Vascular Dementia: From Pathophysiology to Therapeutic Frontiers

Abstract

Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer’s disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood–brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms.

1. Introduction

Dementia is a global public health priority, affecting over 55 million people worldwide, a number projected to nearly triple by 2050 [1,2]. While Alzheimer’s disease (AD) is the most prevalent form, vascular cognitive impairment (VCI) and its most severe form, vascular dementia (VaD), represent the second leading cause, accounting for approximately 15–20% of all dementia cases [3,4]. VaD is not a single entity but a clinically and neuropathologically heterogeneous syndrome where cognitive decline is causally related to cerebrovascular disease [5]. The underlying vascular pathologies can range from a single, strategically located infarct to multiple cortical/subcortical strokes, and, most commonly, diffuse white matter lesions and lacunes caused by cerebral small vessel disease (SVD) [6,7].

The traditional view of dementia is often segregated into neurodegenerative (like AD) and vascular causes. However, a paradigm shift has occurred, with growing recognition that mixed pathologies, particularly the coexistence of AD and cerebrovascular disease, are the rule rather than the exception in elderly dementia patients [8,9]. Cerebrovascular lesions not only contribute independently to cognitive decline but also lower the threshold for dementia in the presence of AD pathology, while conversely, amyloid deposition can compromise vascular integrity through cerebral amyloid angiopathy, creating a bidirectional pathological relationship [10,11]. This crosstalk highlights the critical importance of understanding the vascular contributions to cognitive impairment to develop effective prevention and treatment strategies for all-cause dementia.

The molecular underpinnings of VaD are intricate and involve a destructive cascade initiated by chronic cerebral hypoperfusion and ischemia. This leads to a breakdown of the blood–brain barrier (BBB), endothelial dysfunction, rampant oxidative stress, impaired glymphatic clearance, and sustained neuroinflammation [12,13]. These events converge to inflict damage on the most vulnerable cerebral tissues, particularly the subcortical white matter, leading to oligodendrocyte death, demyelination, axonal damage, and ultimately the disruption of critical neural networks essential for cognitive function [14,15].

Despite its prevalence and devastating impact, there are currently no approved disease-modifying therapies specifically for VaD. Current management is largely limited to the aggressive control of vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking [16,17]. While crucial for prevention, these strategies have limited efficacy in reversing or halting the progression of established cognitive decline. Therefore, a deeper understanding of the specific molecular and cellular mechanisms driving VaD pathogenesis is paramount to identifying novel therapeutic targets.

This review aims to provide a comprehensive synthesis of the molecular mechanisms and pathophysiology underlying VaD. The review will first outline the major pathophysiological subtypes of VaD (Table 1). We will then dissect the core molecular pathways—from endothelial cell dysfunction and oxidative stress to neuroinflammation, glymphatic dysfunction, and white matter injury—that form the mechanistic basis of the disease. The role of genetic predispositions will be discussed. Subsequently, this paper will review the progress in developing sensitive and specific biomarkers, including advanced neuroimaging and fluid-based markers (Table 2), for improved diagnosis and patient stratification. Finally, the review will summarize current management approaches and explore the promising landscape of future therapeutic strategies aimed at directly targeting the molecular drivers of neuronal damage in VaD, while acknowledging the preliminary nature of many novel approaches and the need for rigorous clinical validation.

2. The Spectrum of Cerebrovascular Pathophysiology in VaD

The term VaD encompasses a range of cognitive syndromes caused by different types of cerebrovascular pathologies. The nature of the cognitive deficits often depends on the location, extent, and type of the underlying vascular brain injury. The main categories are summarized in Table 1 and discussed below.

2.1. Post-Stroke Dementia (PSD)

PSD is defined as any dementia that develops within a year following a clinical stroke [18]. It can result from a single, large infarct in a strategically important brain region for cognition, such as the thalamus, hippocampus, or angular gyrus [19,20]. More commonly, it arises from the cumulative effect of multiple cortical or subcortical infarcts (multi-infarct dementia) which progressively degrade neural circuits [21]. The risk of developing PSD is influenced by stroke severity, location, stroke recurrence, and the pre-stroke cognitive status of the individual [22]. The molecular sequelae of ischemic stroke, including excitotoxicity, peri-infarct inflammation, and glial scar formation, are central to the neuronal loss and circuit disruption seen in PSD [23].

Table 1. Major Clinicopathological Subtypes of Vascular Dementia.

Subtype	Primary Underlying Pathology	Key Neuroimaging Features	Typical Clinical Presentation	References
Post-Stroke Dementia (PSD)	Single strategic infarct or multiple large-vessel infarcts (Multi-Infarct Dementia).	Cortical/subcortical infarcts in major arterial territories; focal atrophy.	Stepwise or abrupt cognitive decline following a clinical stroke; deficits depend on infarct location.	[18,19,20,21,22]
Subcortical Ischemic VaD (SIVD)	Cerebral small vessel disease (SVD): arteriolosclerosis, lipohyalinosis.	Confluent white matter hyperintensities (WMHs), multiple lacunar infarcts, cerebral microbleeds, enlarged perivascular spaces.	Insidious onset and gradual progression; prominent executive dysfunction, psychomotor slowing, apathy, gait disturbance.	[24,25,26,27,28,29,30]
CADASIL	Autosomal dominant mutations in the NOTCH3 gene causing VSMC degeneration.	Confluent WMHs with characteristic anterior temporal lobe involvement; multiple lacunes.	Migraine with aura (early), recurrent strokes, mood disturbances, progressive cognitive decline in young to mid-adulthood.	[31,32,33,34,35]
Mixed Dementia (VaD + AD)	Coexistence of cerebrovascular disease (any type) and Alzheimer’s pathology (plaques & tangles).	Features of both VaD (e.g., infarcts, WMHs) and AD (e.g., medial temporal atrophy).	Often amnestic presentation (like AD) but with additional features of vascular disease; typically more rapid decline.	[8,9,10,11]

VaD, Vascular dementia; AD, Alzheimer’s disease; CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; NOTCH3, Neurogenic locus notch homolog protein 3; VSMC, Vascular smooth muscle cell.

Table 1. Major Clinicopathological Subtypes of Vascular Dementia.

