Extracranial Vascular Arterial Stiffness Contributes to Cerebral Small Vessel Disease, Stroke, and Late-Onset Alzheimer’s Disease

1. Introduction

Cerebrocardiovascular disease(s) (CCVD) including coronary artery disease, ischemic heart disease, and stroke are the leading cause of mortality globally and are a major cause of disability [1,2,3]. Further, central conduit extracranial vascular arterial stiffness/stiffening (VAS) as measured using carotid-femoral pulse wave velocity (PWV), is an independent predictor of cardiovascular morbidity and mortality [4,5]. Multiple risk factors for the development of VAS include advancing age [5,6,7]; essential hypertension (HTN) [6,8]; metabolic syndrome (MetS) [9]; diabetes-specifically type 2 diabetes mellitus (T2DM) and insulin resistance (IR) [10,11,12]; obesity [13,14], unhealthy lifestyles such as smoking [15], physical inactivity-sedentary lifestyle [16], and high salt, high caloric intake as occurs with the diet-induced obesity Western style diets [17,18]. Importantly, note that the risk factors for the development of VAS parellel the risk factors for the development of CCVD [19,20]. Also, VAS may begin in youth to middle age and some have even reported that VAS may preceed the development of HTN and metabolic risks in youth [21].

Recent evidence obtained from preclinical and clinical studies have demonstrated an intricate connection between extracranial atherosclerotic vascular disease, HTN and VAS in the peripheral circulation [22]. Further, VAS and subsequent cerebral small vessel disease (SVD) with its association to brain endothelial cell activation and dysfunction (BECact/dys) and blood-brain barrier (BBB) dysfunction and disruption (BBBdd) of the neurovascular unit (NVU) with increased permeability result in neurodegeneration and the development and progression of late-onset Alzheimer’s disease (LOAD) [22,23]. The findings of systemic extracranial atherosclerosis, vascular ossification-calcification remodeling, MetS, and HTN inclusive of both essential and the more predominant isolated systolic hypertension are frequent predisposing factors for the development of VAS [6,8,22,23].

The damaging effects of increased pulsatile pulse pressure (pp) due to VAS is known to be one of the many injurious stimuli to both the systemic and brain endothelial cells (SECs, BECs respectively), which result in the development of SVD, neurodegeneration, and LOAD to support a heart-vessel-brain (HVB) axis (Figure 1 and Figure 2) [23,24,25,26,27].

LOAD is known to have a multifactorial pathogenesis and seldom results from a pure Alzheimer’s-type (Aβ plaques and tau neurofibrillary tangles deposition with neurodegeneration) pathology and often contains one or more vascular pathologies including VAS at autopsy [22,23]. A decade has now passed since the trio of Hughes, Craft, and Lopez [23] suggested that there was a potential role of arterial stiffness in the pathogenesis of Alzheimer’s disease and that is the main reason why the authors have chosen to reexamine this issue in this narrative review.

The primary focus of this narrative review is to explore the role of VAS and how it relates to the development of LOAD via the development of SVD with chronic cerebral hypoperfusion and hypometabolism as illustrated in figure two in order to increase our database of knowledge in this field of study. Also, preclinical rodent models representing hypertension, obesity, insulin resistance, and type 2 diabetes will be utilized in some sections to better understand both structural remodeling and functional changes associated with disease and how they relate to the development and progression of VAS. Importantly, neurovascular unit remodeling and impairment of neurovascular unit integrity develop due to the damaging role of increased systemic pp to the brain’s vulnerable capillary NVUs as a result of high flow and low capillary resistance in the brain [22,23,28].

2. Advancing Age and Essential Hypertension (HTN)

Advancing age is the strongest risk factor for the development of VAS [29]. Fatigue and failure from increased pp associates with chronic wall stress that associates with stiffening of systemic endothelial cell(s) (SECs), elastin fragmentation and loss of the internal elastic lamina and elastin lamellar units with increased collagen stiffening, VSMC stiffening, and the accumulation of advanced glycation endproducts (AGE) and its receptor (RAGE) with increased reactive oxygen species with increased matrix metalloproteinases (MMPs) throughout advancing age (30). Aging is associated with a decrease in elastin and increased stiffer collagen within arterial vessels and an increase in PWV with increased pp [29,30]. Advanced aging is followed by HTN, which is the second most common cause of VAS [30].

