, CSVD-related pathology contributes to neuropsychiatric symptoms such as depression and apathy, expanding the clinical impact of vascular brain injury[42]. AF: Atrial fibrillation; APOE ε4: Apolipoprotein E epsilon 4; CSVD: Cerebral small vessel disease; NVU: Neurovascular unit.

CSVD as a core link

VRFs like hypertension and diabetes cause lipohyalinosis and fibrinoid necrosis of cerebral small arteries and arterioles, leading to wall thickening and luminal stenosis, resulting in chronic cerebral ischemia[72]. Neuroimaging manifests as WMH, enlarged perivascular spaces, lacunes, and microbleeds[39,41]. These lesions disrupt the integrity of white matter tracts connecting functional brain areas, particularly affecting prefrontal-subcortical circuits, leading to impairments in executive function, information processing speed, and gait/balance[40,78], and have been associated with neuropsychiatric symptoms including depression and apathy in patients with MCI and AD, highlighting the broader clinical consequences of cerebrovascular pathology[42]. In early Parkinson’s disease, VRF burden correlates with WMH volume[78].

BBB dysfunction and impaired brain clearance systems

VRFs can damage BBB endothelial cells and tight junctions, increasing permeability. Leaked blood components are toxic to neurons and glia[28,73]. More importantly, BBB dysfunction and altered enlarged perivascular spaces impair glymphatic system and other brain waste clearance pathways, leading to abnormal accumulation of toxic proteins like β-amyloid in the brain, thereby establishing a pathological link between AD and VCI[26,27]. Genetic predisposition, particularly APOE ε4 carriage, may further compromise BBB integrity by altering pericyte function and basement membrane composition, thereby increasing susceptibility to VRF-induced vascular damage[26,69].

Neurovascular unit coupling dysfunction and chronic cerebral hypoperfusion

The neurovascular unit is responsible for precisely regulating local cerebral blood flow NVC during increased neural activity. VRFs impair NVC function by causing endothelial dysfunction and attenuated vasodilatory responses, depriving active neurons of adequate energy supply[74,75]. Long-term aerobic exercise has been shown to improve carotid arterial stiffness, reduce cerebral blood flow pulsatility, and increase global cerebral blood flow in MCI patients, providing direct evidence for cognitive protection via improved vascular elasticity[79].

Neuroinflammation and oxidative stress

A VRF-laden state is often accompanied by systemic and cerebral chronic low-grade inflammation. Activated microglia release pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha, interleukin-6) and simultaneously produce large amounts of reactive oxygen species, inducing oxidative stress[76,77]. This process directly damages neurons and oligodendrocytes and further exacerbates vascular dysfunction and abnormal protein aggregation. Elevated plasma levels of inflammatory markers (e.g., osteopontin) are significantly correlated with neuroimaging markers of VCI and AD[77]. Dysregulation of the tryptophan-kynurenine pathway, particularly an increased quinolinic acid to kynurenic acid ratio, shows promise as a predictive biomarker in patients with post-stroke cognitive impairment[80]. Genetic factors modulate these inflammatory responses. For instance, the APOE ε4 allele, beyond its role in lipid metabolism, exacerbates neuroinflammation by disrupting lipid homeostasis in microglia and astrocytes, promoting a pro-inflammatory phenotype that amplifies cytokine release and oxidative stress following vascular injury[69]. This creates a vicious cycle where vascular damage and genetic susceptibility converge to accelerate neuronal dysfunction (Figure 2).