Subtype	Primary Underlying Pathology	Key Neuroimaging Features	Typical Clinical Presentation	References
Post-Stroke Dementia (PSD)	Single strategic infarct or multiple large-vessel infarcts (Multi-Infarct Dementia).	Cortical/subcortical infarcts in major arterial territories; focal atrophy.	Stepwise or abrupt cognitive decline following a clinical stroke; deficits depend on infarct location.	[18,19,20,21,22]
Subcortical Ischemic VaD (SIVD)	Cerebral small vessel disease (SVD): arteriolosclerosis, lipohyalinosis.	Confluent white matter hyperintensities (WMHs), multiple lacunar infarcts, cerebral microbleeds, enlarged perivascular spaces.	Insidious onset and gradual progression; prominent executive dysfunction, psychomotor slowing, apathy, gait disturbance.	[24,25,26,27,28,29,30]
CADASIL	Autosomal dominant mutations in the NOTCH3 gene causing VSMC degeneration.	Confluent WMHs with characteristic anterior temporal lobe involvement; multiple lacunes.	Migraine with aura (early), recurrent strokes, mood disturbances, progressive cognitive decline in young to mid-adulthood.	[31,32,33,34,35]
Mixed Dementia (VaD + AD)	Coexistence of cerebrovascular disease (any type) and Alzheimer’s pathology (plaques & tangles).	Features of both VaD (e.g., infarcts, WMHs) and AD (e.g., medial temporal atrophy).	Often amnestic presentation (like AD) but with additional features of vascular disease; typically more rapid decline.	[8,9,10,11]

VaD, Vascular dementia; AD, Alzheimer’s disease; CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; NOTCH3, Neurogenic locus notch homolog protein 3; VSMC, Vascular smooth muscle cell.

2.2. Subcortical Ischemic Vascular Dementia (SIVD)

SIVD, often referred to as Binswanger’s disease in its severe form, is arguably the most common form of VaD [24]. It is primarily a manifestation of SVD, a pathology of the brain’s small perforating arteries and arterioles [7,25]. Chronic hypertension and other vascular risk factors lead to lipohyalinosis and arteriolosclerosis of these small vessels, resulting in reduced vessel compliance and cerebral blood flow (CBF) [26]. The hallmark neuropathological features are diffuse, confluent white matter hyperintensities (WMHs) on T2-weighted Magnetic-resonance Imaging (MRI), lacunar infarcts in deep brain structures, cerebral microbleeds, and enlarged perivascular spaces [27,28]. SIVD typically presents with a “subcortical syndrome” characterized by prominent executive dysfunction, slowed processing speed, and gait disturbances, with memory being relatively preserved in the early stages [29]. The underlying pathology is one of chronic hypoperfusion and ischemia of the deep white and grey matter, which are watershed areas highly vulnerable to drops in perfusion pressure [30].

2.3. Hereditary Forms and CADASIL

While most VaD is sporadic, several monogenic forms exist, offering unique insights into the direct consequences of specific vascular gene mutations. The most common hereditary form is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) [31]. CADASIL is caused by stereotyped mutations in the NOTCH3 gene on chromosome 19, which encodes a transmembrane receptor crucial for vascular smooth muscle cell (VSMC) differentiation and survival [32,33]. The mutations lead to the abnormal accumulation of Notch3 extracellular domain protein in the vessel walls of small arteries, leading to VSMC degeneration, vessel fibrosis, and severe stenosis [34]. This results in recurrent subcortical strokes and a progressive leukoencephalopathy, typically leading to dementia and disability in mid-adulthood [35]. Other rare hereditary forms include CARASIL caused by HTRA1 mutations [36].

3. Core Molecular Mechanisms of Neuronal Injury

Regardless of the primary vascular insult, a common set of downstream molecular and cellular pathways are activated, creating a hostile microenvironment that drives the progressive neurodegeneration seen in VaD (Figure 1).

3.1. Endothelial Dysfunction and BBB Breakdown

The neurovascular unit (NVU) is a sophisticated multicellular complex comprising endothelial cells, pericytes, astrocytes, and neurons that collectively maintain brain homeostasis [37]. In VaD, the endothelium is a primary target. Chronic hypoperfusion and vascular risk factors trigger endothelial activation and dysfunction. This is characterized by a switch from a quiescent, anti-thrombotic state to a pro-inflammatory, pro-thrombotic phenotype [38]. Endothelial cells upregulate the expression of adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), facilitating leukocyte infiltration into the brain parenchyma [39]. Furthermore, the production of the vasodilator nitric oxide (NO) by endothelial NO synthase (eNOS) is impaired, while the production of vasoconstrictor endothelin-1 is increased, further compromising CBF [40,41].

A critical consequence of endothelial dysfunction is the breakdown of the BBB. Tight junctions and adherent junctions between endothelial cells are disassembled through the proteolytic activity of matrix metalloproteinases (MMPs), particularly MMP-9, released from activated endothelial cells and astrocytes [42,43]. This leads to increased BBB permeability, allowing serum proteins like albumin, fibrinogen, and thrombin to leak into the brain interstitium [12]. These proteins are neurotoxic: albumin can trigger astrocytic activation and inflammation, while fibrinogen can deposit and impair remyelination [44,45]. This “leaky” BBB is a consistent and early finding in patients with SVD and VaD, and the degree of leakage correlates with the severity of white matter injury [46].

3.2. Oxidative Stress

The brain is highly susceptible to oxidative stress due to its high metabolic rate, high lipid content, and relatively low antioxidant capacity [47]. In VaD, chronic hypoperfusion-reperfusion cycles in the microvasculature create a state of metabolic stress, leading to the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [48]. Key sources of ROS include NADPH oxidase (NOX) enzymes, particularly NOX2 and NOX4 expressed in endothelial cells, microglia, and neurons, as well as uncoupled eNOS and dysfunctional mitochondria [49,50].

ROS inflict widespread damage by oxidizing lipids (lipid peroxidation), proteins, and nucleic acids [51]. Lipid peroxidation of cell membranes compromises their integrity and function. Oxidative damage to DNA can trigger cell cycle arrest or apoptosis. This rampant oxidative stress overwhelms the brain’s antioxidant defense systems (e.g., superoxide dismutase, catalase, glutathione peroxidase), creating a vicious cycle of further cellular damage and inflammation [52]. Markers of oxidative damage are significantly elevated in the brain and cerebrospinal fluid (CSF) of VaD patients [53].

3.3. Neuroinflammation and Immune Activation

Once considered a sterile process, it is now clear that a chronic, non-resolving inflammatory response is a key driver of VaD pathology [13,54]. BBB breakdown and endothelial activation permit the infiltration of peripheral immune cells. Concurrently, resident immune cells of the central nervous system (CNS), primarily microglia and astrocytes, become chronically activated [55].

Initially, microglial activation is a protective response aimed at clearing debris. However, under chronic ischemic stress, microglia adopt a persistent pro-inflammatory phenotype, releasing a barrage of cytotoxic mediators, including pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines, ROS, and glutamate [56,57]. Astrocytes also become reactive, a process known as astrogliosis, contributing to the inflammatory milieu and forming a glial scar that can inhibit axonal regeneration and remyelination [58]. This sustained inflammatory state, fueled by signals from the damaged endothelium and leaky BBB, directly contributes to oligodendrocyte apoptosis, demyelination, and neuronal death [59,60]. The inflammasome, particularly the NLR family pyrin domain containing 3 (NLRP3) inflammasome, has been identified as a key platform for processing and releasing IL-1β in response to vascular stress signals, making it a potential therapeutic target [61].

3.4. White Matter Injury: Oligodendrocyte Death and Demyelination

The subcortical white matter is the “battleground” in SIVD. Oligodendrocytes, the myelin-producing cells of the CNS, are exceptionally vulnerable to ischemic and inflammatory insults [14,62]. They have a very high metabolic rate and limited antioxidant defenses, making them susceptible to damage from hypoperfusion and oxidative stress [63].

