Hypertension: a harbinger of stroke and dementia

INTRODUCTION

Despite remarkable successes in prevention and treatment, hypertension (HTN) remains a major cause of morbidity and mortality worldwide¹. The brain is one of the preeminent “target organs” in which high blood pressure is particularly damaging, contributing significantly to its burden of disease¹. HTN is the biggest risk factor for stroke, the second cause of death worldwide and a major cause of long-term disability². HTN is also a leading risk factor for vascular cognitive impairment (VCI)³, as well as Alzheimer’s disease (AD), the most common cause of dementia in the elderly³. Therefore, HTN is involved in the pathogenesis of two major brain diseases: stroke and dementia. In this brief review, we will first examine the role of HTN in the alterations in cerebrovascular structure and function underlying the pathological effects of HTN on the brain. Then, we will examine the pathophysiological bases of these alterations, focusing on how high blood pressure promotes stroke and cognitive impairment. Finally, we will discuss the impact of preventive and therapeutic approaches to mitigate the deleterious effects of HTN on the brain.

ALTERATIONS IN CEREBROVASCULAR STRUCTURE INDUCED BY HYPERTENSION

Adaptive changes: Hypertrophy and remodeling

Sustained elevations in blood pressure have profound effects on the structure of cerebral blood vessels inducing adaptive changes aimed at reducing the mechanical stress on the arterial wall and at protecting microvessels from pulsatile stress⁴. In hypertrophic remodeling, the media thickens to encroach into the lumen, resulting in increased media cross-sectional area and media/lumen ratio (Fig. 1). The size of vascular smooth muscle cells (VSMCs) increases and there is accumulation of extracellular matrix proteins, such as collagen and fibronectin, in the vessel wall⁵. In eutrophic remodeling, smooth muscle cells undergo a rearrangement that leads to a reduction in the outer and inner diameters, whereas media/lumen ratio is increased and cross-sectional area is unaltered (Fig. 1). In this case, the change in VSMCs size is negligible, and the reduction in lumen is due to a reorganization of cellular and acellular material in the vascular wall, accompanied by enhanced apoptosis in the outer regions of the blood vessel⁵. Remodeling is damaging because it reduces the vessels’ lumen and increases vascular resistance, and has emerged as a potential risk factor for cardiovascular events and cerebrovascular disease⁶.

Figure 1. Effect of HTN on cerebral blood vessels.

HTN induces profound alterations of critical regulatory mechanisms of the cerebral circulation, which, in concert with the structural alterations, compromise the blood supply to the brain and increase the risk for stroke and dementia.

Longstanding HTN induces deposition of collagen and fibronectin and elastin fragmentation, leading to an increase in the stiffness of the wall of large arteries. Arterial stiffening is good predictor of stroke and cognitive decline, and is associated with clinically silent brain lesions in hypertensive patients^{3, 7}.

Atherosclerosis and small vessel disease

HTN is a leading risk factor for atherosclerosis. A 10mmHg increase in arterial pressure increases by 43% the odds of complex aortic atherosclerosis (protruding atheroma, ulcerated plaques, mobiles debris), highly predictive of ischemic strokes⁸. Atherosclerotic lesions are also observed at sites of turbulent flow, such as the carotid bifurcation and the vertebrobasilar system, and less frequently in intracranial arteries (Fig. 2). A potential mechanism may be related to vascular shear stress at those sites leading to expression of innate immunity receptors on macrophages/monocytes and inflammation⁹. Atherosclerotic plaques can cause stroke by releasing fragments and leading to artery-to-artery embolism, or by rupture and/or hemorrhage resulting in acute cerebrovascular occlusions (Fig. 2).

Figure 2. Ischemic brain lesions associated with HTN.

HTN induces atherosclerosis of major extracranial and intracranial arteries which could lead to major infarcts. HTN causes both micro and macrobleeds and is the main pathogenetic factor for small vessel disease responsible for lacunar infarcts, white matter lesions (leukoaraiosis) and microinfarcts.