HTN also increases in prevalence with advancing age and advanced aging and HTN are the two main determinants of VAS [30,31]. Importantly, HTN and VAS are intricately related with bidirectional effects, in that HTN increases VAS and VAS increasingly affects HTN [32]. HTN results in a direct increased mechanical stress and injury to the vascular wall, which includes systemic endothelial activation and dysfunction (SECact/dys) with a proinflammatory phenotype and decreased nitric oxide bioavailability. Additionally, HTN results in oxidative redox stress (OxRS, which includes reactive oxygen, nitrogen, sulfur species and activation of the reactive species interactome (RSI)), inflammation, increased stiffer collagen and elastin degradation and loss of recoil with loss of elastin lamellar units, and activation of the renin-angiotensin-aldosterone system (RAAS). In a like manner, VAS results in a decreased buffering-cushioning effect of the vessel wall, premature arrival of the reflected pulse wave that results in increased systolic blood pressure and increased pp, which results in SEC injury. Further, aging-related HTN may be characterized by a significant increase in systolic blood pressure with little or no change in diastolic blood pressure or even lowering of diastolic blood pressure that it termed ISH [33]. Also, aging associates with increased effects on the MetS and the neurohormonal axis with increased nervous system activity, increased aldosterone and salt sensitivity that result in both increased vascular inflammation with increased tumor necrosis alpha (TNF alpha), monocyte chemoattractant protein-1(MCP-1), interleukin-6 (IL-6), and increased leukocyte infiltration of SECs, which contribute to VAS and subsequent HTN (Figure 3) [33].

Many decades of research have implicated HTN and atherosclerosis as potential modifiable risk factors in the development of VAS, SVD, stroke, with neurodegeneration and LOAD [34,35]. Indeed, both atherosclerosis and HTN are implicated in the development and progression of VAS and SVD; however, they frequently co-exist and may be present simultaneously especially in older individuals. Therefore, it is appropriate to compare and contrast how they each are implicated in the development of VAS to result in SVD (Box 1) [6,36,37].

BOX 1. Comparison of atherosclerosis and essential hypertension (HTN) in the development of vascular arterial stiffness (VAS) and cerebral small vessel disease (SVD). Importantly, the vicious cycle of OxRS-ROS and inflammation are strongly involved in both atherosclerosis and HTN. In general atherosclerosis may be considered to be primarily a tunica intima disease; whereas, HTN is primarily considered to be a tunica media disease. Additionally, vascular ossification and calcification (VOC) occur in distinct locations. VOC occurs primarily in the media with HTN, while it occurs in the intima locations with atherosclerosis; however, VOC can be found in either regional location in both atherosclerosis and HTN. Notably, HTN is a major risk factor for the development and progression of atherosclerosis [21,32,33]. ACE, angiotensin converting enzyme; EC, systemic endothelial cell; ED, elastin-derived; EDPs, elastin-derived peptides; MMPs, matrix metalloproteinases; OxRS, oxidative redox stress; ROS, reactive oxygen species.

Additionally, multiple risk factors for the development of atherosclerosis and eHTN including the MetS play an important role (Figure 4) [37,38].

Atherosclerotic calcifications are the most common form of calcific vasculopathy [39]. Plus, vascular calcifications occur in both atherosclerosis and HTN; however, calcification is more strongly associated with atherosclerosis with increasing VAS. Also, HTN is more strongly associated with SVD since HTN is more commonly associated with microvessels in the brain as compared to atherosclerosis [6,40].

Importantly, studies show that HTN is linked to brain amyloid beta (Aβ) deposition in older adults and suggest that VAS plays a central role in this relationship [41,42,43,44]. VAS consists of a reduced capacity of arteries to expand (impaired vasodilation) as a result of stiffness, which impairs their ability to accommodate or cushion the increase in pressure from blood and ejection pressure from the heart during systole. Thus, VAS with decreased compliance allows for the transmission of increased pulsatile pulse pressure deeper into the periphery and microvessels of the distal-end organ systems microvessels present in the brain with high flow and low resistance. Regardless, VAS due to the effects of HTN and atherosclerosis appears to be an important risk factor for the development of SVD, which allows for the unification of several clinical phenotypes including SVD, cerebrovascular disease, stroke, neurodegeneration, impaired cognition, dementia, and LOAD. Indeed, VAS may be considered a potential modifiable risk factor that may even be considered as a nexus for the development of neurodegeneration and LOAD via BECact/dys, BBBdd, OxRS, neuroinflammation, and SVD (Figure 5) [1,2].