Figure 2 Mechanism Diagram of Neuroinflammation and Oxidative Stress. This figure details the self-perpetuating cycle of neuroinflammation and oxidative stress that amplifies vascular injury. Numbered pathways [(1)-(5)] represent sequential and interconnected steps: (1) Microglial activation: Vascular risk factors and damage-associated molecular patterns trigger the transformation of resting ramified microglia into activated amoeboid M1 phenotype cells. Activation involves NOD-like receptor protein 3 inflammasome assembly, major histocompatibility complex class II upregulation, and increased phagocytic activity[58,76]; (2) Pro-inflammatory cytokine release: Activated microglia release a cascade of pro-inflammatory cytokines including tumor necrosis factor-alpha [endothelial activation, blood-brain barrier (BBB) disruption, neuronal apoptosis], interleukin (IL)-6 (acute phase response), IL-1β (microglial amplification, synaptic impairment), IL-12, and interferon-gamma while anti-inflammatory cytokines (IL-4, IL-10) are suppressed[76,77,80]; (3) Reactive oxygen species (ROS) generation: Cytokines trigger ROS production through multiple enzymatic sources (nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase, myeloperoxidase, inducible nitric oxide synthase) and non-enzymatic sources (mitochondrial electron transport chain, endoplasmic reticulum stress). ROS species (O₂•−, H₂O₂, •OH, ONOO^-) cause lipid peroxidation, protein oxidation, and DNA damage. Mitochondrial dysfunction creates a vicious cycle of further ROS production[58,76]; (4) Cellular damage: ROS and cytokines cause direct damage to multiple cell types: Neurons: Excitotoxicity, synaptic loss, apoptosis, tau hyperphosphorylation. Oligodendrocytes: Demyelination, axonal injury, impaired remyelination. Endothelium: Tight junction disruption, adhesion molecule upregulation, basement membrane degradation, capillary rarefaction. Astrocytes: A1 neurotoxic phenotype conversion, impaired glutamate uptake (to excitotoxicity), loss of neurotrophic support, aquaporin-4 dysregulation (to glymphatic failure)[28,58,73,76,77]; and (5) BBB disruption amplification: Endothelial damage increases paracellular permeability, allows infiltration of peripheral immune cells and entry of neurotoxic plasma proteins (fibrinogen, albumin), which further activate microglia - creating a positive feedback loop to step (1). Pericyte detachment and basement membrane thickening compound the damage[26-28,73]. Genetic modulation (apolipoprotein E epsilon 4): The apolipoprotein E epsilon 4 allele amplifies the entire cascade by disrupting lipid homeostasis, promoting pro-inflammatory microglial polarization, amplifying cytokine responses, exacerbating oxidative stress, impairing β-amyloid clearance, and compromising BBB integrity[69]. Ultimate consequences: This self-perpetuating cycle drives white matter damage, synaptic loss, neuronal death, network disconnection, and impaired neuroplasticity, culminating in the characteristic cognitive deficits of vascular cognitive impairment[35,39-41,53,78]. The resulting pathology also contributes to neuropsychiatric disturbances, further diminishing quality of life[42]. APOE ε4: Apolipoprotein E epsilon 4; VRF: Vascular risk factor; DAMP: Damage-associated molecular pattern; TNF: Tumor necrosis factor; IL: Interleukin; INF: Interferon; ROS: Reactive oxygen species; NADPH: Nicotinamide adenine dinucleotide phosphate; BBB: Blood-brain barrier; QUIN: Quinolinic acid; KYNA: Kynurenic acid; 8-OHdG: 8-hydroxy-2’-deoxyguanosine.

Venous system dysfunction as an emerging field

Age-related decline in internal jugular vein compliance and valve insufficiency leading to spontaneous internal jugular venous reflux is thought to potentially contribute to WMH and cognitive impairment by increasing cerebral venous pressure, promoting vasogenic edema, and BBB leakage[24,25].

Interaction between vascular and neurodegenerative pathology

Vascular and AD pathologies exhibit significant additive and even synergistic effects[6,36]. Autopsy studies have found that the presence of cerebrovascular pathologies such as arteriolosclerosis and old microinfarcts/microbleeds is significantly associated with the clinical severity of AD dementia, even after adjusting for typical AD pathological burden[36]. Genome-wide association studies have identified genetic loci associated with both AD risk and cerebral amyloid angiopathy burden, revealing that genetic factors may simultaneously regulate vascular and neurodegenerative processes[81].

MANAGEMENT OF VRFS ASSOCIATED WITH COGNITIVE DECLINE

Control of traditional risk factors as the evidence-based cornerstone

Active management of traditional VRFs is currently the most effective and evidence-supported strategy for preventing VCI.

Blood pressure management

Intensive blood pressure control is among the interventions with the highest level of evidence. The Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension trial showed that intensive systolic blood pressure control to below 120 mmHg (compared to < 140 mmHg) significantly reduced the composite risk of MCI or probable dementia[16]. However, benefits are not uniform. Post-hoc analysis of the ADVANCE trial suggested that the preventive effect of antihypertensive treatment on dementia/cognitive decline was more pronounced in T2DM patients with baseline cognitive impairment[82]. Management goals should emphasize long-term, stable control. Precision approaches to blood pressure management are emerging. For example, the U-shaped blood pressure-cognition relationship in men vs the dose-response relationship in women[44] suggests that optimal blood pressure targets may differ by sex. Similarly, in patients with established CSVD, excessively intensive blood pressure lowering may exacerbate cerebral hypoperfusion, necessitating individualized targets based on baseline cerebrovascular status.