HTN also promotes highly distinctive alterations in small arteries and arterioles supplying the deep hemispheric white matter and basal ganglia, resulting in a condition known as small vessel disease (SVD) (Fig. 2). The susceptibility of these vessels to SVD may be related to their short linear path from larger vessels at the base of the brain rendering them more vulnerable to the mechanical stresses imposed by HTN¹⁰. The most common pathological substrates of SVD related to HTN is arteriolosclerosis¹¹. The pathological features of arteriolosclerosis include loss of smooth muscle cells from the tunica media, deposits of fibro-hyaline material, narrowing of the lumen and thickening of the vessel wall (lipohyalinosis)¹¹ (Fig. 1 & 2). In more advanced lesions, fibrinoid necrosis of the vessel wall facilitates the rupture of the vessel resulting in microscopic hemorrhages or large hemorrhages typically in basal ganglia or thalamus (Fig. 2). In addition, HTN induced capillary rarefaction, which may also contribute to the associated brain lesions in the periventricular white matter.

ALTERATIONS IN CEREBROVASCULAR FUNCTION INDUCED BY HYPERTENSION

The brain is highly dependent on an adequate delivery of oxygen and glucose from the circulation, and cerebral blood flow (CBF) reductions impair neuronal function and, if protracted, induce brain damage¹². Consequently, cerebrovascular control mechanisms assure that the delivery of oxygen and glucose is well matched to the energy demands of the brain’s cellular constituents. HTN induces profound alterations of these regulatory mechanisms, which, in concert with the structural changes described above, compromise the blood supply to the brain. Next, we will examine the major mechanisms regulating the cerebral circulation and their perturbation by hypertension.

Cerebrovascular autoregulation

Cerebrovascular autoregulation buffers the cerebrovascular effects of the wide fluctuations in arterial pressure that occur during the activities of daily living. Autoregulation allows the brain to maintain a steady blood flow between 60 and 150 mm Hg of mean arterial pressure¹³. Within this range, blood pressure increases result in constriction and blood pressure decreases in dilatation of cerebral resistance vessels, maintaining CBF relatively constant. Cerebral autoregulation depends on the intrinsic ability of VSMCs to constrict when transmural pressure increases (myogenic tone). Myogenic tone depends on the concerted action of ion channels on the VSMCs membrane, as well as stretch activated receptors, resulting in increases in intracellular Ca²⁺ or increases in the Ca²⁺ sensitivity of the contractile apparatus, ultimately leading to phosphorylation of contractile proteins and constriction¹³.

Regulation by endothelial cells

Cerebral endothelial cells have powerful effects on vascular tone and regulate CBF by releasing vasodilators [Nitric oxide (NO), prostacyclin, bradykinin, etc.] and vasoconstrictors [endothelin-1 (ET-1), endothelium-derived constrictor factor, etc.]¹⁴. Endothelium-derived vasoactive factors participate in the maintenance of resting CBF and may play a role in coordinating the vasodilatation of intraparenchymal arterioles with that of upstream pial arteries, and in local adjustments of flow in response to mechanical forces¹². Another important aspect of endothelial cell function is the regulation of the blood brain barrier (BBB). Cerebral endothelial cells have a low vescicular transport and are linked to each other by tight junctions, which prevent the entry of hydrophilic substances into the brain¹⁵. Specialized transport proteins on the endothelial cell membrane regulate the bidirectional transfer of substances into and from the brain parenchyma¹⁵. The integrity of the BBB is vitally important to maintain the homeostasis of the cerebral microenvironments, which is a prerequisite for normal brain function.

