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Published in final edited form as: Alzheimers Dement. 2022 Nov 19;19(2):671–695. doi: 10.1002/alz.12871

Hypertension and Hyperhomocysteinemia as Modifiable Risk Factors for Alzheimer’s disease and dementia: new evidence, potential therapeutic strategies and biomarkers

Ashley Carey 1, Silvia Fossati 1
PMCID: PMC9931659  NIHMSID: NIHMS1846268  PMID: 36401868

Abstract

This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate AD and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class’s effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of preventive strategies.

Keywords: cardiovascular risk, hypertension, hyperhomocysteinemia, dementia, Alzheimer’s disease, prevention, biomarkers, therapeutic strategies, cerebrovascular dysfunction

Introduction

As the aging population exponentially grows, the prevalence and severity of dementias continues to rise (2022 Alzheimer’s Disease Facts and Figures). Although a vast array of neurodegenerative diseases exists, a common neurobiological thread underlies many neurodegenerative disorders, namely progressive degenerative death of neurons and loss of synaptic connections, ultimately leading to some degree of cognitive impairment and in some cases dementia. The neuronal degeneration and synaptic loss associated with multiple types of dementias, including Alzheimer’s Disease (AD), clinically manifests in cognitive impairments, such as memory loss, speech and communication deficits, reduced capacity to organize, plan, and reason, difficulty completing complex tasks, confusion, disorientation, agnosia, as well as psychological challenges, such as personality and behavior changes, depression, anxiety, hallucinations, mood swings, and apathy1. As these symptoms progress, dementia patients progressively lose independence and heavily rely on caregivers, highlighting the heavy caregiving and financial burden that dementia imposes on society. Cases of dementia are estimated to rapidly increase within the coming years due to the aging of the baby-boomer generation and the lack of a cure1. The number of Americans age 65 and older is predicted to double from 52 million in 2018 to 95 million by 2060, representing a potentially substantial social and economic burden and demonstrating the need for more research to help understand the underlying molecular mechanisms and contributions to dementia pathology and risk in order to develop better treatments and more preventative strategies1,2.

In recent years, dementia, more specifically AD, is being recognized more and more as a multi-factorial disorder or syndrome, with the presence of multiple concurrent pathological events leading to loss of optimal neuronal functioning and the development of cognitive impairment. Among these events, cerebral vascular dysfunction, which also results in the reduction of brain oxygen and glucose supplies, has been recognized as one of the earliest pathological features found in the majority of AD patients. Today we know that mixed pathology dementias account for more than half of the total cases, with amyloidosis and vascular disease being the most frequent combination28. Interestingly, it has been recognized that patients with mixed vascular and AD pathologies have nearly twice the incremental risk of dementia compared with patients with only AD-type lesions9. The cerebral vasculature acts as a neuronal lifeline, providing vital metabolites and nutrients required for proper neuronal functioning. Cerebrovascular insults not only negatively affect the cerebral vasculature but every other cell comprising the neurovascular unit, including neurons and glial cells, leading to impairments in major brain functions. Therefore, shifting the focus of AD and dementia research from disease hallmark lesions such as amyloid-beta (Aβ) and tau to studying the contribution of other factors, such as cardiovascular risk factors, and the specific mechanisms through which each cardiovascular risk factor promotes cognitive decline and disease onset is a pressing issue for the research community1013. If specific vascular risk factors can be linked to defined aspects of dementia pathology and the molecular mechanisms through which these risk factors promote dementia-related neurodegeneration can be clarified, preventative medicine will be able screen for these factors or mechanisms earlier in time and combat them before they can facilitate the pathological progression of dementia. Currently, treatment options for dementia are limited to purely conducting damage control on amyloid pathology and managing symptomology. A game changer for dementia treatment would be identifying risk factors that emerge during midlife, the prodromal phase of dementia where pathology begins to accumulate, thus allowing to significantly prevent dementia onset or intervene with early multifactorial disease-modifying treatment strategies. The overall goal and hypothesis of this review is that cardiovascular risk factors, specifically hypertension and hyperhomocysteinemia, can themselves promote dementia pathology as well as potentiate the effects of Aβ and tau, eventually resulting in neurovascular unit failure, neuronal death and synaptic dysfunction, and ultimately in the development of cognitive decline and dementia. The content of this review is based on a literature search conducted on PubMed and Google Scholar utilizing the following key words: “Cardiovascular Risk Factors and AD/Dementia Risk/Pathology”, “Hypertension and AD/Dementia Risk”, “Hyperhomocysteinemia and AD/Dementia Risk”, “Hyperhomocysteinemia and Hypertension Risk”, “Sex Differences and Hypertension-Induced AD/Dementia Risk”, “α-Adrenergic Drugs and AD/Dementia Risk/Pathology”, “β-Blockers and AD/Dementia Risk/Pathology”, “Angiotensin Converting Enzyme Inhibitors and AD/Dementia Risk/Pathology”, “Angiotensin Receptor Blockers and AD/Dementia Risk/Pathology”, “Diuretics and AD/Dementia Risk/Pathology”, “Carbonic Anhydrase Inhibitors and AD/Dementia Risk/Pathology”, “Vitamin Supplementation and AD Risk/Pathology”, “Vascular Dementia Biomarkers”, “Hypertension Biomarkers”, and “Hyperhomocysteinemia Biomarkers”.

Alzheimer’s Disease, Mixed Vascular Dementias, and Cerebral Amyloid Angiopathy

Alzheimer’s Disease (AD) is an extremely prevalent neurodegenerative disease and the most common form of age associated dementia, currently affecting approximately 5.8 million individuals in the United States14. Pathological hallmarks of AD include intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau, parenchymal amyloid beta (Aβ) plaques enriched in the Aβ42 species, vascular Aβ deposits enriched in Aβ40, cerebrovascular dysfunction, cerebral atrophy, synaptic loss and neuronal death, all resulting in cognitive impairment15. AD is clinically characterized by progressive loss of memory and cognitive functioning, with early symptoms including difficulty recalling recent conversations, event or names. As pathology progresses, patients develop impaired communication skills, confusion, behavioral changes, poor judgement, and often experience passiveness and depression1,3.

Increasing evidence has emerged to suggest that AD is a multi-factorial disease, with several simultaneous pathological events working in conjunction with Aβ and tau in order to produce cerebral pathology and, ultimately, cognitive decline. In particular, a growing number of studies implicate cerebrovascular disturbances as substantial players in AD onset. Indeed, cerebral vascular dysfunction has begun to be acknowledged as one of the earliest pathological features found in most AD patients15,16. It is widely accepted that more than half of total cases of dementia consist of mixed pathology dementias, with the most common combination being amyloidosis and vascular disease17. Individuals revealing mixed vascular and AD pathologies have almost twice the dementia risk as those with only AD-type lesions16, demonstrating the importance of considering vascular factors as major contributors to AD risk and pathology. In fact, a recent NIA study conducting autopsies on AD patients revealed that 54% had coexisting pathologies in addition to hallmark AD brain changes, with the most common coexisting abnormality being undetected blood clots and other evidence of vascular disease17. Neuropathological studies have demonstrated that Mixed Vascular-Alzheimer’s Dementia (MVAD) is a typical pathological finding within the aging population, with a 22% prevalence18. Brain autopsy studies conducted by the NIA utilizing samples from individuals diagnosed with dementia have demonstrated that most patients 80 years of age and beyond likely had mixed dementia including AD-related neurodegeneration, vascular disease-related processes, or other conditions involving neurodegeneration14. Moreover, multiple studies propose that the most frequent cause of dementia within the aging population is mixed vascular-degenerative dementia14 [The Dementias: Hope Through Research (NIH.gov)].