Glucose and lipid management

Glycemic control is crucial for preventing cognitive decline in diabetic patients. Although strict glycemic control has limited effect on improving cognition in patients with established dementia, interventions targeting prediabetes and early-stage diabetes may hold significant preventive importance[59,83]. Statins, while lowering cholesterol, may exert beneficial effects on the cerebrovasculature and cognition through their pleiotropic anti-inflammatory, antioxidant, and endothelial function-improving properties, although their direct cognitive benefits remain debated. Genetic background informs precision strategies. The MET-FINGER trial[34] exemplifies this by targeting APOE ε4 carriers - a genetically high-risk group - with a combination of multi-domain lifestyle intervention and metformin, testing whether this subgroup derives enhanced benefit from the dual approach.

Cardiac disease management

Optimizing heart failure treatment to improve cardiac output and standardizing anticoagulation therapy to reduce stroke risk in AF patients are important measures to protect cognitive function in these populations[20,84]. Studies indicate that AF patients who previously received only antiplatelet therapy without oral anticoagulation had a higher prevalence of baseline cognitive impairment and worse prognosis[85].

A PROMISING PREVENTIVE MODEL OF MULTI-DOMAIN LIFESTYLE INTERVENTION

This forms the foundation of VRF management and is the most cost-effective primary prevention approach.

The FINGER study and its extensions

The Finnish FINGER study is a landmark randomized controlled trial demonstrating that a 2-year multi-domain lifestyle intervention (combining nutritional guidance, aerobic and strength training, cognitive training, vascular risk monitoring, and social activity) could significantly improve or maintain cognitive function in older adults at risk for dementia[86]. Post-hoc analysis showed that reduction in the CAIDE dementia risk score during the intervention was associated with slowed hippocampal volume decline[87]. Based on this model, multiple studies worldwide are validating and adapting multi-domain intervention protocols, such as the Singapore SINGER pilot study and the online BetterBrains trial, all showing good feasibility and preliminary positive signals[88,89].

More advanced combination strategies

The MET-FINGER trial innovatively combines an updated FINGER multi-domain lifestyle intervention with metformin (a hypoglycemic drug with potential neuroprotective properties) for testing in a high-risk elderly population enriched for APOE ε4 carriers, representing an important step towards precision prevention[34]. The MET-FINGER trial[34] represents a paradigm shift toward precision prevention: Rather than a one-size-fits-all approach, it enriches for APOE ε4 carriers and combines lifestyle intervention with a repurposed drug (metformin) that may have neuroprotective properties specifically relevant to this genetic subgroup.

Specific dietary and exercise patterns

The Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet and the ORIENT diet, modified for the Chinese population, show neuroprotective potential[90,91]. Both aerobic and resistance training have proven beneficial. A trial protocol for patients with subcortical ischemic VCI proposed that a 12-month progressive resistance training program may delay cognitive decline and WMH progression[92]. An anthocyanin-rich dietary intervention was shown to lower TNF-α levels in older adults with MCI[93].

EXPLORATORY INTERVENTIONS TARGETING NEUROVASCULAR PROTECTION

Beyond controlling downstream VRFs, intervention strategies directly targeting upstream pathogenic mechanisms are under investigation.

Neurovascular and BBB protective agents

Some natural products with multi-target actions, such as the standardized Ginkgo biloba leaf extract EGb 761, have shown effects in improving cerebral blood flow, antioxidant, anti-inflammatory, and BBB protection in preclinical studies, with related clinical trials ongoing[76]. Drugs targeting systems like the renin-angiotensin system are also being evaluated for their potential cognitive benefits.

Novel non-pharmacological interventions

Time-restricted eating, as an emerging metabolic intervention, may improve neurovascular function by enhancing insulin sensitivity, reducing inflammation and oxidative stress, and enhancing autophagy. Studies are planned to explore its impact on NVC response and cognitive function in the elderly brain[74]. Additionally, cognitive training and brain stimulation techniques like transcranial direct current stimulation are being explored as part of multimodal interventions.