Functional hyperemia

Functional hyperemia is a homeostatic mechanism by which the vascular delivery of oxygen and glucose, as well as the removal of metabolites produced by brain activity, are coupled to the energy requirements of neurons and glia¹². Therefore, CBF is dynamically related to the level of neural activity of the different brain regions. A growing body of evidence indicates that neurons, glia and cerebrovascular cells, acting as an integrated unit, mediate the increase in CBF produced by neural activity^{12, 16}. Neural activity induces the release of vasoactive mediators such as NO, prostanoids, carbon monoxide, cytochrome p450 metabolites, H⁺, and K⁺ ions that act at different levels of the cerebral vasculature to mediate the hemodynamic changes underlying the CBF increase¹². Vasodilation of arterioles at the site of activation is accompanied by vasodilation of upstream pial arteries that supply the activated area and this coordinated response is essential for increasing CBF efficiently¹².

Hypertension and cerebrovascular dysfunction

HTN has profound effects on all aspects of the regulation of CBF (Fig. 1). HTN alters cerebrovascular autoregulation leading to a shift of the pressure-flow relationship to the right, such that higher pressures are needed to maintain the same level of cerebral perfusion (Fig. 1). The lateral shift may be also associated with a reduction in resting CBF, resulting in a downward displacement of the curve¹⁷ (Fig. 1). These alterations reduce cerebral perfusion at each level of blood pressure, compromising the ability of the brain to maintain adequate CBF in the face of hypotension or arterial occlusion. The mechanisms of the effects of HTN on autoregulation are not completely understood, but are likely to include a combination of effects on myogenic tone and on the changes in the mechanical characteristics of cerebral blood vessels induced by remodelling and stiffening^{4, 13}. These changes in autoregulation are particularly damaging to the periventricular white matter, which is located at the boundary between different arterial territories¹⁸ and, as such, is most susceptible to hypoperfusion (Fig. 2). Accordingly, the magnitude of autoregulatory dysfunction induced by hypertension correlates with the severity of periventricular white matter injury¹⁹. The HTN-induced autoregulatory impairment also leads to more severe brain damage after arterial occlusion in stroke models, which may underlie the increased susceptibility to large artery stroke.

HTN also alters functional hyperemia and endothelial function. Attenuations in cerebrovascular responses to endothelium-dependent vasodilators have been reported in rodent models of chronic HTN^20–22. Similarly, functional hyperemia, produced in the somatosensory cortex by activation of the facial whiskers, is attenuated in mice treated with slow-pressor doses of angiotensin II (AngII) and in spontaneously hypertensive rats^22,23. The cerebrovascular dysfunction precedes the HTN induced by slow-pressor AngII infusion and persists beyond the elevation in blood pressure at the end of the infusion²¹. Furthermore, doses of AngII that do not elevate blood pressure produce cerebrovascular alterations comparable with those observed with slow-pressor or pressor doses^{21, 24, 25}, suggesting that the cerebrovascular actions of AngII are independent of the elevation in blood pressure.

Consistent with findings in animal models, the increase in CBF induced by brain activation is attenuated in patients with chronic HTN and the cerebrovascular dysfunction correlates with cognitive deficits²⁶. Furthermore, the increase in retinal blood flow produced by light flickering, a model of function hyperemia, is blunted in hypertensive individuals²⁷. Direct evidence of altered cerebrovascular endothelial responses in humans with HTN is lacking. But, the nitric oxide synthase inhibitor L-NAME does not reduce retinal blood flow in patients with HTN, a finding consistent with NO-dependent endothelial dysfunction²⁷. These observations, collectively, indicate that HTN disrupts key cerebrovascular control mechanisms aimed at maintaining the energy homeostasis of the brain, which act in concert with the structural alterations of cerebral blood vessels described earlier to produce brain dysfunction and damage.