3. Atherosclerosis of Extracranial Aorta, Carotids, and Vertebral Arteries

Atherosclerosis is a leading cause of vascular disease (cardiovascular, cerebrovascular, and peripheral vascular disease) globally [45] and is significantly associated with LOAD when utilizing carotid intima-media thickness to assess the degree of atherosclerosis [46]. Additionally, atherosclerosis is a systemic chronic, progressive, and dysfunctional endothelial-intimal disease associated with SECact/dys that initially occurs at side branches, bifurcations and regions of turbulent blood flow. Atherosclerosis typically begins at the extracranial iliac and femoral arterial bifurcations, aorta, and progresses cephalad over time to involve the coronaries, carotids, and vertebral extracranial arteries, which eventually progress to the branching cranial arteries extending from the circle of Willis and its arterial branches to the larger pial arteries of the brain where the smaller arterial microvesssels develop mostly arteriolosclersis, hyalinosis or lipohyalinosis [3,27,47,48]. Atherosclerosis is also a focal occurring, chronic proinflammatory, fibroproliferative, angiogenic, prothrombotic, multifactorial disease beginning in the arterial intima that is facilitated by multiple injurious species as in Figure 1. The development of atherosclerosis is critically dependent on the penetration and retention of atherogenic modified-oxidized low-density lipoprotein-cholesterol (modLDL-C/small dense LDL-C particles and oxLDL-C), triglyceride-rich lipoproteins, and decreased high density lipoproteins (HDL-C) of the atherogenic lipid triad phenotype, hemodynamic stress, OxRS, inflammation via a monocyte to lipid laden macrophage foam cells within the intimal space. Once initiated in the intima the disease progresses to involve the vascular smooth muscle cells (VSMCs) of the tunica media and the proinflammatory aspect of this disease now involves the uptake of inflammatory monocytes that eventually remodel to lipid-laden macrophage foam cells with further intimal growth that may eventually involve the tunica media. These remodeling changes may then initiate VSMC hypertrophy, proliferation, migration that associates with increased collagen, hyaluronan, and proteoglycans along with the fragmentation, degradation, and loss of elastin that contributes to VAS during the progression of atherogenesis (Figure 6 and Figure 7) [3,49,50,51,52,53,54].

There is convincing evidence that T2DM and the MetS are associated with greater arterial stiffness and atherosclerosis as compared to non-diabetic individuals [55]. Importantly, increased VAS may help to explain the increased CCVD risk in individuals with diabetes and the MetS (Figure 7) [55,56].

Interestingly, not only does the elevated glucose in T2DM cause an increase in AGE, which promotes collagen crosslinking but also interacts with its receptor RAGE and gives rise to increased OxRS that can increase the fragmentation of elastin within the media. Concurrently, this increase in glucose and AGE instigate a phenotypic switch in the VSMCs of the media from a contractile type to a synthetic type that increases the synthesis of stiffer collagen, proteoglycan, and hyaluronon ECM components as in Figure 7 to result in increased VAS [57].

Even though atherosclerosis is defined as being a chronic progressive intimal disease, it is important to note that even when there is continued atheroma lipid expansion that these lesions do not usually become clinically symptomatic unless they are superimposed with progressive remodeling changes including the deposition of thrombotic material (intraplaque hemorrhage), inflammation, calcification, and malignant-like invasion via angiogenesis of the atheromatous plaque with plaque hemorrhage and rupture [47,51]. Additionally, current theories regarding dementia pathogenesis currently suggest that there is a continuum between atherosclerotic vascular disease and dementia such as occur in LOAD [58].

In addition to the extracranial arteries the extension of the extracranial internal carotids and the fusion of the vertebral arteries to form the basilar artery allow for the formation of the ultimate collateral circulation of the intracranial arteries known as the circle of Willis [59]. Importantly, Roher et al. have demonstrated that these circle of Willis arteries in older individuals with LOAD have extensive remodeling changes of atherosclerosis with luminal narrowing as compared to those without LOAD [60]. Further, Beach et al. along with others have shown that atherosclerosis of the circle of Willis associate with Aβ neuritic plaques, tau neurofibrillary tangles, and LOAD [61,62].