Interventions for specific populations

Trials such as SERVED Memory, FAVORITE (iron supplementation for prevention), Demin (online lifestyle intervention), and LETHE (digital tool) are designed for high-risk groups like post-stroke/TIA patients and first-degree relatives of dementia patients, exploring the feasibility of targeted prevention strategies[15,94-96]. Future precision approaches will likely stratify patients by dominant pathology. For instance, patients with predominant CSVD on magnetic resonance imaging might benefit more from strict blood pressure control and antithrombotic therapy, while those with mixed AD-vascular pathology might require combination approaches targeting both amyloid (e.g., anti-amyloid antibodies) and vascular pathways. Sex-specific strategies are also warranted given the differential risk profiles observed in women with diabetes[61] and the U-shaped blood pressure-cognition relationship in men vs the linear relationship in women[44].

INTEGRATION INTO PRIMARY CARE AND PUBLIC HEALTH

Systematic reviews show that general practitioners are more inclined to offer non-pharmacological advice (e.g., increased physical activity, cognitive and social stimulation) rather than prescribe medication to patients with subjective memory complaints or MCI[97]. This reflects the spirit of current guidelines. Efforts like the German AgeWell.de study, which closely integrates multi-component prevention with primary care, are important attempts to explore how to implement and scale dementia prevention models within real-world healthcare systems[98]. As summarized in Table 1, which provides a quick-reference synthesis of major VRFs, their mechanisms, biomarkers, and evidence-based management strategies.

Table 1 Summary of core vascular risk factors, pathogenic mechanisms, biomarkers, and management strategies for cognitive decline.

Vascular risk factor	Key pathogenic mechanisms	Neuroimaging biomarkers	Fluid biomarkers	Management strategies	Level of evidence
Hypertension	Large artery stiffness, CSVD, BBB disruption, neuroinflammation	WMH volume, lacunes, microbleeds, enlarged perivascular spaces	CSF/serum albumin ratio (BBB permeability), inflammatory markers	Intensive BP control (SBP < 120 mmHg); monitor BPV	Class A (SPRINT MIND trial and post-hoc analysis[16])
Diabetes	Insulin resistance, AGEs, microvascular complications, impaired β-amyloid clearance	WMH, hippocampal atrophy, cerebral microinfarcts	HbA1c, AGEs, insulin resistance markers	Glycemic control (early stage); metformin; multifactorial intervention	Class B (observational cohorts[58,59])
Atrial fibrillation	Cardioembolism, chronic hypoperfusion, systemic inflammation	Silent infarcts, WMH, cortical microinfarcts	NT-proBNP, hs-cTnT, D-dimer	Anticoagulation (DOACs/warfarin); rate/rhythm control	Class A (RCTs for stroke prevention[84,85])
Obesity/metabolic syndrome	Endothelial dysfunction, impaired neurovascular coupling, adipokine dysregulation	WMH, reduced CBF, microvascular rarefaction	Adipokines (leptin, adiponectin), IL-6, TNF-α	Multi-domain lifestyle intervention (FINGER model[80])	Class A (FINGER RCT[86])
Atherosclerosis	Large artery stenosis, hypoperfusion, embolic events	Carotid IMT, intracranial plaque, CBF reduction	LDL-C, hs-CRP, Lp-PLA2	Statins; antiplatelet therapy; lifestyle modification

CSVD: Cerebral small vessel disease; BBB: Blood-brain barrier; AGE: Advanced glycation end product; WMH: White matter hyperintensities; CBF: Cerebral blood flow; IMT: Intima-media thickness; HbA1c: Glycated hemoglobin; CSF: Cerebrospinal fluid; NT-proBNP: N-terminal pro-B-type natriuretic peptide; hs-cTnT: High-sensitivity cardiac troponin T; IL: Interleukin; TNF: Tumor necrosis factor; LDL-C: Low-density lipoprotein cholesterol; hs-CRP: High-sensitivity C-reactive protein; Lp-PLA2: Lipoprotein-associated phospholipase A2; BP: Blood pressure; SBP: Systolic blood pressure; BPV: Blood pressure variability; DOAC: Direct oral anticoagulant; SPRINT MIND: Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension.

LIMITATIONS OF EXISTING EVIDENCE

Despite significant progress, numerous challenges and unknowns remain in this field.