Key role of oxidative stress in the cerebrovascular effects of HTN

Several lines of evidence suggest that reactive oxygen species (ROS) are key mediators of the cerebrovascular damage produced by HTN. HTN promotes ROS production in cerebral blood vessels and ROS scavenger counteract the effects of hypertension on functional hyperemia and endothelial dysfunction, including alterations of the BBB^{21, 24, 25, 28}. In models of AngII hypertension, ROS production is elevated in brain regions regulating cardiovascular function²². Suppression of ROS in one of these regions, the subfornical organ, prevents the alterations in functional hyperemia and endothelium-dependent responses induced by slow-pressor administration of AngII²². In this model, the cerebrovascular dysfunction involves, in addition to direct vascular effects of circulating AngII, also activation of neurohumoral mechanisms leading to vasopressin release and upregulation of ET-1 in cerebral blood vessels²². ET-1, in turn, leads to vascular ROS production through activation of endothelin type A (ET_A) receptors²². In contrast, the cerebrovascular alterations induced by acute administration of higher AngII doses are entirely depended on a direct action of AngII on cerebral blood vessels leading to oxidative and nitrosative stress^{24, 25}. Cerebrovascular endothelin-1, via ET_A receptor and ROS, is also involved in the cerebrovascular effects of the HTN induced by chronic intermittent hypoxia, a model of obstructive sleep apnea²⁹. Oxidative stress has also been implicated in other vascular effects of HTN including vascular remodeling and inflammation³⁰. The evidence for a role of ROS in the white matter damage produced by SVD is suggestive but limited. Increased markers of oxidative stress have been described in white matter lesions in autopsy studies³¹. Furthermore, reduced circulating levels of NO metabolites, possibly reflecting increased oxidative stress, have been reported in patients with white matter lesions detected by magnetic resonance imaging (MRI)³². More studies are clearly needed.

Among the potential sources of ROS in cerebral blood vessels⁶, the enzyme NADPH oxidase has emerged as a major contributor in the cerebrovascular effects of HTN³³. Importantly, cerebral blood vessels have a greater capacity to produce NADPH oxidase-derived ROS than systemic vessels³⁴. The cerebrovascular dysfunction induced by AngII is not observed in mice lacking Nox2 and NADPH inhibition abrogates the alterations in endothelium-dependent vasodilation and functional hyperemia induced by AngII^{24, 25}. Nox2-derived radicals are also involved in the cerebrovascular remodeling induced by AngII hypertension.

BRAIN LESIONS UNDERLYING VASCULAR COGNITIVE IMPAIRMENT

VCI includes a wide spectrum of cognitive alterations caused by cerebrovascular factors and ranging from mild cognitive impairment affecting a single cognitive domain, such as executive function, to full blown vascular dementia affecting multiple domains and impairing the activities of daily living³. Stroke is a major cause of cognitive impairment. Up to 1/3 of stroke patients have cognitive impairment within 3 months, and having a stroke doubles the risk of dementia (post-stroke dementia)³. Furthermore, the risk of VCI is increased in patients with no history of stroke in which imaging shows brain infarcts (silent infarcts)³. A single stroke affecting a region important for cognition, like the thalamus or the frontal lobe, can lead to cognitive impairment (strategic-infarct dementia)³. VCI and dementia can also result from multiple strokes destroying large amounts of brain tissue (multi-infarct dementia)³. However, SVD remains a major cause of VCI contributing up to 45% of dementia cases³. Next, we will examine the neuropathological alterations caused by cerebral SVD that have been linked to VCI.

Lacunar infarcts

Lacunar infarcts, small (<20mm in diameter) rounded lesion most commonly found in the basal ganglia, are commonly associated with SVD and are a strong predictor of VCI³⁵. They have been attributed to acute occlusion of small perforating cerebral arteries (40–200µm diameter) due to SVD pathology or, less likely, embolism from upstream vessels³⁶. More recently, evidence of white matter BBB disruption has been provided in patients with lacunes, raising the possibility that BBB alterations are early pathogenic events that could lead to secondary ischemia and inflammation³⁶. Therefore, multiple factors are likely to be involved in the pathogenesis of lacunar infarcts.