A major contributor to cerebrovascular dysfunction in AD is Cerebral Amyloid Angiopathy (CAA), defined as the deposition of Aβ specifically at the brain vasculature19. CAA has become increasingly recognized as a major component in the pathology of AD, being evident in approximately 85–95% of AD patients19,20, and is also frequently found in non-demented elderly people21. In fact, an aging study conducted autopsies of 1079 deceased patients (mean death age= 89.7 years) and demonstrated that 36% of patients exhibited some level of CAA pathology22. Aβ40 is the most abundant peptide in vascular deposits2326. Certain Aβ40 variants, such as the Dutch mutant (Aβ40E22Q) which contains a Glutamic acid to Glutamine mutation at amino acid 22 and corresponds to a human familial disorder within the Dutch population manifesting as early onset CAA, cerebral hemorrhages, strokes, and cognitive dysfunction, have been shown to induce accelerated endothelial cell dysfunction and cerebral vascular pathology, as they are significantly more aggregation-prone than the Aβ40-WT peptide2632. Cerebrovascular Aβ deposits contribute to increased blood brain barrier (BBB) permeability and heightened incidents of microhemorrhages, leading to leakage of neurotoxic proteins and infiltration of blood-borne peripheral immune cells from the cerebral blood vessels into the brain parenchyma, causing high levels of neuroinflammation and dysfunction of the neurovascular unit33,34. CAA has been found to disrupt cerebral capillaries as well as small and medium diameter arteries and arterioles, which leads to focal ischemia, decreased cerebral blood flow, and subsequent neuronal death35. Proper neuronal function relies greatly on adequate cerebral perfusion to deliver oxygen and required nutrients, like glucose, to the brain and when cerebral blood flow is disrupted due to pathology like AD and CAA, neurons are particularly sensitive to the resulting oxygen and glucose deprivation19,36,37.

Contribution of Cardiovascular Risk Factors to AD Onset and Pathology

Due to the emerging evidence suggesting that cerebrovascular dysfunction plays a prominent role in AD pathology, many studies have begun to investigate the relationship between cardiovascular diseases and the pathological conditions associated with AD. Studies within the last decade have suggested that cardiovascular risk factors, including hyperhomocysteinemia (Hhcy), hypertension, atherosclerosis, and others3841, can exacerbate AD pathology and can increase individuals’ risk for developing AD. A study published in 2022 has revealed that a rapidly progressing cardiovascular risk trajectory anticipated an increased AD and vascular dementia risk, as well as increased memory decline risk, while a stable or controlled cardiovascular risk trajectory was able to partially alleviate this correlation42. Vascular aging and cardiovascular risk factors lead to cerebral endothelial dysfunction and thus cerebral hypoperfusion, which may be an early contributor to AD pathology43. Importantly, stroke and dementia confer risks for each other and many of the same, often modifiable, risk factors, protective factors, and molecular mechanisms, are shared between these 2 diseases44. Cerebral hypoperfusion induces a metabolic energy crisis, leading to a cascade of events that compromises many cells composing the neurovascular unit, including neurons, and increases oxidative stress and neuroinflammation45. Dysfunction of neuronal metabolism has also been found to upregulate the expression of β-secretase, which is an enzyme involved in the cleavage of the amyloid precursor protein (APP) to form amyloidogenic Aβ species, thus exacerbating Aβ accumulation and deposition46. It is also known that Aβ deposition can contribute to endothelial dysfunction and damage, particularly causing vasoconstriction and disrupting endothelial barrier integrity, which can further induce cerebral blood flow reduction19. Recently, cerebral hypoperfusion and ischemia have also been shown to promote neuroinflammation and increase pro-inflammatory cytokines through NLRP3 and AIM2 inflammasome upregulation in microglia and astrocytes47. Endothelial dysfunction, oxidative stress, and high levels of neuroinflammation compromise the integrity of the BBB, also impeding Aβ clearance and leading to more Aβ accumulation. Although the exact chronology of the AD timeline remains unclear, it is apparent that dysfunction of the BBB triggers an extremely damaging cycle, where cerebral perfusion progressively gets more impaired, leading to further exacerbation of neurodegenerative processes43. This review focuses on the contributions of hypertension and Hhcy to the risk of developing AD and mixed dementia syndromes, as well as on their ability to precipitate cognitive dysfunction. Improving this knowledge will help to identify possible early biomarkers and preventive therapies that could be applied at the prodromal asymptomatic phase of the disease, before cognitive symptoms arise.

Hypertension and AD risk

Hypertension has gained increasing recognition as a risk factor for AD development and several studies have demonstrated that midlife hypertension specifically contributes to AD pathology. Hypertension can arise from abnormalities in both systolic and diastolic blood pressure. Systolic blood pressure represents the amount of pressure blood exerts against the artery walls as the heart is beating (normal range < 120 mmHg), while diastolic blood pressure is a measure of the amount of pressure blood exerts against the artery walls while the heart is at rest between beats (normal range < 80 mmHg)48.

Recent evidence has emerged suggesting a relationship specifically between elevated systolic blood pressure and increased risk for AD and cognitive impairment. The Honolulu-Asia Aging Study has demonstrated an association between elevated midlife systolic blood pressure and increased risk of cognitive dysfunction, revealing that individuals with midlife systolic blood pressure > 140 mmHg have a 1.77 times higher risk for developing dementia later in life49. A recent meta-analysis similarly revealed that a relationship exists between systolic hypertension, when systolic blood pressure is > 160 mmHg, and AD risk, while diastolic hypertension was not significantly associated with AD risk50. A longitudinal study from the “Whitehall II Cohort” has also demonstrated that systolic blood pressure ≥ 130 mmHg during midlife (age 50), but not in late-life, was associated with higher incidence of dementia, while high diastolic blood pressure did not reveal this relationship51. This study also indicated that the longer the time individuals exhibited systolic hypertension in midlife, the further their AD risk increased51. A study conducted in 2021 demonstrated that high resting heart rate (≥80 bpm), which is highly associated with hypertension, corresponded to a higher risk of dementia as well as accelerated progression of cognitive decline in an aging population52. Another recent longitudinal study has revealed that longer duration of hypertension during early adulthood corresponded to weakened verbal memory performance during midlife, demonstrating hypertension as a risk factor for cognitive decline53. It was also shown that systolic blood pressure is negatively associated with blood flow in the cortex as well as specifically in the hippocampus, with a decrease in cortical and hippocampal perfusion as systolic blood pressure increases54. Interestingly, this study found that individuals with hypertension also experience this trend, but there seems to be an optimal mid-range systolic blood pressure that allows perfusion to be maximized and this should be further explored54.

Ample evidence has shown that late-life hypotension is also a risk factor for the development of AD pathology. A recent meta-analysis comparing 138 publications has found no significant association between late-life hypertension and AD risk, but rather late-life hypotension and low diastolic blood pressure were associated with greater risk for the development of AD and cognitive impairment55. Surprisingly, this study revealed that slightly elevated diastolic blood pressure later in life, specifically between the range of 90–100 mmHg, reduces risk for dementia by 23% in individuals included in the studies analyzed55. Additionally, it has been demonstrated that a longitudinal decrease in mean arterial pressure was associated with memory decline and increase in phosphorylated tau, but only in participants that started the study with hypertension, suggesting that hypertension can prime individuals to be more sensitive to the negative effects of late-life hypotension, a common phenomenon in the aging population56. High blood pressure variability has also been implicated as a risk for AD and cognitive decline. The “Three-City Study” conducted in 2014 demonstrated that individuals with higher variability in their systolic blood pressure measurements had higher risk for AD57. Another study analyzing visit-to-visit variability in blood pressure revealed that higher blood pressure variability was associated with increased cognitive impairment, indicated by worse outcomes on the Mini-Mental State Examination (MMSE)58. An even more recent study revealed an association between high systolic blood pressure variability and white matter integrity loss59. Interestingly, the correlation between blood pressure variability and the integrity of cerebral white matter was significant stronger in individuals with CAA pathology and CAA patients with higher blood pressure variability demonstrated progressively worse executive function59. All these studies demonstrate a clear relationship between blood pressure and dementia risk, but future studies are needed in order to dissect the specific mechanisms by which midlife hypertension or late-life hypotension cause or exacerbate AD and CAA pathology, as well as the direct relationship between high, low or variable blood pressure and cerebrovascular risk.