The hostile microenvironment created by inflammation, ROS, and excitotoxicity triggers oligodendrocyte apoptosis [64]. Furthermore, oligodendrocyte precursor cells (OPCs), which are present in the adult brain and capable of differentiating to replace lost oligodendrocytes, are also impaired. The inflammatory environment can arrest OPC maturation, preventing effective remyelination [65,66]. The result is a net loss of myelin (demyelination) and damage to the underlying axons. This disconnects cortical and subcortical regions, disrupting the large-scale neural networks required for higher-order cognitive functions like executive control and processing speed, leading directly to the clinical syndrome of SIVD [15,67].

3.5. Glymphatic Dysfunction and Impaired Waste Clearance

The glymphatic system functions as a newly identified paravascular pathway which extends throughout the brain to remove amyloid-β and tau proteins and other metabolic waste products from brain tissue [68]. This system relies on the convective flow of CSF through periarterial spaces, exchange with interstitial fluid facilitated by aquaporin-4 (AQP4) water channels on astrocytic endfeet, and drainage along perivenous spaces [69]. The combination of various factors in VaD disrupts glymphatic function which leads to dangerous waste accumulation that intensifies neurodegenerative damage.

The glymphatic clearance process becomes impaired because of cerebrovascular pathology through multiple pathways. The stiffened arteries and decreased pulsatile flow in hypertensive small vessel disease reduce the pressure that drives CSF to enter the periarterial space [70]. The loss of vascular smooth muscle cells and pericytes in SVD causes vasomotion to decrease which worsens the perivascular pumping mechanism [71]. The redistribution of AQP4 from astrocytic endfeet to the parenchymal membrane (loss of AQP4 polarization) and reactive astrogliosis disrupts the essential water transport needed for glymphatic exchange [72].

The blood–brain barrier disruption in VaD prevents the glymphatic system from functioning properly. The process of protein leakage into tissues and the inflammatory response around blood vessels creates blockages in perivascular spaces while blood-derived fibrinogen proteins physically obstruct drainage routes [73]. The glymphatic system operates under circadian control and reaches its peak activity during sleep periods especially during non-rapid eye movement (REM) sleep stages [74]. Sleep disturbances which frequently affect VaD patients create a self-reinforcing cycle that worsens glymphatic dysfunction while allowing pathological substances to build up [75].

Glymphatic failure in VaD produces effects which go beyond the accumulation of waste products. The high rate of mixed pathology in VaD patients can be explained by impaired amyloid-β clearance because vascular dysfunction speeds up amyloid deposition [76]. The body fails to eliminate inflammatory mediators and damage-associated molecular patterns (DAMPs) which leads to their accumulation and causes ongoing neuroinflammation. The presence of neurotoxic metabolites in the brain leads to direct damage of neurons and oligodendrocytes which affects watershed areas that experience reduced blood flow [77].

3.6. Temporal Evolution of Molecular Cascades

The correct order of VaD disease progression needs to be understood because it helps researchers find optimal treatment times and create treatments that match disease stages. The molecular sequence of events follows a standard pattern, but the time course depends on the degree of vascular injury and individual resistance factors [78]. The first detectable signs of the disease appear before patients show symptoms and these changes start with endothelial dysfunction and small increases in BBB permeability [79]. Endothelial cells in this preclinical stage produce less nitric oxide while showing higher adhesion molecule expression and initial tight junction breakdown. The first signs of glymphatic dysfunction appear because of decreased arterial pulsatility and the loss of pericytes during the early stages of the disease [80]. The tests conducted at this stage demonstrate both enlarged perivascular spaces and minimal white matter changes on diffusion tensor imaging (DTI) and fluid biomarkers indicate small increases in endothelial activation markers [81].

The disease progresses to the early symptomatic phase (mild cognitive impairment stage) because BBB breakdown becomes more severe and albumin begins to leak into brain parenchyma [82]. The body experiences elevated oxidative stress when antioxidant defenses reach their maximum operational capacity. The initial protective response of microglial activation develops into a long-lasting pro-inflammatory state which produces continuous cytokine and reactive oxygen species release [83]. The first sign of oligodendrocyte stress becomes apparent through early apoptosis that specifically attacks the vulnerable periventricular areas of the brain. The clinical presentation of patients includes executive dysfunction and processing speed deficits while neuroimaging shows white matter hyperintensities and early lacunes [84].

In established VaD, the pathological cascades reach their full expression. Chronic neuroinflammation becomes self-sustaining through activation of the NLRP3 inflammasome and other inflammatory platforms [85]. The brain shows its most severe oligodendrocyte death and demyelination in the frontal and periventricular white matter areas. The extent of axonal damage becomes severe enough to produce detectable increases in neurofilament light chain levels which appear in both CSF and plasma samples [86]. The severe condition of glymphatic failure leads to the accumulation of various toxic substances. The damaged white matter tracts cause secondary neurodegeneration to spread throughout cortical areas which results in network-wide dysfunction [87].

The advanced stage of the disease shows permanent structural damage through tissue loss and gliosis and complete breakdown of essential neural networks [88]. The brain demonstrates accelerated aging signs through cellular senescence which occurs when compensatory mechanisms reach their limits. The molecular chain reactions create an unfavorable setting which prevents all attempts to fix or regenerate tissues thus making treatments for late-stage diseases useless [89].

The established time frame provides essential information which enables researchers to study biomarkers and develop fresh therapeutic solutions. Early interventions that protect endothelial function and BBB integrity can stop the progression of disease but treatment at later stages needs to target multiple disease mechanisms at once [90].

4. Genetic Risk Factors

Beyond the well-established monogenic form of CADASIL (NOTCH3), research has sought to identify genetic risk factors for the more common, sporadic forms of VaD. The genetic architecture appears complex, involving multiple genes of small effect, many of which are related to vascular health, inflammation, and lipid metabolism.

The apolipoprotein E (APOE) ε4 allele, the strongest genetic risk factor for AD, has also been implicated in VaD, although its role is more controversial [91]. Some studies suggest APOE ε4 increases the risk of PSD and may lower the threshold for dementia in the presence of vascular pathology, possibly by exacerbating BBB breakdown and promoting cerebral amyloid angiopathy (CAA) [92,93]. Emerging preclinical and early human evidence indicates that APOE ε4 may also impair glymphatic function, providing another potential linking this allele to both vascular and Alzheimer pathology [94].

Polymorphisms in the gene encoding methylenetetrahydrofolate reductase (MTHFR), which can lead to hyperhomocysteinemia—a known vascular risk factor—have been associated with SVD and VaD in some populations [95]. Homocysteine can promote endothelial dysfunction and oxidative stress. Genes involved in inflammatory pathways, such as IL-6 and TNF-α, have also been investigated, with some polymorphic variants showing a modest association with VaD risk [96].