3.1. Vascular Ossification/Calcification (VOC)

VOC may be defined as the deposition of calcium phosphate complexes in the form of hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂] in vessels, which result in increased VAS [63]. While VOC of arteries is one of the characteristics of atherosclerosis and vascular aging [64,65], it also is capable of being increased in pathological processes such as HTN, diabetes, CKD, and hereditary disorders (Figure 8) [66,67,68].

VOC may occur at different locations (intimal or media calcifications or both) in the arterial wall that are known to be associated with different risk factors and outcomes [63,69]. Indeed, arterial calcification is no longer thought to be just a passive process associated with aging, but involves a reprogramming of the tunica media VSMCs from a contractile state to a synthetic proliferative and migratory phenotype capable of becoming an osteogenic cell within the media and intima [68,70]. Importantly, these local VSMC cues are different for atherosclerotic aortic intimal calcification, which involves inflammation, OxRS, and apoptosis in contrast to medial calcification that associates with aging, HTN, senescence, and uremia of renal failure with multiple elevations of uremic toxins and specifically elevated calcium and phosphate levels [67,70]. Interestingly, elastin degradation/fragmentation results in the release of bioactive elastin degradation products (EDPs), which are capable of inducing an osteogenic switch of VSMCs from a contractile to a synthetic phenotype and once switched these cells are capable of producing calcification in the tunica media that have a predilection to adhere to these damaged elastin lamellae within either the media or the elastin of the internal elastic lamina (IEL) of intima regions [71]. Importantly, McEniery et al., have pointed out that in both preclinical animal and human studies that arterial calcification is associated with aortic stiffness and HTN [72].

4. Endothelial Interface: Systemic Endothelial Cells (SECs) and Brain Endothelial Cells (BECs)

The brain endothelial functional interface is highly selective and acts as a continuous monolayer of gatekeeper BECs with barrier functions that provide tight (specialized occludin, claudin, junctional adherens molecule proteins) and adherens junctions (VE-Cadherins) to create a BBB and prevent paracellular trafficking in contrast to SECs that only have VE-Cadherins. Importantly, both the BECs and SECs interface with their most luminal layer of extracellular matrix (ECM) termed the endothelial glycocalyx (ecGCx) that serves as a protective shield to the vessel contents [73,74] are known to initially separate the circulating blood from the CNS cells and interstitial fluid and further BECs are also known to have a paucity of pinocytosis as compared to SECs [75,76].

SECs and BECs activation indicate an endothelial proinflammatory response, while SECs and BECs dysfunction indicate a decrease in protective (antioxidant, anti-inflammatory, antithrombotic, and vasodilation effects) bioavailable nitric oxide (NO) [36,53,77]. The peripheral SECs are constantly being exposed to numerous injurious stimuli as in Figure 1, which are capable of inducing SECact/dys. These exposures are known to instigate SEC activation of leukocytes to the central nervous system (CNS) neurovascular units BBB with increased permeability but also deliver increased peripheral cytokines and chemokines (pCC). Further, these increased pCC associate with endothelial dysfunction and decreased NO with increased OxRS and neuroinflammation, which eventually create a double vicious cycle between OxRS and inflammation via the nuclear factor-kappa B in SECs and at the NVU BEC BBB interface (Figure 9) [77].

Notably, these double vicious cycles in Figure 5 contribute to a proconstrictive state at the precapillary arterioles and true capillary of the NVU in addition to leukocyte adhesion and even stalling of cerebral blood flow. Also, advanced glycation endproducts and their receptors (AGE/RAGE) activation result in increased OxRS that in turn activates local MMP-2, 9 with increased proteolysis including the BBB tight and adherens junctions with resulting increased permeability. These changes contribute to endothelial nitric oxide synthase (eNOS) uncoupling and decreased NO bioavailability with hypoperfusion and hypometabolism to regional neurons with neurodegeneration, impaired cognition, brain atrophy and LOAD.