Hyperhomocystenemia and AD Risk

In addition to hypertension, another major cardiovascular risk factor that has been implicated as a contributor to AD pathology and risk is Hhcy. Hhcy is a disorder involving excess plasma homocysteine (Hcy) levels due to Hcy metabolism disruption typically caused by low folate and vitamin B12 and B6 levels, which are needed to metabolize Hcy, and/or high methionine levels, which is the precursor to Hcy60. Hhcy is prevalent in 5–7% of the US population, with prevalence increasing with age60. Hhcy is gaining more attention as a major risk factor for AD and vascular dementia, being found to promote similar dementia-associated pathologies as hypertension, such as oxidative stress, vascular inflammation, and endothelial cell dysfunction6163. A study conducted in 2018 demonstrated that AD patients had elevated serum Hcy levels when compared to control subjects64. In a recent meta-analysis, it was demonstrated that AD, as well as dementia and vascular dementia patients exhibit elevated plasma Hcy levels when compared to non-demented individuals65. It was also recently demonstrated that even patients with mild cognitive impairment (MCI) show higher Hcy levels compared to control subjects66,67. Levels of Hcy have also recently been found to correlate with dementia severity. Individuals with moderate to severe dementia had higher Hcy levels compared to patients with MCI or mild dementia66.

Recent meta-analyses and longitudinal aging studies have further solidified evidence that high plasma or serum Hcy levels and the often-associated deficiencies in folate as well as vitamin B6 and B12 significantly contribute to increased AD risk and AD-associated pathology and cognitive decline. Many current studies have provided further evidence that elevation of Hcy levels corresponds to increased risk for AD and other types of dementia68,69. A meta-analysis conducted in 2019 has demonstrated that a linear relationship exists between Hcy levels in the blood and AD risk, with risk increasing for every 5 μmol/L increase in Hcy69. Another study has similarly demonstrated that increased plasma Hcy was correlated with increased dementia, AD, and vascular dementia risk, with each 5 μmol/L increase in plasma Hcy specifically increasing dementia risk by 9% and AD risk by 12%65. An additional study recently published also revealed that older individuals with elevated serum Hcy (≥10.6 μmol/L) were 4–5 times more at risk for dementia and AD development versus those with normal serum Hcy (9.0–10.5 μmol/L)70. Interestingly, this same study has revealed that elderly individuals with low serum Hcy (≤8.9 μmol/L) are also 4–5 times more likely to develop dementia and AD compared to those with normal serum Hcy levels70. This is extremely similar to the chronological risk that blood pressure levels have on the likelihood of dementia development, as hypertension and hypotension have both been found to increase dementia risk, but only when they are present at certain periods of an individual’s life, being midlife and late life, respectively. In general, a correlation between elevated serum Hcy levels and the cognitive, behavioral, and psychological symptoms of AD has been established64. A study analyzing the cognitive abilities of AD patients has demonstrated that elevated Hcy is associated with impairment of memory, especially short and long-term spatial and verbal memory, and motor planning71. Another study additionally demonstrated that higher Hcy levels lead to worsened neuropsychiatric symptom and functional impairment severity, as well as more severe and frequent cognitive impairment in AD and vascular dementia66.

As previously mentioned, abnormalities within bodily concentrations of vitamins and metabolites required for Hcy production and metabolism have been found in dementia patients and these abnormalities have also been implicated to promote cognitive decline and increase dementia risk. A study conducted in 2021, found reduced serum Vitamin B6, B12, and folate levels in AD patients compared to normal age-matched controls67. Similarly, a study conducted within the Chinese population has revealed that patients with AD have reduced serum Vitamin B2, B9, B12, D, and E levels versus controls, with specifically vitamin B12 deficiency being highly associated with elevated AD risk72. Despite this, conflicting results were revealed by Soni et al. 2018, which found no differences in Vitamin B12 and folate levels between AD and control patients, but this study lacked a large population of patients and also would have benefited from being conducted in a more longitudinal manner64. Another recent study has also shown that elevations in methionine levels, the precursor to Hcy and often the metabolite that Hcy is broken back down into, correlated with decreased dementia risk68. Specifically, this study showed that an increased methionine to Hcy ratio was associated with lower AD and dementia risk, as well as a diminished rate of brain tissue volume loss68. Interestingly, a longitudinal aging study recently published has demonstrated that low plasma folate levels in individuals 50 years or older was correlated with faster cognitive decline73. Plasma folate levels <21.8 nmol/L were associated with episodic memory impairment, while plasma folate levels <11.2 nmol/L corresponded to overall global cognitive function decline73.

Additionally, there a several studies conducted in vivo in animal models demonstrating the Hhcy promotes AD and CAA pathology, particularly increased Aβ accumulation, tau phosphorylation, neuroinflammation, BBB permeability and microhemorrhages, cerebral blood flow deficits and cognitive impairment7481. Overall, these studies convey convincing evidence that Hhcy is a major cardiovascular risk factor that potentiates dementia risk and pathogenesis, yet the causality of these effects and the molecular mechanisms linking Hhcy’s to increased AD risk and pathology require further investigation. Interestingly, a recent study demonstrated that Hcy has the ability to self-assemble into amyloid-like toxic fibrils, which can seed the aggregation of Aβ1–42 and increase intracellular amyloid staining in a yeast model82. These results open a new avenue, suggesting that metabolites, such as Hcy, can self-assemble and cross-seed the aggregation of pathological proteins, such as Aβ, providing a possible mechanistic explanation for the increased AD risk.

Hyperhomocystenemia as a Risk Factor for Hypertension

Hcy has also been found to impact blood pressure and promote hypertension due to its strong vascular effects, namely through increasing arterial stiffness and promoting vasodilatory impairment83,84. A very early study has concluded that elevated Hcy levels are significantly associated with isolated systolic hypertension within older adults85. Another early study has demonstrated that every ~5 μmol/L increase in Hcy is associated with a 0.5 mmHg diastolic blood pressure increase and a 0.7 mmHg systolic blood pressure increase in men, while women demonstrated a 0.7 mmHg increase in diastolic blood pressure and a 1.2 mmHg increase in systolic blood pressure86. This study also demonstrated that increased bodily Hcy levels are associated with increased hypertension risk, with men having a two-fold risk increase and women having a three-fold risk increase, demonstrating an increased vulnerability of the female sex86. A more recent study specifically demonstrated that 1 lnHcy (log transformation of tHcy level) was associated with a 3.78 mmHg systolic blood pressure increase and a 3.02 mmHg diastolic blood pressure increase87. Another study conducted in the Chinese population showed that a 5 μmol/L increase in tHcy corresponded to a ~0.445 mmHg increase in systolic blood pressure and a ~0.215 increase in diastolic blood pressure88. This study also concluded that the incidence of hypertension was far more apparent in individuals with tHcy levels ≥ 15 μmol/l, with this trend being more evident in women compared to men88, although this was contradicted by a different study, which found higher risk in men89. Other studies conducted within the Chinese population, including Yang et al., 2017, revealed that increased Hcy levels corresponded to increased blood pressure and elevated hypertension risk90. A follow up study, Yang et al., 2018, more specifically found that both systolic and diastolic blood pressure were significantly increased in individuals from the general Chinese adult population with tHcy levels greater than 10 μmol/L91. When considering the prevalence of Hhcy and hypertension comorbidity, a study conducted in 2019 demonstrated that 44.7% of patients in this study that exhibited hypertension also had Hhcy92. Even more recent data demonstrated that out of a population of hypertensive patients, 36.1% comorbidly exhibited Hhcy, with Hcy levels within the serum averaging 14.1 μmol/L93. It has also been shown that following ischemic stroke, patients with hypertension and Hhcy most prevalently exhibited early cognitive impairment, specifically decreased visual space and executive scores and decreased delayed recall scores, compared to post-stroke patients with hypertension or Hhcy alone94.