More recently, genome-wide association studies (GWAS) have begun to identify novel loci associated with SVD imaging markers, such as WMHs. Loci near genes involved in endothelial function, blood pressure regulation, and extracellular matrix integrity have been pinpointed, though their direct link to a clinical VaD diagnosis requires further validation [97,98]. The genetic landscape of sporadic VaD is an active area of research, with larger, more diverse cohorts needed to uncover robust associations.

5. Diagnosis and the Quest for Biomarkers

The diagnosis of VaD is challenging due to its clinical heterogeneity and frequent overlap with AD. Diagnosis relies on a combination of clinical assessment (evidence of cognitive decline and cerebrovascular disease) and, crucially, neuroimaging. The development of reliable biomarkers is a major goal to improve diagnostic accuracy, track disease progression, and serve as surrogate endpoints in clinical trials.

5.1. Neuroimaging Biomarkers

MRI is the cornerstone of VaD diagnosis. Standard MRI sequences can visualize the macroscopic signatures of cerebrovascular disease [25,99].

• T2-weighted and FLAIR sequences are highly sensitive for detecting WMHs, which are a key feature of SVD. The volume and progression of WMHs are correlated with cognitive decline [27].
• T1-weighted sequences identify chronic lacunar and cortical infarcts and can be used to measure brain atrophy, which is also an indicator of disease severity.
• Susceptibility-weighted imaging (SWI) or T2-gradient echo sequences are exquisitely sensitive for detecting cerebral microbleeds, which are markers of fragile, leaky small vessels [28].

Advanced MRI techniques provide deeper, quantitative insights into the microstructural and physiological consequences of vascular disease.

• Diffusion Tensor Imaging (DTI) measures the random motion of water molecules to assess white matter microstructural integrity. Metrics like fractional anisotropy (FA) and mean diffusivity (MD) can detect subtle axonal damage and demyelination within WMHs and even in normal-appearing white matter, often before changes are visible on conventional MRI [100,101].
• Arterial Spin Labeling (ASL) and Dynamic Susceptibility Contrast (DSC)-MRI are perfusion imaging techniques that can non-invasively quantify CBF, providing a direct measure of cerebral hypoperfusion [102].
• Dynamic Contrast-Enhanced (DCE)-MRI can be used to quantify BBB permeability, providing a direct in vivo marker of BBB breakdown [46].

5.2. Fluid Biomarkers

Fluid biomarkers, measured in CSF or blood, offer a less invasive and potentially more scalable approach for diagnosis and monitoring. The search for VaD-specific fluid biomarkers is ongoing, with a focus on markers reflecting the core pathologies (Table 2).

• Markers of Neuronal and Axonal Injury: CSF and plasma levels of neurofilament light chain (NfL), a marker of axonal damage, are elevated in VaD, often to a greater extent than in AD [103].
• Markers of Inflammation: Pro-inflammatory cytokines, markers of glial activation (e.g., GFAP, YKL-40, sTREM2), and endothelial adhesion molecules (e.g., VCAM-1) are being investigated in both CSF and blood, with many showing elevated levels in VaD patients [54,104].
• Markers of BBB and Endothelial Dysfunction: The CSF/serum albumin ratio (Qalb) is a classic marker of BBB integrity and is often elevated in VaD [12]. Soluble forms of tight junction proteins and markers of pericyte injury are also emerging as candidate biomarkers [105].

The main challenge is specificity, as many of these markers are also altered in other neurodegenerative and inflammatory conditions. A panel of multiple biomarkers, combining plasma markers like p-tau for AD pathology and NfL for axonal injury, will likely be necessary for accurate differential diagnosis [103].

5.3. Biomarker Dynamics Across Disease Stages

The progression of biomarkers in VaD follows a specific timeline which mirrors the natural progression of disease pathology. The appropriate selection of biomarkers depends on disease stage and disease progression monitoring because researchers need to understand these biological processes [106] (Table 3).

The first detectable preclinical stage changes become detectable through DCE-MRI and CSF/serum albumin ratio measurements that show minimal BBB permeability changes [107]. The plasma levels of endothelial activation markers VCAM-1 and ICAM-1 start to increase. The advanced DTI metrics demonstrate their ability to detect white matter microstructural changes which occur before WMHs become visible to standard imaging techniques. The glymphatic system shows initial signs of breakdown according to DTI-ALPS (Diffusion Tensor Image Analysis Along the Perivascular Space) measurements [108].

Neuroimaging biomarkers become more important during the prodromal/MCI stage because WMH volume continues to increase while lacunes begin to develop [109]. The CSF shows elevated levels of inflammatory markers which include GFAP, YKL-40 and sTREM2. The levels of Neurofilament light chain start to rise because of continuous axonal damage. The brain areas that depend on watershed regions for blood supply show measurable blood flow reduction according to perfusion imaging [110].

In established dementia, all biomarker categories show marked abnormalities. The imaging results show white matter destruction throughout the brain together with multiple lacunes and significant brain tissue loss [111]. The levels of fluid biomarkers achieve equilibrium points at which NfL demonstrates the most direct relationship with clinical disease severity. Notably, the rate of biomarker change may be more informative than absolute levels for predicting progression [112].

5.4. Clinical Utility of Biomarkers for Diagnosis and Prognosis

Biomarkers in VaD provide various clinical functions which include early disease detection and differential diagnosis and both prognostic assessment and treatment monitoring. The diagnostic worth of biomarkers depends on their particular type and the current stage of disease development (Table 2 and Table 3).

Neuroimaging functions as the main diagnostic instrument for medical purposes. The combination of WMH burden, lacunes, and microbleeds on MRI supports differentiation from healthy aging; diagnostic performance varies across cohorts, definitions, and imaging protocol, and combining markers improves diagnostic confidence [113]. The medical process of frontotemporal dementia (FTD) diagnosis requires additional testing to identify the condition apart from AD. The CSF Aβ42/40 ratio combined with p-tau measurements helps scientists identify mixed pathology which affects about 40% of VaD patients who receive clinical diagnoses [114]. The diagnostic accuracy of MRI improves through the use of advanced imaging techniques such as DTI and ASL perfusion which enable the detection of early-stage diseases when standard MRI results remain unclear [115].

The demand for prognostic applications continues to rise because they help doctors deliver improved patient guidance and support clinical trial development. The risk of dementia conversion becomes 1.5 times higher when baseline WMH volume and progression rate increase by 10 mL [116]. Plasma NfL levels serve as an accessible prognostic tool because patients with levels above 40 pg/mL experience accelerated cognitive deterioration and elevated death risk [117]. The combination of imaging data with fluid biomarkers produces enhanced predictive results because new models achieve AUC values ranging from 0.85 to 0.90 for predicting 2-year cognitive changes [118].

For treatment monitoring, biomarkers offer objective measures of therapeutic response. The permeability changes in the BBB that DCE-MRI measures become detectable for treatment effects within 3–6 months [119]. GFAP and other inflammatory markers demonstrate their ability to react to anti-inflammatory treatments. Serial NfL measurements have the potential to function as substitute endpoints in clinical trials which could speed up drug development processes [120].