Diffuse white matter damage

Another manifestation of SVD is diffuse white matter damage or “leukoaraiosis”, indicating a reduction in white matter density^{3, 11}. High systolic blood pressure precedes the development of leukoaraiosis, and blood pressure lowering slows down its progression³⁷. Often present in the periventricular white matter, leukoaraiosis could result from hypoxia-hypoperfusion. The periventricular white matter is thought to be more susceptible to hypoperfusion since it is located at the boundary between separate arterial territories¹⁸ (Fig. 2). Supporting this hypothesis, CBF is reduced in normal appearing periventricular white matter of patients with leukoaraiosis³⁸ and hypoxia inducible genes are expressed in white matter lesions³⁹. Endothelial dysfunction and BBB alterations produced by HTN could cause leakage of plasma proteins leading to oxidative stress, inflammation and edema, which compresses the tissue and contributes to hypoperfusion and demyelination³⁶. Hypoxia could induce production of metalloproteases in oligodendrocyte precursors contributing to the BBB opening^{31, 40, 41}.

Microinfarcts

SVD is also associated with ischemic lesions not visible to the naked eyes (microinfarcts)⁴². Cerebral microinfarcts are small infarcts (<1mm diameter) thought to be very common in the elderly, although their detection in vivo is challenging due to their small size⁴². It is estimated that 1 or 2 microinfarcts in routine postmortem examination suggests the presence of hundreds of microinfarcts throughout the brain⁴³. Microinfarcts are common in patients with vascular or mixed dementia, but are an independent predictor of VCI⁴². Number and the location of the microinfarcts are major determinants of cognitive dysfunction, the cortical location being more closely associated with dementia⁴².

Cerebral microbleeds and macrobleeds

SVD also produces hemorrhagic manifestations. Cerebral microbleeds are small perivascular hemorrages (2–10 mm) that can be detected histologically at autopsy or in vivo using iron-sensitive MRI sequences⁴⁴. Microbleeds, which are observed in 10–20% of the elderly often in association with other SVD pathologies, are an independent predictor of cognitive decline⁴⁴. HTN is a major risk factor of microbleeds, which in this condition are typically located in the basal ganglia, thalamus, brainstem and cerebellum⁴⁵. Microbleeds are frequently associated also with cerebral amyloid angiopathy, but in this case they tend to have a lobar distribution⁴⁴. HTN is well known to cause large cerebral hemorrhages, typically in the basal ganglia or thalamus (Fig. 2). The relationship between microbleeds and cerebral hemorrhages is not entirely clear, but microbleeds are associated with an increased risk of brain hemorrhage⁴⁶.

HTN AND ALZHEIMER’S DISEASE

AD and VCI are, respectively, the first and second most common cause of dementia in the elderly³. Although traditionally considered separate pathologies, increasing evidence indicate that AD and VCI share common pathogenetic mechanisms¹⁶. Vascular risk factors, such as HTN, smoking, hyperlipidemia and diabetes, are also risk factors for AD¹⁶. In particular, midlife HTN doubles the risk of AD later in life and accelerates the progression of the dementia⁴⁷. Up to 50% of cases of dementia have mixed pathology featuring both vascular (SVD) and neurodegenerative lesions (amyloid plaques and neurofibrillary tangles)⁴⁸. Several studies have shown that HTN-induced lesions and AD may have an additive or synergistic effect and produce a more severe cognitive impairment than either process alone¹⁶.

Several post-mortem studies have also reported more atherosclerosis in cerebral vessels of AD patients compared with non-demented controls, a finding associated with increased amyloid plaques and neurofibrillary tangles^{49, 50}. Furthermore, an increased amount of amyloid plaques and neurofibrillary tangles have been reported in the brain of hypertensive patients⁵¹. β-amyloid (Aβ), a peptide involved in the pathogenesis of AD, is elevated in the blood of patients with VCI and could potentially contribute to vascular insufficiency and white matter injury^{52, 53}. Furthermore, increases in diastolic blood pressure in midlife are linked to an increase in AD risk and to a reduction in plasma Aβ decades later⁵⁴, suggesting that the vascular dysfunction induced by HTN may inhibit the vascular transport of brain Aβ into the plasma. HTN interacts with Apoε4 to promote amyloid deposition in healthy individuals, suggesting an interaction between vascular and genetic factors in increasing the susceptibility to AD⁵¹. Patients with HTN and elevated AD biomarkers have increased gray matter atrophy, suggesting that HTN may exacerbate gray matter damage in AD⁵⁵.