Common Cellular Mechanisms

Hypertension has been found to affect both the structural integrity as well as the function of cerebrovascular endothelial cells. Hypertrophy and remodeling of cerebrovascular vessels and increased media-to-lumen ratio has been found under conditions of hypertension, attributed to enlargement of vascular smooth muscle cells and build-up of extracellular matrix proteins inside the walls of cerebral vessels95,96. Hypertension is also a major factor involved in the development of atherosclerosis, which can occur intracranially, and atherosclerotic plaques can narrow the diameter of cerebral vessels, contributing to reductions in cerebral blood flow19. Atherosclerotic plaques often will rupture leading to thrombosis of the vessel, which can cause cerebral vascular occlusion, further disrupting cerebral blood flow19. In addition to structural changes, endothelial dilatory function has been found to be impaired due to hypertensive pathology in mouse models of AD. Cerebral vessels isolated from APP/PS1 AD mice with high systolic blood pressure had impairments of endothelial dilatory function in response to acetylcholine compared to vessels from wild-type mice and had exacerbated impairments compared to vessels from APP/PS1 mice with normal blood pressure ranges97. It is also known that hypertension decreases nitric oxide (NO) bioavailability and thus impairs NO-mediated vasodilatory functions of endothelial cells, which can contribute to increased vasoconstriction of vessels98. Increased systolic blood pressure in APP/PS1 mice was also found to contribute to decreased barrier function of cerebral endothelial cells, due to decreased expression of endothelial tight junction proteins such as Occludin, ZO-1, and Claudin-5, as well as increased instances of cerebral endothelial cell death97.

These hypertension-induced changes in structure and function of cerebrovascular endothelial cells promote impairment of cerebral blood flow autoregulation, increased BBB permeability, increased presence of microhemorrhages, and decreased cerebral micro-vessel density, which can lead to hypoperfusion and promote an ischemic cerebral environment that may contribute to AD pathology19. A major pathological issue for hypertensive patients is the loss of proper cerebral autoregulation, which helps sustain cerebral homeostasis by maintaining cerebral perfusion constant despite changes in peripheral blood pressure levels99,100. Loss of cerebral autoregulation elevates transmission pressure to the cerebral capillaries, which has been found to cause loss of BBB integrity, cerebral edema, and neuroinflammation101. Hypertensive patients experience a shift within their cerebral blood flow regulation limits, causing an increase in both the lower and upper limits of blood flow regulation56,99,102. When the lower limit of autoregulation corresponds to a higher blood pressure level, cerebral hypoperfusion is established at significantly higher blood pressure levels compared to individuals with normal blood pressure56,99,102. The resulting ischemic cerebral environment can lead to a neuronal energy crisis due to the lack of nutrient and oxygen availability and thus the inability to meet the high energy demands required to sustain proper neuronal function103, as well as neurovascular uncoupling and neuronal damage due to increases in neuroinflammation, reactive oxygen species and calcium influx, which can increase individual’s risk for AD15,104,105. Hypertension has also been found to increase Aβ deposition possibly through increased amyloidogenic processing of the APP through β-secretase or due to decreased clearance function resulting from BBB dysfunction95,106. Due to the evidence suggesting that midlife hypertension can contribute to increased risk of AD and promote the progression of AD pathology, utilizing anti-hypertensive drugs to reduce the incidence of midlife hypertension can be a promising intervention to decrease the development of AD and cognitive decline later in life.

Sex Differences in Hypertension Induced AD Risk

Following age, female sex is the second greatest AD risk factor, with two-thirds of late-onset AD patients being women107109. Women not only have increased AD risk, but more severe pathology and exacerbated disease progression compared to men110. Due to this, it is important to consider whether there are sex differences in hypertension as a risk factor for dementia in order to create more targeted preventive strategies111. One of the early studies that has demonstrated that vascular risk factors increase dementia risk differentially depending on sex has revealed that hypertension correlated to increased vascular dementia risk only within women112. Recently, more evidence has backed these early findings up. A study conducted in 2021 has revealed that midlife hypertension correlated with a 65% increased risk for dementia exclusively in women113. Additionally, this study demonstrated that the hypertension during midlife resulted in a 73% elevated risk of dementia in women, but this was not evident in men113. Other recent studies demonstrated that elevation of systolic blood pressure correlated with increased dementia risk exclusively in women114, and that midlife hypertension was correlated with memory decline specifically in women115. Interestingly, diastolic blood pressure levels were significantly correlated with decreased dementia risk in men, but this was not evident in women114. When compared to normotensive individuals, men in varying hypertension stages had lower dementia risk, but dementia risk increased with worsened hypertension stages in women and midlife high blood pressure had a dose-response relation to increased dementia (including vascular dementia and AD) risk in women, but not in men114. A study conducted in 2022 specifically within a cohort of women demonstrated that increased systolic blood pressure and pulse pressure correlated with a significant increase in MCI risk and cognitive performance116. Overall, these studies point to a higher susceptibility of the female sex to the effects of midlife hypertension on increasing the risk for AD and dementia.

Molecular Mediators and Possible Effective Pharmacological Treatments

Adrenergic Receptors and Control of Blood Pressure

α1-adrenergic receptors are located predominantly on smooth muscle cells within blood vessels117,118. These adrenergic receptors are coupled to Gq proteins which stimulate Phospholipase C, leading to increased release of intracellular calcium and eventually the activation of Protein Kinase C, causing a downstream protein phosphorylation cascade117. Activation of α1-adrenergic receptors leads to contraction of smooth muscle and vessel vasoconstriction, which if overactivated can lead to hypertension117,119. α2-adrenergic receptors, which are coupled to inhibitory Gi/o proteins, which cause inhibition of adenylyl cyclase, are found on pre-synaptic neurons and their activation in this location leads to decreased sympathetic activity through negative feedback mechanisms and can contribute to reduction of systemic blood pressure117,118. α2-adrenergic receptors are also located on post-synaptic neurons that communicate with the smooth muscle of vessels, where activation of these receptors can contribute to smooth muscle cell constriction, which can also contribute to high blood pressure117. β1-andrenergic receptors are found primarily in cardiac muscle and are coupled to Gs120 proteins that activate adenylyl cyclase, resulting in increased levels of the second messenger cAMP117. These receptors, when activated, function to increase the contractile force of the heart and to increase heart rate, which can also contribute to hypertension117,120. Due to the high impact that the adrenergic system has on blood pressure and incidence of hypertension, drugs that can target these receptors effectively to reduce blood pressure may be beneficial as an intervention strategy to decrease midlife hypertension and thus decrease future risk of AD development.

Adrenergic Drugs and Reduction of AD Risk and Pathology

The utilization of anti-hypertensive drugs targeting the adrenergic system has become of increasing interest as a possible therapeutic strategy to decrease AD pathology and the incidence of cognitive impairment, as summarized in Table 1. The Aβ peptide has been found to decrease cerebral blood flow by inducing vasoconstriction and endothelial dysfunction in cerebral vessels through Aβ-mediated activation of α1-adrenergic signaling121. Prazosin and Urapidil, both of which are α1-adrenergic receptor antagonists, have been found to alleviate Aβ-mediated vasoconstriction of cerebral vessels by blocking α1-adrenergic signaling121. Additionally, antagonism of the α1-adrenergic receptor by Prazosin has been found to prevent cognitive and memory impairments in the APP23 mouse model of AD, through possibly promoting an anti-inflammatory response122. Tamsulosin, another antagonist of the α1-adrenergic receptor, has recently been found to improve age-related memory impairment in rats due to increased hippocampal neurogenesis and prevention of apoptosis within the hippocampus123. An even more recent study demonstrated that knockdown of α1-adrenergic receptors within APP/PS1 AD mice improved performances on y-maze, open field test, Morris water maze and elevated plus maze124. Additionally, knockdown of α1-adrenergic receptors lessened brain amyloid burden and specifically the α1-adrenergic receptor inhibitor, terazosin, significantly decreased Aβ deposition and attenuated hyperphosphorylation of tau, glial activation, neuronal death, and synaptic dysfunction124. It has been found that the expression of α1-adrenergic receptors is preserved in the cerebrovasculature within the aging population and in individuals that have CAA, further supporting the feasibility of using α1-adrenergic antagonists to combat dementia related vascular pathology125. Not many studies have investigated how drugs that target the α2-adrenergic system affect AD pathology. Overall, more studies exploring the effects of α2-adrenergic drugs in animal models of AD and more clinical and epidemiological studies on the use of α-adrenergic drugs in humans and their effects on AD risk are needed.

Table 1.