NO synthesized and secreted by SECs and BECs is known to function as a vasculo-protectant, in that, it has antiplatelet, antithrombotic, anti-inflammatory, antiatherosclerotic and vasorelaxant effects as a gasotransmitter synthesized by the endothelial nitric oxide synthase (eNOS) enzyme. NO is capable of undergoing paracrine signaling to the immediate surrounding pericytes (at the level of capillary NVUs) and vascular smooth muscle cells (at the level of arterioles and arteries) to result in vasorelaxation due to its activation of soluble guanylyl cyclase to increase the synthesis of 3,5-cyclic guanosine monophosphate [78].

Decreased NO bioavailability as occurs in CCVDs due to endothelial dysfunction is due largely to eNOS uncoupling, wherein increased OxRS results in the excessive oxidation of the essential coenzyme tetrahydrobiopterin (BH4) to the ineffective dihydrobiopterin (BH2). Notebly, the eNOS reaction will only run if its essential coenzyme is fully reduced to its BH4 moiety. Also, elevated asymmetrical dimethyl arginine (ADMA), a known competitive inhibitor of eNOS enzyme reaction) is capable of decreasing bioavailable NO [77,78]. Indeed, SEC and BEC dysfunction with decreased bioavailable NO sound an alarm not only to the SECs and BECs but also other supportive cells of extracranial arteries (VSMCs) and the microvessel NVU mural supportive cells (Pcs and connecting astrocyte endfeet of NVU) as well as the CNS cells (Figure 10) [25,78].

ECs (SECs and BECs) are the first cells to be exposed to multiple injurious species as in figures 1 and 6 and they react to these injuries with an injury response that has multiple phases resulting in structural and functional responses. Over the past decade authors have observed at least 10 ultrastructural remodeling phenotypes in the thoracic aorta and NVU ECs in various models that associate with BECact/dys, BBBdd, SVD, and VAS in aortic ECs and microvascular NVU BECs from various models (Figure 11) [25,26,27].

4.1. Western Diet-Induced Obesity Is Also Known to Contain a High-Salt Component That Increases VAS.

Importantly, the heavily consumed Western diet is consistently known to have not only a high fat and carbohydrate component but also a high sodium-salt component that also contributes to an increase in VAS [74,75]. Elevations of sodium chloride in the Western diet are toxic to the vascular endothelium and are known to result in endothelial glycocalyx dysfunction and damage with attenuation and/or loss, EC OxRS, ECact/dys that induces a proinflammatory endothelium with decreased NO bioavailability, activation of MMP-2, 9, TGFβ, transglutaminase 2, elastin fragmentation and increased collagen with decreased elastin/collagen ratio and crosslinking in addition to activating the RAAS and increase AT-1 receptors along with increased endothelial sodium channel (eNAC) activity to promote VAS as illustrated in Figure 10 [79,80,81].

5. Metabolic Syndrome (MetS): Role in the Development of VAS

The MetS is a metabolic disorder that consists of a cluster of multiple risk factors including hyperlipidemia (obesity), hyperinsulinemia (IR), essential HTN-ISH, hyperglycemia (impaired glucose tolerance (IGT) and T2DM and associated variables. In addition to paralleling the obesity epidemic, the MetS associates with an increased risk for the development of T2DM and cerebrocardiovascular disease [38]. Each of the previous four H (horsemen) risk factor clustering, in addition to the MetS itself, play an important role in the development of VAS and LOAD [9,82,83]. MetS is a strong predictor of CCVD disease and VAS, which is increasingly being recognized as a CCVD risk factor, plus components of the MetS are capable of interacting to synergistically impact carotid intimal media thickness and VAS (Figure 12) [83,84].

While the MetS may be viewed as a risk syndrome, it provides a definite platform for the clustering of multiple risk factors and variables that is now known to associate with VAS and this not only helps to broaden our knowledge but also to further bridge the relationship of MetS, VAS, SVD, and neurodegeneration as outlined in the sequence of events as previously outlined in Figure 2, Figure 4 and Figure 5.

6. Extracellular Matrix (ECM) Elastin, Elastin-Derived Peptides (EDPs), Collagen, and Vascular Smooth Muscle Cells (VSMCs) of the Arterial Tunica Media in Vascular Arterial Stiffening (VAS)

In addition to structural remodeling and functional changes in the ECs, VAS also develops due to remodeling alterations in the vascular extracellular matrix characterized by a degraded and fragmented decrease in the elastic recoil protein elastin via elastinolysis and an increase in the stiffer organized collagen via increased synthesis by media VSMCs [50,85]. These findings are further facilitated by the processes of OxRS, inflammation/metainflammation, and AGEs with increased collagen crosslinking that lead to decreased elasticity and vessel compliance with increased PWV and damaging pulsatile pp [85,86]. The VSMCs also develop a synthetic phenotype responsible for increased synthesis of stiffer collagen and proteoglycans (PGNs) that become synthetic, hypertrophic, and capable of migration in contrast to normal contractile phenotypes, termed phenotypic switching (Figure 13) [50,87].