Experimental studies also support an interaction between HTN and Aβ. In mouse models of AD, Aβ attenuates functional hyperemia and endothelium-dependent vasodilatation through mechanisms involving Nox2-derived ROS^56–58. However, unlike AngII, the vascular effects of Aβ require the scavenger receptor and Aβ “receptor” CD36⁵⁹. It is conceivable that hypertension and Aβ have an additive or synergistic pathogenic effect on cerebrovascular function. Consistent with this hypothesis, brain deposition of Aβ is increased in hypertensive mice⁶⁰, an effect attributed to inhibition of the perivascular and transvascular clearance of Aβ secondary to vascular dysfunction and damage (Fig. 3). HTN may also facilitate the transfer of Aβ from blood to brain through the receptor for advanced glycation products (RAGE)⁶¹. Cerebral hypoxia-ischemia, which can occur with HTN, can also facilitate β-secretase-mediated cleavage of β-amyloid from its precursor protein and increases the brain Aβ burden^{62, 63}.

Figure 3. Interaction between HTN and AD.

HTN increases the deposition of Aβ and might aggravate the cerebrovascular dysfunction induced by Aβ. HTN could impair the vascular clearance of Aβ and increase its cleavage from the amyloid precursor protein (APP). Both of these effects would lead to increased Aβ concentration in the brain parenchyma and blood vessels, aggravating the attendant vascular and synaptic dysfunction.

These observations, collectively, suggest that HTN may promote the development of AD through several mechanisms (Fig. 3). First, HTN could impair the vascular clearance of the peptide, enhancing Aβ accumulation in brain and vessels. Second, HTN could increase the cleavage of Aβ from the amyloid precursor protein. Both of these effects would lead to increased Aβ concentration in the brain parenchyma and blood vessels, aggravating the attendant vascular and synaptic dysfunction. Speculations aside, our understanding of human HTN and AD is far from complete and, consequently, the relationship between these two conditions is even less well understood. Nevertheless, since the pathological processes underlying AD starts decades before their clinical manifestation⁶⁴, HTN is likely to exert its effects in the presymptomatic phase of the disease, stressing the need for early diagnosis and therapy.

Treatment of HTN and prevention of stroke and dementia

The National High Blood Pressure Education Program (NHBPEP) of the National Heart Lung and Blood Institute, introduced over 40 yrs ago, has led to remarkable advances in the public awareness and treatment of HTN. This highly successful program is credited with a 70–80% reduction in the morbidity attributable to HTN, mainly heart attacks and strokes¹. The effect of HTN control on the incidence of stroke is indeed substantial, and for each 10 mm Hg decrease in systolic blood pressure, there has been a 1/3 decrease in stroke risk².