5.5. Biomarkers as Windows into Pathological Mechanisms

Beyond their clinical utility, biomarkers provide insights into dominant pathological processes in individual patients, enabling mechanistic stratification for precision medicine approaches [121].

The markers VCAM-1, ICAM-1 and von Willebrand factor help to identify patients with primary vascular disease who need vascular-targeted treatments the most [122]. The inflammatory biomarkers are also helpful in identifying patients who have neuroinflammation as their main condition because these patients might benefit from anti-inflammatory treatments. Elevated NLRP3 inflammasome components suggest suitability for inflammasome inhibitors [123].

The combination of DTI-ALPS and CSF flow imaging enables doctors to detect patients who need sleep optimization or AQP4 function-targeting therapies [124]. The presence of myelin basic protein and oligodendrocyte-specific proteins indicates that remyelination approaches may be beneficial for treating white matter injury [125].

The mechanistic profiling system allows doctors to choose specific treatments and combination therapies through analysis of individual disease patterns rather than depending on clinical symptoms [126].

6. Current and Future Therapeutic Strategies

It is important to acknowledge at the outset that despite decades of research, no disease-modifying therapies are specifically approved for VaD in the United States, and the therapeutic landscape remains challenging. The following sections present both current management strategies and new investigational therapeutic methods which have not received sufficient Phase III clinical trial evidence [127] (Figure 2 and Figure 3).

6.1. Aggressive Management of Vascular Risk Factors

The cornerstone of VaD management is prevention and the strict control of modifiable vascular risk factors [16]. The following are key examples of risk factor management strategies, not an exhaustive list of available interventions [128].

Table 2. Selected Current and Emerging Biomarkers for Vascular Dementia.

Biomarker Type	Marker	What It Measures	Utility in VaD	Disease Stage	Mechanistic Pathway	References
Neuroimaging	White Matter Hyperintensities (WMH) on FLAIR MRI	Chronic ischemic white matter damage, gliosis, demyelination	Core diagnostic feature of SVD; volume & progression correlate with cognitive decline	Early to Advanced	Hypoperfusion, BBB breakdown	[27,99,113]
	Diffusion Tensor Imaging (DTI)/Free-Water Imaging	White matter microstructural integrity (axonal damage, neuroinflammation)	Detects early, subtle white matter damage; sensitive to change	Preclinical to Early	Axonal injury, inflammation	[100,101,115]
	Perfusion MRI (e.g., ASL)	Cerebral blood flow (CBF)	Quantifies chronic hypoperfusion, a key upstream driver	All stages	Vascular dysfunction	[102,110]
	Dynamic Contrast-Enhanced (DCE)-MRI	Blood–brain barrier (BBB) permeability	Direct in vivo measure of BBB leakiness, an early event	Preclinical to Early	Endothelial dysfunction	[46,107,119]
	DTI-ALPS (Diffusion Tensor Image Analysis Along the Perivascular Space)	Glymphatic function	Assesses perivascular drainage and waste clearance	Preclinical to Established	Glymphatic dysfunction	[108,124]
CSF Fluid	Neurofilament Light Chain (NfL)	Axonal injury and degeneration	Elevated in VaD; reflects ongoing neuronal damage	Early to Advanced	Axonal degeneration	[86,103,117]
	CSF/Serum Albumin Ratio (Qalb)	BBB integrity	Established marker of BBB breakdown	All stages	BBB dysfunction	[12,82,107]
	GFAP/YKL-40/sTREM2	Astrocyte and microglia activation	Markers of neuroinflammation; elevated in VaD	Early to Established	Neuroinflammation	[54,83,104]
	Aβ42/40 ratio	Concurrent AD pathology	Identifies mixed dementia cases	All stages	Amyloid pathology	[114,127]
	p-tau (181, 217)	Tau pathology	Distinguishes AD from pure VaD	All stages	Neurodegeneration	[103,114]
Blood Fluid	Plasma NfL	Systemic measure of axonal injury	Highly correlated with CSF NfL; minimally invasive	Early to Advanced	Axonal degeneration	[103,117,120]
	Plasma GFAP	Astrocyte reactivity	Elevated in VaD and SVD	Early to Established	Astrogliosis, BBB damage	[104,123]
	Plasma p-tau species	Alzheimer’s disease co-pathology	Crucial for differential diagnosis	All stages	Tau pathology	[103,114,127]
	Plasma Aβ42/40 ratio	Amyloid pathology	Emerging marker for mixed pathology	All stages	Amyloid accumulation	[127,128]

AD, Alzheimer’s disease; ALPS, Analysis Along the Perivascular Space; ASL, Arterial spin labeling; Aβ, Amyloid-beta; BBB, Blood–brain barrier; CBF, Cerebral blood flow; CSF, Cerebrospinal fluid; DCE-MRI, Dynamic contrast-enhanced magnetic resonance imaging; DTI, Diffusion tensor imaging; DTI-ALPS, Diffusion tensor image analysis along the perivascular space; FLAIR, Fluid-attenuated inversion recovery; GFAP, Glial fibrillary acidic protein; MRI, Magnetic resonance imaging; NfL, Neurofilament light chain; p-tau, Phosphorylated tau; Qalb, CSF/serum albumin ratio; sTREM2, Soluble triggering receptor expressed on myeloid cells 2; SVD, Small vessel disease; VaD, Vascular dementia; WMH, White matter hyperintensities; YKL-40, Chitinase-3-like protein 1.

Table 2. Selected Current and Emerging Biomarkers for Vascular Dementia.

Biomarker Type	Marker	What It Measures	Utility in VaD	Disease Stage	Mechanistic Pathway	References
Neuroimaging	White Matter Hyperintensities (WMH) on FLAIR MRI	Chronic ischemic white matter damage, gliosis, demyelination	Core diagnostic feature of SVD; volume & progression correlate with cognitive decline	Early to Advanced	Hypoperfusion, BBB breakdown	[27,99,113]
	Diffusion Tensor Imaging (DTI)/Free-Water Imaging	White matter microstructural integrity (axonal damage, neuroinflammation)	Detects early, subtle white matter damage; sensitive to change	Preclinical to Early	Axonal injury, inflammation	[100,101,115]
	Perfusion MRI (e.g., ASL)	Cerebral blood flow (CBF)	Quantifies chronic hypoperfusion, a key upstream driver	All stages	Vascular dysfunction	[102,110]
	Dynamic Contrast-Enhanced (DCE)-MRI	Blood–brain barrier (BBB) permeability	Direct in vivo measure of BBB leakiness, an early event	Preclinical to Early	Endothelial dysfunction	[46,107,119]
	DTI-ALPS (Diffusion Tensor Image Analysis Along the Perivascular Space)	Glymphatic function	Assesses perivascular drainage and waste clearance	Preclinical to Established	Glymphatic dysfunction	[108,124]
CSF Fluid	Neurofilament Light Chain (NfL)	Axonal injury and degeneration	Elevated in VaD; reflects ongoing neuronal damage	Early to Advanced	Axonal degeneration	[86,103,117]
	CSF/Serum Albumin Ratio (Qalb)	BBB integrity	Established marker of BBB breakdown	All stages	BBB dysfunction	[12,82,107]
	GFAP/YKL-40/sTREM2	Astrocyte and microglia activation	Markers of neuroinflammation; elevated in VaD	Early to Established	Neuroinflammation	[54,83,104]
	Aβ42/40 ratio	Concurrent AD pathology	Identifies mixed dementia cases	All stages	Amyloid pathology	[114,127]
	p-tau (181, 217)	Tau pathology	Distinguishes AD from pure VaD	All stages	Neurodegeneration	[103,114]
Blood Fluid	Plasma NfL	Systemic measure of axonal injury	Highly correlated with CSF NfL; minimally invasive	Early to Advanced	Axonal degeneration	[103,117,120]
	Plasma GFAP	Astrocyte reactivity	Elevated in VaD and SVD	Early to Established	Astrogliosis, BBB damage	[104,123]
	Plasma p-tau species	Alzheimer’s disease co-pathology	Crucial for differential diagnosis	All stages	Tau pathology	[103,114,127]
	Plasma Aβ42/40 ratio	Amyloid pathology	Emerging marker for mixed pathology	All stages	Amyloid accumulation	[127,128]