The ECM of the arterial tunica media is composed of elastin, collagen, glycoproteins and proteoglycans, which confers tensile strength and provides viscoelasticity of the conduit arterial vessel walls [88,89,90]. Importantly, when the elastin undergoes elastinolysis there is the generation of elastin-derived fragments that are a rich source of EDPs [90,91,92]. Elastin fibers can be degraded and fragmented by mechanical fatigue, calcification, glycation, lipid peroxidation, and importantly, protease-elastase digestion with fragmentation-degradation [93]. Elastolysis-elastinolysis or elastin degradation is due primarily to elastases that are comprised by MMPs (MMP-2, 7, 9, and 12) and cathepsin cysteine proteases, such as cathepsin S that are activated in response to OxRS primarily generated within the vessel by ECact/dys, activated macrophages, and synthetic VSMCs (Figure 14) [90,91,92,93,94].

It is known that VSMCs become stiff similar to SECs when examined by atomic force microscopy measurements in addition to increasing synthesis of stiffer collagen and PGN [95]. This VSMC stiffness contributes to the overall global increase in aortic stiffening with aging. Notably, this VSMC stiffness is in addition to the fragmentation of elastin with the loss of elastic recoil, increased collagen and PGN synthesis by the synthetic VSMC phenotypes and the stresses placed upon the VSMCs due to mechanotransduction [96,97]. Phenotypic switching from contractile to synthetic, proliferative, and migratory VSMC in VAS allows these migratory VSMC to become mobile and traverse the media to the IEL where they are capable of degrading the IEL and create a neointimal subendothelial space [90,91]. In the Ren2 models, angiotensin-II (AngII) elevation and OxRS are important for the invasive nature of the IEL with the creation of the neointima (Figure 15) [50].

The phenotypic switch of the VSMCs in hypertension and diabetic obese models as in figures 9, 10, and 11 result in the degradation of elastin lamella and the IEL resulting in the EDFs and the production of bioactive EDPs [97]. Bioactive EDPs (matrikines-elastokines) and interactions with their receptor elastin receptor complex (ERC) result in multiple functions that contribute to VAS. Bioactive EDPs promote inflammation, react with RAGE to increase ROS, NFkappaB, and MMP activation. activate cytokines including TNFα and IL-6, increase crosslinking of collagen, and promote VSMC phenotypic switching. These contributions amplify further elastin degradation all of which, promote VAS in CCVDs [88,97,98].

At this juncture it is noteworthy to point out that transglutaminase 2 (TG2) is an enzyme ubiquitously expressed in the vasculature, which promotes the synthesis and crosslinking of extracellular matrix collagen. Increased transglutaminase 2 (TG2) is a known collagen crosslinker that associates with VAS and affects the extracellular matrix by increasing collagen deposition, and crosslinking (in a calcium-dependent manner) that has been long recognized as critical player in vascular stiffening [99,100]. In this regard it is notable that Ramirez-Perez et al. were able to show that cystamine (a nonspecific TG2 inhibitor) was able to reduce vascular stiffness in Western diet-fed female mice; however, they did not determine the extent of these findings in regards to the role of cystamine also being an antioxidant (cystamine metabolized to cysteine and thiosulfate) that could also contribute to the vascular destiffening effects in these models [100].

7. Conclusion and Future Directions

Recently, there has been considerable epidemiological, clinical-pathological and basic science observations that has allowed the research community to reconsider the important role of vascular factors in cognitive impairment. These observations have made it possible to now identify vascular dysfunction and damage (including VAS and SVD) as being critical components of the pathophysiology of age-related dementias including LOAD (Figure 16) [101,102,103,104].

Over time there has been accumulating and consistent evidence that support and definitely implicate both VAS and SVD in the pathogenesis of impaired cognition, neurodegeneration, and dementia including LOAD (Figure 17) [ 27, 105, 106, 107].