Heterogeneity in diagnosis and classification

VCI diagnosis still primarily relies on neuropsychological assessment and neuroimaging, lacking specific, easily accessible biological diagnostic markers. VCI itself exhibits high clinical and pathological heterogeneity, with varying patterns of cognitive impairment, progression rates, and treatment responses[35,99]. Future classification systems need to better integrate clinical, imaging, and biomarker information.

Translational bottleneck in mechanism research

Most mechanistic evidence comes from animal models, but existing vascular contributions to cognitive impairment and dementia animal models often fail to fully mimic the complex cerebrovascular and cognitive changes resulting from long-term, multi-factorial VRF exposure in humans[32,33]. Understanding of the roles of the venous and glymphatic systems in cognitive decline is still in its infancy.

Heterogeneity and lack of precision in intervention studies

Results of existing intervention trials are heterogeneous, potentially influenced by baseline age, sex, genetic background (e.g., APOE), cognitive status, and comorbidities[82]. Most successful intervention studies target individuals in the at-risk or very early disease stage[86]. For established VCI or mixed dementia, there is a lack of disease-modifying therapies proven to definitively reverse or significantly slow disease progression.

Challenges in biomarker sensitivity and specificity

Although various biomarkers have emerged (e.g., BBB permeability, WMH volume, plasma β-amyloid 40/42, neurofilament light chain, inflammatory markers), there is still a lack of a highly sensitive, specific, and easily accessible early warning biomarker system available before clinical symptoms appear[28-30]. Consortia like the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia consortium are dedicated to developing and validating fluid and imaging biomarkers for CSVD, a critical foundational effort[31].

Insufficient diversity and representativeness of study populations

Participants in many large trials and cohort studies are predominantly highly educated and white[100]. Research in diverse populations like African Americans and South American indigenous groups reveals the complexity of risk factor-cognition relationships, highlighting the importance of enhancing study diversity and considering population-specific factors[50,52].

Challenges in real-world implementation

While effective in clinical trials, complex multi-domain interventions face issues of adherence, cost-effectiveness, and sustainability when scaled up in community and primary care settings.

FUTURE RESEARCH DIRECTIONS

Develop multimodal, multi-omics biomarker panels

Integrate neuroimaging (high-resolution vessel wall imaging, perfusion, BBB assessment), blood/cerebrospinal fluid biomarkers (neurodegenerative, vascular injury, inflammation), and digital biomarkers for early diagnosis, risk stratification, and treatment monitoring.

Build precision risk prediction models

Utilize artificial intelligence and big data analytics to combine genetic, lifestyle, clinical, and biomarker data to develop individualized dementia risk prediction tools, identifying subgroups most likely to benefit from specific interventions.

Design next-generation intervention trials

Employ adaptive trial designs to more efficiently screen effective intervention combinations; test novel drugs targeting specific mechanistic pathways (e.g., anti-inflammatory, endothelial-protective, senolytics) in synergy with lifestyle interventions; focus on ultra-long-term prevention studies starting in early life (young adulthood, midlife).

Strengthen integration with primary care and public health

Develop simple screening tools and stepped management pathways suitable for primary care settings, seamlessly embedding vascular risk management into routine geriatric health management and public health policies.

CONCLUSION

VRFs play a central, life-course-dependent role in the onset and development of cognitive impairment. From hypertension, diabetes, and atherosclerosis to cardiac diseases, these modifiable factors erode the foundation of cognitive health through multiple, intertwined mechanisms, including inducing CSVD, damaging the BBB, causing neurovascular unit dysfunction, and triggering chronic neuroinflammation and oxidative stress. Current evidence strongly supports that active management of VRFs throughout the life course, particularly in midlife, is one of the most effective strategies for preventing or delaying cognitive decline and dementia. Comprehensive management schemes based on intensive blood pressure control and promotion of healthy lifestyles have become the core of clinical practice, while multi-domain intervention models represented by FINGER provide a promising roadmap for population-level dementia prevention.

However, challenges persist. There is an urgent need to overcome diagnostic heterogeneity, develop translational models more reflective of human disease, validate practical early biomarkers, and drive a paradigm shift from “one-size-fits-all” to “individualized precision prevention”. Future research must focus on integrating multidimensional data to build precision risk stratification models and tailor intervention strategies for individuals with different risk profiles. Only through sustained collaboration and innovation across disciplines, including neuroscience, vascular medicine, epidemiology, data science, and public health, can we more effectively address the increasingly severe global health challenge of VCI, ultimately achieving the overarching goal of maintaining brain health for all and extending healthy lifespan.