AD, Alzheimer’s disease; ALPS, Analysis Along the Perivascular Space; ASL, Arterial spin labeling; Aβ, Amyloid-beta; BBB, Blood–brain barrier; CBF, Cerebral blood flow; CSF, Cerebrospinal fluid; DCE-MRI, Dynamic contrast-enhanced magnetic resonance imaging; DTI, Diffusion tensor imaging; DTI-ALPS, Diffusion tensor image analysis along the perivascular space; FLAIR, Fluid-attenuated inversion recovery; GFAP, Glial fibrillary acidic protein; MRI, Magnetic resonance imaging; NfL, Neurofilament light chain; p-tau, Phosphorylated tau; Qalb, CSF/serum albumin ratio; sTREM2, Soluble triggering receptor expressed on myeloid cells 2; SVD, Small vessel disease; VaD, Vascular dementia; WMH, White matter hyperintensities; YKL-40, Chitinase-3-like protein 1.

Table 3. Stage-Specific Biomarker Profiles in Vascular Dementia.

Disease Stage	Clinical Features	Key Biomarker Changes	Therapeutic Implications	References
Preclinical	No symptoms; at-risk individuals	Subtle BBB permeability (DCE-MRI) Enlarged perivascular spaces Mild endothelial markers elevation Early glymphatic dysfunction	Prevention strategies; vascular risk factor control	[79,80,81,108]
Prodromal/MCI	Mild executive dysfunction	Progressive WMH Rising NfL and inflammatory markers Reduced CBF DTI abnormalities	Early intervention window; consider disease-modifying therapies	[84,109,110]
Mild Dementia	Clear functional impairment	Extensive WMH and lacunes Plateau inflammatory markers High NfL levels Brain atrophy begins	Combination therapies; symptom management	[86,87,111]
Moderate-Severe	Dependency in ADLs	Severe structural damage Network disconnection Maximal biomarker abnormalities	Supportive care; limited therapeutic options	[88,89,112]

ADLs, Activities of daily living; BBB, Blood–brain barrier; CBF, Cerebral blood flow; DCE-MRI, Dynamic contrast-enhanced magnetic resonance imaging; DTI, Diffusion tensor imaging; MCI, Mild cognitive impairment; NfL, Neurofilament light chain; WMH, White matter hyperintensities.

Table 3. Stage-Specific Biomarker Profiles in Vascular Dementia.

Disease Stage	Clinical Features	Key Biomarker Changes	Therapeutic Implications	References
Preclinical	No symptoms; at-risk individuals	Subtle BBB permeability (DCE-MRI) Enlarged perivascular spaces Mild endothelial markers elevation Early glymphatic dysfunction	Prevention strategies; vascular risk factor control	[79,80,81,108]
Prodromal/MCI	Mild executive dysfunction	Progressive WMH Rising NfL and inflammatory markers Reduced CBF DTI abnormalities	Early intervention window; consider disease-modifying therapies	[84,109,110]
Mild Dementia	Clear functional impairment	Extensive WMH and lacunes Plateau inflammatory markers High NfL levels Brain atrophy begins	Combination therapies; symptom management	[86,87,111]
Moderate-Severe	Dependency in ADLs	Severe structural damage Network disconnection Maximal biomarker abnormalities	Supportive care; limited therapeutic options	[88,89,112]

ADLs, Activities of daily living; BBB, Blood–brain barrier; CBF, Cerebral blood flow; DCE-MRI, Dynamic contrast-enhanced magnetic resonance imaging; DTI, Diffusion tensor imaging; MCI, Mild cognitive impairment; NfL, Neurofilament light chain; WMH, White matter hyperintensities.

Hypertension: Antihypertensive treatment is paramount. Large clinical trials have shown that lowering blood pressure reduces the risk of stroke and may slow the progression of WMHs and cognitive decline [17,129]. The SPRINT-MIND trial suggested that intensive systolic blood pressure control (<120 mm Hg) could significantly reduce the risk of mild cognitive impairment [130].

Diabetes Mellitus: Tight glycemic control is important to prevent micro- and macrovascular complications that contribute to VaD. New antidiabetic agents like glucagon-like peptide-1 (GLP-1) receptor agonists may offer additional neuroprotective benefits [28,131].

Hyperlipidemia: Statin therapy, while primarily for stroke prevention, may have pleiotropic effects including improving endothelial function and reducing inflammation, though its direct benefit on cognition in established VaD requires more evidence [132].

Lifestyle Modifications: Smoking cessation, regular physical activity, a healthy diet (e.g., Mediterranean or DASH diet), and maintaining a healthy weight are all strongly recommended and have been shown to support brain and vascular health [133].

6.2. Symptomatic and Neuroprotective Approaches: An Expanding Frontier

The therapeutic approaches described below represent selected examples of promising strategies currently under investigation. It should be emphasized that most of these interventions lack definitive Phase III trial evidence and should be considered investigational [134].

Cholinesterase inhibitors (e.g., donepezil, galantamine) and the N-Methyl-D-aspartate.

(NMDA) receptor antagonist memantine, which are standard treatments for AD, have been tested in VaD with mixed and modest results [135]. Their limited efficacy underscores the different primary pathology and has propelled research into novel mechanisms that directly address the core tenets of VaD: endothelial dysfunction, neuroinflammation, white matter injury, and cellular senescence.

6.2.1. Targeting Endothelial Function and Cerebral Perfusion

The compromised blood flow in VaD is a primary therapeutic target. Drugs that modulate vascular tone and health are under active investigation.