Alpha-Adrenergic Drugs’ Effects on Incidence of Cognitive Impairment and Dementia Pathology

Incidence of Cognitive Impairment
Hypertension Drug Category Drug Name (s) Model Finding Reference
α1-adrenergic receptor antagonists Prazosin APP23 AD mouse model Prevents cognitive and memory impairment (122)
α1-adrenergic receptor antagonists Tamsulosin Aged rats Improves age-related memory impairment (123)
Knockdown of α1-adrenergic receptors Knockdown of α1-adrenergic receptors APPswe/PS1 AD mice Improved performances on y-maze, open field test, morris water maze and elevated plus maze (124)
Incidence of Dementia Pathology
Hypertension Drug Category Drug Name (s) Model Finding Reference
α1-adrenergic receptor antagonists Prazosin and Urapidil Middle cerebral artery segments from Male wild-type C57BL/6 mice Prevents Aβ-mediated vasoconstriction of cerebral vessels by blocking α1-adrenergic signaling (121)
α1-adrenergic receptor antagonists Tamsulosin Aged rats Increased hippocampal neurogenesis and prevention of hippocampal cell apoptosis (123)
Knockdown of α1-adrenergic receptors Knockdown of α1-adrenergic receptors APPswe/PS1 AD mice Decreased cerebral amyloid burden (124)
α1-adrenergic receptor inhibitor Terazosin APPswe/PS1 AD mice Decreased amyloid-beta deposition, hyperphosphorylation of tau, glial activation, neuronal death, and synaptic dysfunction (124)

β-blockers have long been utilized to treat hypertension, but some studies have also begun to investigate these anti-hypertensive drugs’ effects on AD pathology and cognitive impairment (Table 2). In Tg2576 mouse models of AD, the β-blocker propranolol was able to attenuate cognitive impairment in novel object recognition and fear conditioning tests, as well as hippocampal Aβ42 deposits and hyperphosphorylated tau126. The β1-adrenergic receptor selective antagonist nebivolol, which also has additional NO-associated vasodilatory abilities, has been used as an anti-hypertensive, and has been shown to reduce Aβ deposition in the brains of Tg2576 AD mice with chronic treatment, but it was unable to prevent cognitive impairments127. Although benefits of β-blockers on AD pathology have been observed in vivo with AD animal models, conflicting evidence regarding β-blockers effects on AD and dementia risk have been seen in analysis of human patients. The Honolulu-Asia Aging Study conducted in 2013 revealed that patients taking β-blockers consistently demonstrated decreased cognitive impairment risk compared to patients taking other categories of anti-hypertensive drugs or no anti-hypertensive drugs at all128. Two recent studies conducted by the same group demonstrated that within a hypertensive population of nearly 70,000 Danish individuals being treated with β-blockers, those taking β-blockers with high BBB permeability, such as propranolol and carvedilol, exhibited 24% reduced AD risk compared to those taking low BBB permeability β-blockers, such as atenolol, bisoprolol, and sotalol129,130. This decreased risk was only true for AD but not dementia as a whole and the reduced risk of AD from taking β-blockers did not differ from other antihypertensive medications129,130. The authors hypothesized that by inhibiting β-adrenergic receptors, CSF-related waste clearance could be improved, thus helping prevent Aβ accumulation and AD pathology, especially in patients taking high BBB permeable beta blockers129. In contrast, a recent study investigating the effect of β-blockers on the longitudinal risk of vascular dementia, AD, and mixed forms of dementia has revealed that β-blockers are significantly associated with increased risk for the development of vascular dementia, but not AD or mixed forms of dementia131. However, long-term beta blocker administration has been shown to exacerbate neuroinflammation; specifically, metoprolol increased phagocytic markers and produced impaired cognition, learning and memory in both wildtype and APP overexpressing mice containing the London and Swedish mutation132. This study also demonstrated in vitro that treatment with beta-blockers elevated synaptic phagocytosis by primary microglia, while interestingly beta-adrenergic agonists prevented synaptosome phagocytosis132. Similarly, a recent study explored how agonism of beta-adrenergic receptors affects AD related pathology. Treatment of 16-month-old 3xTg-AD mice with CL-316,243, a selective β3AR agonist, improved recognition index by 19% in the novel object recognition test, suggesting improvement in memory133. Tau pathology was not affected by administration of the β3AR agonist but there was a 27% reduction of the insoluble Aβ42/Aβ40 ratio in the hippocampus of 3xTg-AD mice133. This collection of experimental results demonstrates that beta-blockers have been found to be associated with both decreased or increased AD pathology and risk. Additionally, it has been shown that agonism of beta-adrenergic receptors can also be beneficial on AD pathology development. Therefore, further studies are needed to dissect whether and when beta adrenergic antagonists or agonists would be beneficial to combat risk of AD and which specific mechanisms these drugs work through to affect AD pathology.

Table 2.

Beta-Adrenergic Drugs’ Effects on Incidence of Cognitive Impairment and Dementia Pathology

Incidence of Cognitive Impairment
Hypertension Drug Category Drug Name (s) Model Finding Reference
β-blocker Propranolol Tg2576 AD mice Attenuated cognitive impairment on novel object recognition and fear conditioning tests (126)
β1-adrenergic receptor selective antagonist Nebivolol Tg2576 AD mice Unable to prevent cognitive impairment (127)
β-blockers Humans Reduced cognitive impairment risk vs. patients taking other or no anti-hypertensive drugs (128)
β-blockers High BBB permeability β-blockers, propranolol and carvedilol; 24% reduced AD risk vs. low BBB permeability β-blockers (129) (130)
β-blockers Humans Increased vascular dementia risk (131)
β-blockers Metoprolol APP AD mice Impaired cognition, learning and memory (132)
selective β3AR agonist CL-316,243 3xTg-AD mice Improved recognition index by 19% in novel object recognition test (133)
Incidence of Dementia Pathology
Hypertension Drug Category Drug Name (s) Model Finding Reference
β-blocker Propranolol Tg2576 AD mice Decreased hippocampal Aβ42 deposits and hyperphosphorylated tau (126)
β1-adrenergic receptor selective antagonist Nebivolol Tg2576 AD mice Reduce cerebral Aβ deposition (127)
β-blockers Metoprolol APP AD mice Worsened neuroinflammation and increased phagocytic markers (132)
β-blockers Primary microglia Increased synaptic phagocytosis (synaptic degradation) (beta-adrenergic agonists prevented synaptosome phagocytosis) (132)
selective β3AR agonist CL-316,243 3xTg-AD mice 27% reduction within insoluble Aβ42/Aβ40 ratio in the hippocampus (133)

The Renin-Angiotensin System and Blood Pressure Control

The Renin-Angiotensin System (RAS) is a major player in the control of systemic blood pressure. Renin, which is released from the kidneys into the bloodstream, facilitates the conversion of angiotensinogen, released from the liver, into angiotensin I. Angiotensin-Converting Enzyme (ACE) functions to then convert angiotensin I into angiotensin II134. Angiotensin II is a potent vasoconstrictor, which increases blood pressure and thus can lead to the development of hypertension134. Angiotensin II’s effects on the RAS can also impact the brain and can contribute to vascular forms of dementia through promoting endothelial dysfunction and cerebrovascular remodeling due to increased levels of neuroinflammation and oxidative stress134. Through binding to the angiotensin 1 receptor, angiotensin II has been found to promote Aβ deposition through several processes, such as elevating APP mRNA levels and increasing β-secretase activity and has also been found to promote tau phosphorylation and increase reactive oxygen species production135. Due to the RAS’s contribution to dementia development and pathology, drugs targeting this system may be beneficial for reducing individual’s risk for developing AD.