The effects of HTN treatment on VCI have been more difficult to assess⁶⁵, and there is still a debate as to whether HTN control leads to a better cognitive outcome, e.g., refs^{10, 65}, except for the prevention of post-stroke dementia³. Some studies have shown a cognitive benefit from blood pressure lowering especially in the younger of the old, e.g., PROGRESS, HYVET, SHEP, SYST-EUR, whereas other studies have not, e.g., SCOPE, ADVANCE, PRoFESS (see ref.^{10, 65} for a review). No specific class of anti-hypertensive agents has been consistently found to be more effective³. Limitations of all these studies have been short follow up, low rates of incident dementia, lack of accounting for co-treatments, and heterogeneity of the cognitive assessment, among others^{3, 65}. Despite the controversy, a recent American Heart Association statement strongly recommends blood pressure lowering in patients who have suffered a stroke (Class I, level of evidence level B), and encourages treatment in the younger of the elderly (Class IIa, level of evidence B)³. The degree of blood pressure lowering remains uncertain, but there is evidence that more aggressive lowering may lead to a greater improvement in cerebral perfusion¹⁷. The blood pressure threshold for starting treatment remains to be defined. Data from the Honolulu Heart Program/Honolulu Asian Aging Study suggest that 17% of late-life dementia cases are attributable to midlife systolic pressure levels between 120 and 140 mm Hg⁶⁶. Similarly, a progressive cognitive decline has been reported for blood pressures between 120–140mmHg⁶⁷, arguing for starting treatment at pre-hypertensive blood pressure levels.

Treatments targeting oxidative stress have long been considered to treat HTN and related complications⁶⁸, but it has been difficult to develop agents that cross the BBB and effectively reduce oxidative stress in brain⁶⁹. Similarly, epidemiological studies have not shown a beneficial impact of dietary antioxidants on late life dementia, e.g., ref⁷⁰. NADPH oxidase inhibitors would be valuable and there is great interest in developing agents that could be used for cardiovascular and brain diseases⁶⁹. On the other hand, the link between HTN and AD provides clues to potential therapeutic interventions that could benefit both diseases. Calcium-channel antagonists and inhibitors of the renin-angiotensin system increase Aβ removal from the brain and protect against cognitive dysfunction in mouse models^{71, 72}. The renin-angiotensin system has been of particular interest in light of the observation that angiotensin converting enzyme activity is increased in patients with AD and that this enzyme may degrade Aβ, but there are many unresolved issues⁷². Nevertheless, these preclinical observations raise the possibility of using specific blood pressure lowering agents in patients with HTN at risk for AD. Furthermore, dietary interventions and exercise have been shown to be promising, and would also be valuable as a primary or adjuvant therapeutic approach⁷³.

Conclusions

The evidence reviewed in this article indicates that HTN, despite resounding successes in controlling its impact on morbidity and mortality, remains one of most pervasive and devastating diseases with broad consequences for worldwide health. HTN has profound effects on the brain and contributes in a substantive manner to stroke and dementia, highly prevalent diseases projected to have an even greater public heath impact in decades to come due to population aging. Large and small cerebral vessels have emerged as key targets of HTN, resulting in pathological alteration of the vascular wall, impairment of vital hemodynamic responses regulating cerebral perfusion, and disruption of BBB permeability leading to major alterations in the brain microenvironment. Although oxidative stress and inflammation are important factors in the pathogenesis of these events, the cellular and molecular bases of the susceptibility of the white matter to HTN and other cerebrovascular risk factors have not been fully elucidated and represent a fruitful area of future research. The vascular changes induced by HTN not only increase the susceptibility of the brain to ischemic-hypoxic damage in vulnerable white matter regions, but also promote the expression of AD neuropathology. The realization that HTN has an impact on AD represents a major departure from traditional views on the pathogenesis of AD, a disease in which vascular factors were thought not to play a role¹⁶. However, our understanding of the interaction of HTN with AD is rudimentary at best, and much needs to be learned on the vascular biology of their respective effects on the cerebral vasculature and resulting cognitive impact. While current approaches to treat hypertension have dramatically reduced stroke incidence and mortality, the role of blood pressure control in the prevention of late life dementia has been more difficult to assess. Questions remain on the blood pressure threshold for therapy initiation, length of treatment and the blood pressure reduction needed to maximize benefits and reduce risks. Whatever the impact on cognition, however, the great benefits for general health afforded by blood pressure control justify early and aggressive intervention. Non-pharmacological strategies based on diet and exercise may be particularly valuable in younger patients facing treatment for a lifetime.