Phosphodiesterase (PDE) Inhibitors: Cilostazol, a PDE3 inhibitor, has demonstrated effects beyond its primary role in intermittent claudication. It possesses antiplatelet, anti-inflammatory, and vasodilatory properties that enhance cerebral blood flow. Although evidence is mixed, some trials, particularly in East Asia, have suggested that cilostazol can reduce the recurrence of stroke and may slow the progression of white matter lesions and cognitive decline in patients with SVD [136,137]. Its mechanism is thought to involve increasing cyclic AMP (cAMP) levels, which improves endothelial barrier function and reduces inflammation. Another class, PDE5 inhibitors (e.g., sildenafil), is also being explored preclinically for its ability to increase cerebral blood flow and have neuroprotective effects, although clinical data in VaD remains limited [138].

6.2.2. Combating Neuroinflammation

Given the central role of chronic inflammation, targeting specific inflammatory pathways is a highly promising strategy.

NLRP3 Inflammasome Inhibition: The NLRP3 inflammasome is a key protein complex that, when activated by cellular stress signals (like those in VaD), triggers the release of potent pro-inflammatory cytokines IL-1β and IL-18. It is considered a master regulator of sterile inflammation. Preclinical models of SVD have shown that inhibiting NLRP3 can significantly reduce microglial activation, protect the BBB, and preserve white matter integrity [61]. Several brain-penetrant small molecule inhibitors of NLRP3 are now in early-phase clinical trials for various neurological conditions; their application to VaD remains investigational and will require dedicated trials [139].

Targeting Microglia: Minocycline, a tetracycline antibiotic with well-documented anti-inflammatory properties, can cross the BBB and suppress pro-inflammatory microglial activation. While it showed promise in preclinical models and small pilot studies [140], larger clinical trials have yielded mixed results, suggesting that more targeted approaches to modulate microglial phenotypes (e.g., shifting from a pro-inflammatory to a pro-resolving state) may be necessary.

6.2.3. Cellular Senescence and Senolytics

A novel and exciting area of research is cellular senescence—a state of irreversible cell cycle arrest. Senescent endothelial cells and glial cells accumulate in the aging brain and contribute to VaD by secreting a cocktail of inflammatory proteins, known as the senescence-associated secretory phenotype (SASP) [141].

Senolytics: These are drugs that selectively induce apoptosis in senescent cells. In animal models of cognitive decline, clearing senescent cells with senolytics (such as the combination of Dasatinib and Quercetin, or Fisetin) has been shown to reduce neuroinflammation, improve neurogenesis, and restore cognitive function [142]. The rationale is that by removing the source of the chronic, pro-inflammatory SASP, the brain microenvironment can be restored to a healthier state. Clinical trials using senolytics for age-related conditions are underway, and their potential to treat VaD by “rejuvenating” the neurovascular unit is an area of intense investigation [143].

Research indicates that SGLT2 inhibitors which were first developed for diabetes treatment now show evidence of senolytic effects together with their established metabolic advantages. Preclinical studies demonstrate that SGLT2 inhibitors can decrease senescent cell numbers through their activation of AMPK and inhibition of mTOR signaling pathways [144]. The drugs show promise because they have proven safety records while multiple cardiovascular trials with cognitive assessments are currently underway [145].

6.2.4. Promoting White Matter Repair and Remyelination

Since SIVD is fundamentally a disease of the white matter, strategies aimed at protecting and repairing oligodendrocytes are critical.

Oligodendrocyte Protection and OPC Differentiation: Research is focused on identifying compounds that both protect mature oligodendrocytes from ischemic and inflammatory death and stimulate OPCs to differentiate and create new myelin sheaths. Several molecular targets that inhibit OPC differentiation (e.g., LINGO-1, hyaluronan) have been identified, and blocking them can promote remyelination in disease models [66]. While most of this work has focused on multiple sclerosis, the principles are directly applicable to VaD. For instance, the antimuscarinic drug clemastine has been repurposed and shown to enhance remyelination, creating a potential therapeutic pathway for white matter repair [146].

6.2.5. Metabolic and Pleiotropic Approaches

GLP-1 Receptor Agonists: Originally developed for type 2 diabetes, drugs like liraglutide and semaglutide have demonstrated potent neuroprotective effects in preclinical models of both AD and vascular injury. Their mechanisms are pleiotropic, including reducing inflammation, improving insulin signaling in the brain, decreasing oxidative stress, and supporting synaptic function [131,147]. Given the high comorbidity of metabolic syndrome and VaD, these agents are highly attractive candidates, and large-scale clinical trials assessing their cognitive outcomes are ongoing.

Metformin: Metformin serves as the initial antidiabetic medication which researchers now study for its brain-protecting properties beyond glucose control. The compound activates AMPK and simultaneously reduces neuroinflammation and shows potential to enhance autophagy and improve mitochondrial function [148]. Large observational studies suggest reduced dementia risk in diabetic patients on metformin, though prospective trials in VaD are needed [149].

NAD+ precursors: NAD+ precursors represent a promising therapeutic strategy for NAD+ metabolism. The combination of aging with vascular disease results in lower NAD+ levels which causes problems with cellular energy production and DNA repair mechanisms [150]. Preclinical research shows that NAD+ precursors NMN and NR protect blood vessels through their ability to boost endothelial function and reduce inflammation [151]. While research studies involving early human participants have demonstrated safety benefits together with cognitive advantages, more extensive large-scale clinical trials must be conducted for confirmation [152].

6.2.6. Challenges and Realistic Expectations

While the therapeutic methods described above show promise, multiple obstacles exist to achieve clinical success from preclinical achievements. The various forms of VaD create a major challenge because people with different main disease types will react differently to treatment approaches [153]. The majority of clinical trials have employed wide participant selection criteria without biomarker-based subgrouping which could reduce treatment effectiveness for patients who would benefit from the intervention [154].

The blood–brain barrier acts as a barrier which prevents many potential compounds from entering the central nervous system. Researchers are currently testing drug delivery methods that combine focused ultrasound with nanoparticle formulations although these approaches exist only in experimental stages [155]. The advanced medical state and elderly condition of VaD patients requires close safety checks because they face higher risks of adverse effects and drug interactions [156].

The most important requirement is to start interventions before the current standard time. The point of clinical diagnosis indicates when major permanent tissue damage has already occurred. The research confirms that screening programs should identify high-risk individuals before they develop clinical symptoms, but more evaluation is required to determine their operational feasibility and cost-effectiveness [157].

6.2.7. Targeting Glymphatic Function

Research into VaD has revealed new therapeutic approaches because of the recent discoveries about glymphatic system dysfunction. Sleep optimization serves as an immediate solution because the glymphatic system performs its best clearance work during sleep periods especially during slow-wave sleep [158]. CPAP therapy for sleep apnea patients with vascular disease improves glymphatic function while lowering their vascular risk according to research [159].

Scientists continue their research to develop pharmacological methods which will boost glymphatic system performance. Low-dose omega-3 fatty acid supplements show evidence that they can enhance AQP4 polarization and glymphatic flow [160]. Scientists are working on creating new substances which show promise to block AQP4 expression and function during preclinical research. The glymphatic pulsatility receives benefits from antihypertensive medications which improve arterial compliance according to research [161].