Renin-Angiotensin System Drugs and Reduction of AD Risk and Pathology

Two main drugs that target the RAS include Angiotensin Converting Enzyme Inhibitors (ACEIs; prevents conversion of angiotensin I into the vasoactive angiotensin II) and Angiotensin Receptor Blockers (ARBs; prevents angiotensin II from binding to the angiotensin 1 receptor), both of which have been shown to demonstrate beneficial effects on AD pathology. Treatment of Tg2576 AD mice with the ACEI Captopril has been found to decrease neurodegenerative AD pathology by reducing amyloidogenic APP processing and Aβ plaque deposition and by lowering reactive oxygen species levels within the hippocampus136. Perindopril, another ACEI, has been found to preserve learning and memory and to delay the onset of AD pathology in rats with Aβ injections into their hippocampus137. Both Captopril and Perindopril have been found to decrease the release of pro-inflammatory mediators from microglia in vitro, which is a common pathological event in AD, and short term treatment of 5XFAD mice with both of these ACEIs was found to cause reduction of Aβ burden and decreased expression of the microglial marker CD11b138. Captopril was further shown to play a neuroprotective role by regulating activation of microglia’s inflammatory response, with Captopril treatment of BV2 microglia causing decreased inflammatory nitric oxide and TNF-α expression and increased anti-inflammatory IL-10 production in vitro, suggesting that Captopril shifts microglia to assume a more neuroprotective, anti-inflammatory phenotype139. The same study also demonstrated that Captopril treated 5XFAD AD mice exhibited decreased Aβ burden accompanied by increased CD11b expression, suggestive of increased microglial activation likely of the M2 phenotype, as suggested by the anti-inflammatory profile assumed by Captopril treated microglia in vitro139. A study conducted in 2021 found that in an AD rat model, the mean escape latency in the Morris Water Maze test was substantially decreased in animals treated with captopril and donepezil, suggesting improved learning and memory140. Additionally, this study demonstrated that ROS levels and 8-hydroxy-2’-deoxyguanosin were substantially decreased in AD rats taking captopril and donepezil140. Treatment with captopril decreased cerebral cell death and demonstrated an ability to rescue memory deficits also in a Drosophila model expressing the Aβ42 transgene, but this trend was not seen in flies expressing human tau, suggesting that ACEIs may work through targeting Aβ pathology141. Another recent study also conducted in Drosophila that overexpressed APP and the human β-site APP-cleaving enzyme (BACE) in neurons, demonstrated that treatment of AD flies with the ACEI Isinopril improved learning and memory deficits on the aversive phototaxic suppression assay and reduced ROS levels142. Although ACEIs have been found to exhibit beneficial effects on AD pathology, some studies have demonstrated detrimental effects of ACEIs, with the main concern being that the Angiotensin Converting Enzyme is capable of cleaving Aβ peptides into less aggregable species, thus its inhibition may actually lead to enhanced Aβ deposition143. This was demonstrated in APP Swedish transgenic mice treated with ACEI, captopril, resulting in increased cerebral Aβ deposition144. Additionally, this study demonstrated that transgenic AD mice with ACE deficiency had elevated Aβ42 deposition and neuronal apoptosis144, and included a longitudinal component conducted over 8 years in male hypertensive patients. Patients using ACEIs had a more rapidly declining mean intelligence quotient then those not prescribed ACEIs, but this was interestingly not true for women144. Therefore, the potential use of ACEI to decrease AD pathology in humans may be controversial as well as sex-dependent.

Regarding the Angiotensin Receptor Blockers, valsartan and losartan have been found to reduce Aβ levels as well as decrease Aβ oligomerization in neuronal cultures145. Additionally, Tg2576 mice that were treated with the ARB valsartan, demonstrated decreased cerebral Aβ deposition in vivo and lower levels of cognitive impairment due to improvements in spatial learning abilities146. Telmisartan has been found to decrease glial activation in 5XFAD mice, resulting in reduced AD pathology147. Human APP mouse models treated with the ARB losartan, demonstrated preservation of cognitive function and maintenance of proper cerebrovascular activity, particularly in terms of the dilatory ability of the vasculature148. Moreover, the utilization of ARBs correlated with decreased Aβ accumulation in cognitively healthy patients and slower rates of decline in several cognitive domains within AD patients149. Losartan was also able to alleviate cerebral cell death and reversed memory deficits in drosophila expressing human Aβ42, while similarly to ACEIs, losartan was unable to rescue cerebral cell death in flies expressing human tau, suggesting that RAS inhibitors in general may work through specifically targeting Aβ-mediated AD pathology141.

A recent meta-analysis investigating the relationship between drugs that block the RAS and individuals’ risk of dementia revealed that individuals that take either ACEIs of ARBs demonstrated significantly reduced occurrence of dementia development150. Another longitudinal study analyzing the effect of ACEIs and ARBs on dementia risk demonstrated that hypertensive individuals who took ACEIs had a 26% decreased risk for development of dementia compared to those who did not take ACEIs, while hypertensive individuals who took ARBs had a 40% lower risk for developing dementia compared to those who did not take ARBs151. Interestingly, the decreased risk was specifically significant for vascular forms of dementia rather than AD151. A study comparing the effect of anti-hypertensive drugs acting on the RAS versus other categories of anti-hypertensive drugs on the reduction of AD onset risk found that RAS acting anti-hypertensives were slightly more effective at reducing risk of AD onset152. When comparing the effectiveness of ARBs versus ACEIs, it was found that individuals taking ARBs had a greater reduction in AD risk compared to those taking ACEIs, suggesting that blocking the angiotensin receptor directly may be more protective152. Interestingly, this study revealed that these various anti-hypertensive drugs’ ability to reduce the risk of AD onset varies based on sex as well as ethnicity, which needs to be investigated further152. A recent longitudinal analysis following non-demented subjects 55 to 90 years of age found that participants utilizing an ARB had slower brain atrophy rates compared to those taking ACEIs153. It was also demonstrated that AD patients utilizing ARBs exhibited a 9.4% slower decline in delayed recall performance compared to those who utilized ACEIs. ARB use was also associated with better performance over time on the Trail Making Test (TMT-A) and the Digit Symbol Substitution Test (DSST), both of which assess attention and psychomotor processing speed154. In addition, within cognitively healthy older individuals, those who took ARBs demonstrated a slower rate of cortical Aβ accumulation in the caudal anterior cingulate, precuneus and precentral and postcentral gyri versus those taking ACEIs. However, in patients with AD or MCI, there was no difference in amyloid accumulation rates in patients taking ARBs versus ACEIs155. The effects of Renin-Angiotensin System drugs on dementia risk and incidence of cognitive impairment and dementia pathology is outlined in Table 3.

Table 3.

Renin-Angiotensin System Drugs’ Effects on Dementia risk and Incidence of Cognitive Impairment and Dementia Pathology