Future directions regarding the importance of extracranial vascular stiffening (VAS) revolve around a resurgence of interest regarding the role of not only VAS but also microvessel remodeling that occurs in VCID and how it relates to the development of neurodegeneration as a co-occurance or mixed dementia (MD) of aging along with the LOAD type dementia. While the authors have focused on the importance of VAS throughout this narrative review, we posit that an integrative approach with somewhat of a paradigm shift of an umbrella approach be strongly entertained to examine these burgeoning age-related dementias (Figure 18) [104].

VCID is the second most common cause of dementia after LOAD [108] and it is a common co-occurring form of dementia. At autopsy seldom does one find just pure changes of LOAD (Aβ neuritic plaques and tau NFTs) dementias [108,109]. Indeed, there is a quite complicated interaction between VCID and LOAD pathologies in the evolution of these two most common causes of global dementia, which includes VAS as one of the early component mechanisms in its development and progression [103,108,109]. Therefore, it is suggested that this problem of age-related dementia be approached in an integrative manner without discriminating between being a strictly sporadic Alzheimer’s disease or LOAD and VCID/VaD and consider their co-occurrence as a MD, since they share so many similar risks factors. As the emerging knowledge continues to grow in the field of VCID and their emerging biomarkers (MarkVCID biomarker consortium: https://markvcid.partners.org/about/news), it is felt that the co-occurrence of LOAD and VaD/VCID (i.e. mixed dementia) will continue to become a more futuristic concept allowing the MD concept to flourish [104,105,106].

Notably, there exists a gender difference in the development of VAS and LOAD, in that female individuals have a greater risk for the development of both VAS and LOAD in older populations that are post-menopausal [110,111]. It is possible that the increased risk for females in the development of LOAD may be due to their increase in VAS. Mechanisms for this relationship may involve how VAS relates to the increased risk of SVD with hypoperfusion, CCH, hypometabolism, and neurodegeneration with atrophy and impaired cognition in LOAD as illustrated and discussed previously in figure legends 16-18.

Limitations include those inherent to any narrative review that is focused primarily on a certain topic such as the role of extracranial VAS and its involvement in the development and progression of LOAD. However, this limitation does allow this review to remain focused on its central theme or focus.

Targeting multiple modifiable risk factors have become the main therapeutic strategy to improve arterial stiffness and the additional use of omega-3 fatty acid intake, RAAS antagonists, metformin, HMG-CoA reductase inhibitors have been found to be useful in those individuals with HTN and diabetes as well as those individuals at high cardiovascular risk [112]. In addition to metformin, both of the antidiabetic drugs (SGLT-2 inhibitors and GLP-1R agonists) have the potential and have been shown to decrease VAS [94,113,114,115]. However, there is currently a lack of therapeutic strategies specifically directed at the treatment of VAS. Notably, Ramirez-Perez, et al. recently found that cystamine (a non-specific TG2 antagonist with antioxidant effects) was able to reduce VAS in female Western diet-fed mice [100] and these results may help to instigate future trials with other treatment modalities to specifically decrease VAS. Additionally, authors have recently suggested that sodium thiosulfate may be an innovative, multi-target repurposed strategy for the treatment of LOAD that is based on sodium thiosulfates capability of having anti-inflammatory, antioxidant, chelating, and possible restorative effects of improving the bioavailability of hydrogen sulfide and NO that could also help to attenuate the deleterious effects of VAS and remodeling of the vessel wall in atherosclerosis and hypertension in peripheral artery disease and the development and progression of LOAD [116].

Additional future directions for the treatment of VAS may include the following five points, which may help to attenuate or delay the onset of the development and progression of SVD and LOAD (Box 2) [20,21,22,23].

Box 2. Five key points regarding the future directions in the treatment of extracranial vascular arterial stiffening (VAS) in order to attenuate or decrease the development and progression of SVD and LOAD. Aβ, amyloid beta; HTN, hypertension; LOAD, late-onset Alzheimer’s disease; SVD, cerebral small vessel disease.

Finally, the authors are in hopes that this narrative review will provide readers with an increased database of knowledge in this field of study such that they can continue to develop novel more specifically targeted therapeutic interventions to improve VAS. Thus, reducing the associated neurological remodeling and functional changes associated with the development of SVD and delay the progression of LOAD in this global and ever-increasing aging society at risk.