The future of VaD therapy will likely involve a precision medicine approach, using biomarkers to identify the dominant pathology in a given patient (e.g., inflammation vs. hypoperfusion) and tailoring treatment accordingly. Furthermore, combination therapies targeting multiple pathways simultaneously—for instance, an anti-inflammatory agent combined with a drug that promotes vascular health and remyelination—may hold the key to finally halting or reversing the progression of this devastating disease.

6.3. Framework for Therapeutic Implementation

The multiple treatment options for VaD demand a structured treatment plan because of its complex nature. The framework establishes its methodology through disease progression stages and primary disease mechanisms and treatment goals that can be achieved (

Table 4. Therapeutic Strategies Categorized by Mechanism and Stage.

Therapeutic Category	Specific Interventions	Mechanism	Classification	Optimal Disease Stage	Level of Evidence	References
Vascular Risk Management	Antihypertensives, Statins, Antiplatelet agents	Prevent further vascular injury	Disease-modifying (prevention)	All stages (critical in preclinical/early)	Strong (Phase III data)	[17,129,130,132]
Metabolic Optimization	GLP-1 agonists, SGLT2 inhibitors, Metformin	Multiple: anti-inflammatory, neuroprotective	Potentially both	Early to moderate	Moderate (Phase II ongoing)	[131,144,145,146,147,148,149]
Cerebral Perfusion	Cilostazol, PDE5 inhibitors	Enhance blood flow, reduce inflammation	Disease-modifying	Early to moderate	Moderate (regional approval)	[136,137,138,139]
Anti-inflammatory	NLRP3 inhibitors, Minocycline	Reduce neuroinflammation	Disease-modifying	Early to moderate	Limited (Phase I/II)	[61,85,137,140]
Cellular Senescence	Senolytics (D + Q, Fisetin)	Remove senescent cells	Disease-modifying	Early to moderate	Preclinical only	[141,142,143]
White Matter Repair	Clemastine, Anti-LINGO-1	Promote remyelination	Disease-modifying	Early to moderate	Limited (Phase II)	[66,125,146]
Symptomatic	Cholinesterase inhibitors, Memantine	Neurotransmitter modulation	Symptomatic	Mild to moderate	Weak (mixed results)	[135]
Glymphatic Enhancement	Sleep optimization, CPAP, Omega-3	Improve waste clearance	Potentially both	All stages	Emerging	[158,159,160,161]

CPAP, Continuous positive airway pressure; D + Q, Dasatinib plus Quercetin; GLP-1, Glucagon-like peptide-1; LINGO-1, Leucine-rich repeat and Ig domain-containing Nogo receptor-interacting protein 1; NLRP3, NLR family pyrin domain containing 3; PDE5, Phosphodiesterase type 5; SGLT2, Sodium-glucose cotransporter 2.

).

6.4. Precision Medicine Approach to VaD Treatment

The future of VaD treatment will depend on precision medicine strategies which use specific treatment plans based on individual disease profiles instead of using only clinical symptoms for diagnosis. The treatment method needs complete biomarker evaluation to determine the main biological processes which will help choose the most suitable therapy [162].

The first step for treating patients with endothelial dysfunction and hypoperfusion (identified by reduced CBF on ASL-MRI and elevated endothelial markers) involves cilostazol or PDE5 inhibitors because these medications directly impact blood vessel function [163]. The treatment method that provides the most advantages to patients with elevated CSF sTREM2 and GFAP levels should implement anti-inflammatory approaches that utilize NLRP3 inhibitors or the repurposed medication minocycline [164].

The best results will emerge from implementing combination strategies which tackle various pathways. The treatment strategy for patients who have both vascular and inflammatory conditions in their blood vessels would involve PDE inhibitors to improve vascular function and GLP-1 agonists and anti-inflammatory drugs to enhance metabolic health [165]. The first step of sequential therapy requires vascular stabilization before doctors can proceed with neuroprotective treatments following acute injury management [166].

The monitoring system would enable doctors to modify treatment plans through biomarker data which shows how patients respond to their current therapy. The normalization of inflammatory markers would allow for lowering anti-inflammatory doses, but BBB leakage would require increased vascular protection measures [167]. The adaptive treatment strategy delivers the best possible results through the reduction in harmful side effects from treatments that do not provide benefits.

7. Conclusions and Future Directions

Vascular dementia is a complex and devastating disorder at the intersection of cerebrovascular health and neurodegeneration. Our understanding has evolved from a simplistic infarct-based model to a sophisticated appreciation of a molecular cascade initiated by chronic hypoperfusion and BBB failure, particularly in the context of SVD.

The core pathological pillars of endothelial dysfunction, oxidative stress, neuroinflammation, glymphatic dysfunction, and white matter injury work in concert to destroy vulnerable oligodendrocytes and neurons, leading to the disconnection of vital neural networks.

Research now shows that vascular and neurodegenerative diseases create a mutual relationship which helps explain dementia development in elderly people. The condition of vascular dysfunction leads to direct tissue damage and prevents the proper removal of neurotoxic proteins including amyloid-β. The presence of amyloid angiopathy together with tau pathology creates damage to blood vessels which weakens their structural integrity. The complex link between vascular and neurodegenerative elements results in a mixed pathology that needs treatment approaches which address both conditions simultaneously.

The path forward requires a multi-pronged approach. First, public health initiatives must continue to emphasize the aggressive control of vascular risk factors from midlife onwards, which remains our most effective tool for prevention. Second, the field must continue its quest for highly specific and sensitive biomarkers. A validated panel of imaging and fluid-based markers will be transformative, enabling early diagnosis, accurate prognosis, patient stratification for clinical trials, and objective monitoring of therapeutic response.

Third, and most critically, the development of disease-modifying therapies must be accelerated. However, we must maintain realistic expectations given the complexity of VaD and the disappointing translation of many preclinical successes. Future clinical trials should move beyond repurposed AD drugs and focus on agents that target the fundamental molecular pathways of VaD. Combination therapies that simultaneously target inflammation, oxidative stress, endothelial dysfunction, and glymphatic impairment may be necessary to combat the multifaceted nature of the disease. Furthermore, strategies aimed at promoting repair, such as enhancing BBB integrity or promoting remyelination, offer exciting new frontiers. Biomarkers serve as the most effective tool for medical progress when used to choose treatments through precision medicine strategies. The identification of specific disease mechanisms in individual patients enables healthcare providers to develop customized treatment plans which surpass conventional standardized medical protocols. The future of VaD treatment holds promising results because scientists keep working on new investigational treatments as they gain a better understanding of disease mechanisms and biomarkers and develop more advanced therapeutic approaches. By continuing to unravel the intricate molecular maze of VaD, we can move closer to the ultimate goal of preserving cognitive function in the face of vascular brain injury. The upcoming ten years will show whether experimental treatments under development will lead to actual medical advantages for the numerous patients suffering from this fatal disease.