Dementia Risk and Incidence of Cognitive Impairment
Hypertension Drug Category Drug Name (s) Model Finding Reference
ACEI Perindopril Rats with hippocampal Aβ injections Preserved learning and memory (137)
ACEI Captopril and Donepezil AD model rats induced by expression of human Aβ42 Decreased mean escape latency within the Morris Water Maze (improved learning and memory) (140)
ACEI Isinopril Drosophila overexpressing APP and the human β-site APP-cleaving enzyme in neurons Improved AD related learning and memory deficits on aversive phototaxic suppression assay (142)
ACEI Humans Men had declining mean intelligence quotient vs. those not taking ACEIs (144)
ARB Valsartan Tg2576 AD mice Reduced cognitive impairment (improved spatial learning) (146)
ARB Losartan Human APP AD mice Preserved cognitive function (148)
ARBs AD patients Decreased rates of cognitive decline (149)
ARB Losartan Drosophila expressing the Aβ42 transgene Reversed memory deficits (141)
ACEIs and ARBs Humans Reduced occurrence of dementia (150)
ACEIs and ARBs Hypertensive humans ACEIs: decreased vascular dementia development by 26%
ARBs: decreased vascular dementia development by 40%
(151)
ACEIs and ARBs Hypertensive humans ACEIs: decreased vascular dementia development by 26%
ARBs: decreased vascular dementia development by 40%
(151)
ACEIs and ARBs Humans ARBs more effectively decreased AD risk versus ACEIs (152)
ACEIs and ARBs AD patients ARBs exhibited 9.4% slower decline in delayed recall performance versus ACEIs; ARBs were associated with better performance on the Trial Making Test and the Digit Symbol Substitution Test (154)
Incidence of Dementia Pathology
Hypertension Drug Category Drug Name (s) Model Finding Reference
ACEI Captopril Tg2576 AD mice Reduced amyloidogenic amyloid precursor protein processing, amyloid-beta plaque deposition, hippocampal reactive oxygen species (136)
ACEI Perindopril Rats with hippocampal Aβ injections Delayed AD pathology onset (137)
ACEI Captopril and Perindopril Microglia Decreased release of pro-inflammatory mediators (138)
ACEI Captopril and Perindopril 5XFAD AD mice Reduced cerebral Aβ burden and decreased expression of microglial marker CD11b (138)
ACEI Captopril BV2 microglia Shifted microglia to neuroprotective, anti-inflammatory M2 phenotype: Decreased inflammatory nitric oxide and TNF-α expression and increased anti-inflammatory IL-10 production (139)
ACEI Captopril 5XFAD AD mice Decreased Aβ burden and increased CD11b expression (139)
ACEI Captopril and Donepezil AD model rats induced by expression of human Aβ42 Decreased ROS levels and 8-hydroxy-2’-deoxyguanosin (140)
ACEI Captopril Drosophila expressing the Aβ42 transgene Decreased cerebral cell death and rescued memory deficits (141)
ACEI Isinopril Drosophila overexpressing APP and the human β-site APP-cleaving enzyme in neurons Reduced ROS levels (142)
ACEI Captopril Human APP Swedish transgenic AD mice Increased cerebral amyloid-beta deposition (144)
ACE Deficiency Transgenic AD mice with ACE deficiency Elevated Aβ42 deposition and neuronal apoptosis (144)
ARB Valsartan and Losartan Neuronal Cultures Reduced Aβ levels and decreased Aβ oligomerization (145)
ARB Valsartan Tg2576 AD mice Decreased cerebral Aβ deposition (146)
ARB Telmisartan 5XFAD AD mice Decreased glia activation (147)
ARB Losartan Human APP AD mice Preserved vascular dilatory function (148)
ARBs Cognitively healthy patients Decreased Aβ accumulation (149)
ARB Losartan Drosophila expressing the Aβ42 transgene Alleviated cerebral cell death (141)
ACEIs and ARBs Humans with no dementia ARBs caused slower brain atrophy rates versus ACEIs (153)
ACEIs and ARBs Cognitively healthy elderly humans ARBs produced slower rate of cortical Aβ accumulation versus ACEIs (155)

Diuretics and Blood Pressure Control

Diuretics are another common form of antihypertensive medications that can reduce blood pressure by increasing urination, thus increasing excretion of water from the body156. Specifically, diuretics cause reduced reabsorption of sodium chloride within the kidney, which results in urine that is more concentrated in sodium, which the body compensates by excreting more water156. Increased excretion of water from the body, thus lowers blood volume which results in a reduction of blood pressure. A study conducted in 2013 utilizing data from the “Ginkgo Evaluation of Memory Study” conducted in elderly cognitively healthy adults or elderly adults with MCI revealed that utilization of antihypertensive drugs in general diminished the hazard ratio for incidence of AD in cognitively healthy participants, but people with MCI only revealed decreased AD risk when taking diuretics157. Similarly, the “Cache County Study of Memory Health and Aging” found that utilization of any anti-hypertensive medication correlated with lessened AD incidence, and that it was specifically found that thiazide and potassium-sparing diuretics correlated with the most drastic AD risk reduction158. Another study that analyzed data from 15 longitudinal studies (52,599 people) demonstrated that diuretics consistently correlated with decreased dementia and AD risk compared to other antihypertensive drugs159. A study conducted in 2016 with 6,537 participants found that decreased risk for dementia was seen with loop diuretics as well160. A recent meta-analysis found that individuals taking diuretics, as well as ARBs, had lower AD risk versus those with no antihypertensive use and that specifically thiazide and potassium-sparing diuretics correlated with decreased AD risk and maintained cognitive abilities161. In a study investigating Aβ accumulation via PiB PET analysis in hypertensive subjects, it was shown that the use of diuretics, as well as ARBs, predicted lower cerebral amyloid accumulation162. An even more recent study conducted autopsy analysis and determined that utilization of any anti-hypertensive drugs correlated with a less severe Braak stage of neurofibrillary tangles and less evidence of CAA, but specifically use of diuretics was associated with lower Braak stage, lower neuritic plaque density, less diffused plaques, and less CAA pathology163. The effects of diuretics on dementia risk and incidence of cognitive impairment and dementia pathology are summarized in Table 4.

Table 4.

Diuretics’ Effects on Dementia Risk and Incidence of Cognitive Impairment and Dementia Pathology

Dementia Risk and Incidence of Cognitive Impairment
Hypertension Drug Category Drug Name (s) Model Finding Reference
Diuretics Cognitively healthy elderly humans/elderly humans with MCI Usage of antihypertensive drugs decreased hazard ratio for AD incidence in healthy participants; participants with MCI had decreased AD risk specifically with diuretic use (157)
Diuretics Thiazide and potassium-sparing Usage of antihypertensive drugs decreased AD risk; Thiazide/potassium-sparing diuretics most drastically decreased AD risk (158)
Diuretics Humans Diuretics most consistently correlated with decreased dementia/AD risk versus other anti-hypertensive drugs (159)
Diuretics Loop Humans Decreased dementia risk (160)
Diuretics/ARBs Thiazide/Potassium-Sparing Humans Usage of diuretics, specifically thiazide/potassium-sparing, (and ARBs) lowered AD risk and maintained cognitive abilities (161)
Incidence of Dementia Pathology
Hypertension Drug Category Drug Name (s) Model Finding Reference
Diuretics Hypertensive humans Diuretics (and ARBs) predicted less cerebral amyloid accumulation (162)
Diuretics Humans Usage of anti-hypertensive drugs correlated with less severe Braak stage of neurofibrillary tangles and less CAA; Diuretics correlated with lower Braak stage, lower neuritic plaque density, less diffused plaques, and less CAA pathology (163)

Carbonic Anhydrase Inhibitors and Reduction of AD Risk and Pathology

Carbonic anhydrase inhibitors (CAIs), such as Methazolamide (MTZ) and Acetazolamide (ATZ), were first developed as diuretics, and have recently begun to be investigated as potential therapeutics for AD164,165. CAIs inhibit carbonic anhydrases, which catalyze the reversible hydration of CO2 to bicarbonate and a proton. CAIs reduce Na+ reabsorption in the kidney and promote alkaline diuresis156,166. MTZ and ATZ are both already FDA approved not only for hypertension, but also for treatment of glaucoma, by reducing intraocular pressure and for high-altitude sickness, via reduction in pulmonary vasoconstriction, as well as through their ability to increase cerebral blood flow, and reduce cerebral edema165,167. Based on the vast array of diseases that CAIs are beneficial for it is clear that they work through multiple molecular mechanisms, which still remain to be elucidated165. Interestingly, recent studies are highlighting CAI’s potential as promising drugs to also treat neurovascular pathology associated with AD and CAA, through their ability to prevent Aβ-mediated mitochondrial dysfunction and cell death164,165 (Table 5).

Table 5.

Carbonic Anhydrase Inhibitors’ Effects on Incidence of Dementia Pathology

Incidence of Dementia Pathology
Hypertension Drug Category Drug Name (s) Model Finding Reference
CAIs MTZ Neurons, cerebrovascular endothelial cells, and cerebrovascular smooth muscle cells Protected cells from Aβ-induced mitochondrial cytochrome c release and apoptosis (26) (169)
CAIs MTZ Neurons and glial cells Inhibited DNA fragmentation, mitochondrial cytochrome c release, and caspase 9 and 3 activation (170)
CAIs MTZ Mice with hippocampal Aβ injections Decreased neuronal and microglial caspase 3 activation and neuronal loss. (170)
CAIs MTZ and ATZ Neurons and cerebrovascular cells Protected cells from Aβ-induced mitochondrial dysfunction (inhibited mitochondrial membrane depolarization and hydrogen peroxide production) (171)

The CAI MTZ was first observed to be among a small number of drugs able to prevent CytC release from isolated mitochondria and in Huntington models168. Our group was the first to show that MTZ could protect cerebral endothelial cells and cerebral vascular SMCs from mitochondrial cytochrome c release and apoptosis typically induced by Aβ species26,169. A following study further demonstrated that in vitro treatment of neurons and glial cells with MTZ inhibited fragmentation of DNA, release of mitochondrial cytochrome c, and caspase 9 and 3 activation, which are all pathological events typically caused by Aβ170. This same study provided in vivo demonstration that intraperitoneal MTZ treatment of mice injected with Aβ into the hippocampus decreased the activation of caspase 3 in both neurons and microglia located around the area of injection170. A more recent study dissecting the molecular mechanism responsible for the mitochondrial effects of CAIs analyzed 2 widely used CAIs, MTZ and ATZ, and showed that both drugs were able to protect neurons and cerebrovascular cells from mitochondrial dysfunction triggered by Aβ, specifically by inhibiting depolarization of the mitochondrial membrane as well as preventing the generation of hydrogen peroxide171. This study also revealed that ATZ had protective effects at concentrations 10 times lower than MTZ, which has very important clinical relevance171. The results of these various studies provide strong evidence that these FDA approved CAIs could be therapeutically effective for treating various aspects of AD pathology. Further studies in transgenic AD animal models are ongoing and clinical trials will be needed to clarify if this therapy is efficient to reduce cognitive dysfunction in AD, vascular dementia, as well as in subjects presenting these conditions comorbid with hypertension. Importantly, since CAIs also have BP lowering effects and they are able to increase CBF and vasoreactivity, these drugs would be ideal to tackle the AD/hypertension comorbidity as well as comorbid AD and other cerebrovascular pathologies.

Clinical Trials

Anti-Hypertensive Drugs to Prevent Dementia and Decrease Dementia Pathology

Due to promising leads within pre-clinical data, several clinical trials have been conducted to determine if various anti-hypertensive drugs can lower dementia risk and pathology in humans, with a majority focusing on renin-angiotensin system targeting drugs. A study conducted in 2012 included 48 patients with essential hypertension and apparent AD, with a subset being treated with Telmisartan, an ARB, and being compared to patients taking a calcium channel blocker172. Patients treated with Telmisartan demonstrated decreased CSF IL-1β and TNF-α levels, elevated mini-mental state examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) scale scores as well as higher levels of improvement on these tests by the end of the study. Interestingly, these patients also demonstrated higher CSF Aβ42 levels172. A similar study included a total of 20 patients with probable AD and essential hypertension that were treated with Telmisartan and compared to patients taking a calcium channel blocker (Amlodipine). In this study, patients on Telmisartan showed no improvement in cognitive test scores but demonstrated increased regional CBF levels within the right supramarginal gyrus, superior parietal lobule, cuneus and lingual gyrus173. These results suggest that treatment of AD patients with Telmisartan reveals contradicting results, and that more studies are clearly required. A study conducted in 2017 investigated the dementia incidence rate in older participants taking difference classes of anti-hypertensive medications174. Interestingly, after about 7 years of follow-up this study concluded that patients taking ARBs (and calcium channel blockers) demonstrated decreased dementia risk compared to patients taking other classes of anti-hypertensive medications174. A more recent phase 2 trial, the RADAR trial, investigating whether the ARB, Losartan, could decrease brain atrophy in AD diagnosed patients demonstrated that Losartan was not effective at reducing brain atrophy rates in patients with AD175. A randomized, blinded preclinical trial conducted in hypertensive rats post-stroke induction and treated with ARB, Candesartan, or compound-21 (an angiotensin type 2 receptor (AT2R)- agonist) demonstrated that both treatments preserved cognition, decreased cytotoxicity, and prevented microgliosis post-stroke176. These results suggest that AT2R stimulation, directly or indirectly by blocking the angiotensin 1 receptor, prevents cognitive impairment, cell death, and neuroinflammation post-stroke176. Another study conducted in 2020 investigated dementia risk in non-demented patients with a mean age of 74.5 who were taking angiotensin-2 stimulating drugs, ACEIs, or both drug types177. Results from this study revealed that participants taking angiotensin 2 stimulating anti-hypertensives exhibited a 45% decreased dementia incidence rate and patients taking both drugs had a nonsignificant 20% decreased dementia incidence rate compared to those taking ACEIs177. A study from 2012 investigated the effects of the BBB-crossing ACEI, Ramipril, on 14 cognitively normal participants with mild hypertension178. The participants were treated with Ramipril or placebo, followed by assessment of CSF Aβ42 and ACE activity, arterial function, and cognition178. Participants treated with Ramipril demonstrated inhibited CSF ACE activity and lowered blood pressure, but treatment with this ACEI had no positive effect on CSF Aβ42, arterial function, or cognition178. Another study investigated cognitive decline rates in patients with mild to moderate AD treated with centrally acting ACEIs versus patients not currently treated with centrally acting ACEIs179. AD patients taking centrally acting ACEIs, specifically Perindopril, revealed improved activities of daily living (ADL) rating, as well as slowed disease progression (Clinical Dementia Rating Scale, CDR-SB)179. In terms of other classes of anti-hypertensive drugs, very few clinical trials have been conducted. The “Ginkgo Evaluation of Memory Study” investigated whether usage of specific classes of antihypertensive drugs could improve learning and memory in adults older than 75 years of age180. Participants taking potassium-sparing diuretics demonstrated improved verbal learning and memory (California Verbal Learning test) versus participants not taking anti-hypertensive medications or taking other classes of medication, while interestingly this study demonstrated no cognitive benefit of taking ACEIs or AT2RBs180. Very few clinical trials have been conducted to investigate how adrenergic drugs affect dementia risk and pathology. A study conducted in 2018 determined that healthy participants 75 years of age or older that were supplemented with Guanfacine, an α-2a-adrenoceptor agonist, failed to demonstrate improved prefrontal cognitive function181. A recent study investigated CBF via MRI analysis in mild to moderate AD patients (mean age of 72.8 years) taking the calcium channel blocker, Nilvadipine182. This study showed that AD patients taking Nilvadipine demonstrated preserved cerebral autoregulation and increased CBF specifically within the hippocampus, revealing positive cerebrovascular effects of this anti-hypertensive drug182. Based on the results of these clinical trials, it is unclear whether certain anti-hypertensive drugs have beneficial pathological outcomes for AD patients and whether these drugs are certain to reduce dementia risk. A large limitation within a majority of these studies is that many participants within these studies are well past the prodromal phase of AD, where pathology begins to accumulate. Future clinical trials are needed in order to determine the optimal age that starting these anti-hypertensive drug treatments have beneficial effects, especially considering that mid-life hypertension has the highest impact on AD risk. If at risk individuals can be identified earlier in life and treatment with anti-hypertensive drugs is started earlier, these drugs may have a more preventative effect and longitudinal clinical trials may have a better outcome. Additionally, no clinical trials have yet determined whether carbonic anhydrase inhibitors, which preclinically improve cerebrovascular apoptosis, oxidative stress, and mitochondrial dysfunction, in addition to lowering blood pressure and increasing CBF, could be a more effective treatment to prevent and reduce AD pathology and risk.

Vitamin Supplementation to Prevent Dementia and Decrease Dementia Pathology

It is known that vitamins such as vitamin B12, B6, and Folate are vital for Hcy metabolism, thus lowering Hcy levels in individuals with Hhcy. Extensive evidence has been outlined in this review to suggest that Hhcy contributes to AD risk, and several major clinical trials have been conducted to determine whether vitamin supplementation can lower AD risk and pathological severity. A clinical trial conducted in 2010 supplemented MCI patients that were over the age of 70 with high dosages of folic acid, vitamin B12 and vitamin B6 and compared brain atrophy rates to MCI patients treated with a placebo183. This study demonstrated a slowing of brain atrophy rates in MCI patients that were treated with folic acid and vitamin B6 and B12, with participants showing Hcy levels >13 μmol/L specifically having a 53% lower brain atrophy rate compared to individuals in the placebo group183. Similarly, a study conducted in 2013 involving aged participants with elevated dementia risk (with MCI) demonstrated that treatment with high dosages of folic acid, vitamin B6, and vitamin B12 decreased and slowed the rate of atrophy within AD vulnerable gray matter regions by as much as 7-fold, with this effect being specific to participants with Hhcy184. Another study looking specifically at folic acid supplementation in AD patients demonstrated that patients treated with folic acid had a trend towards improved cognition, based on a slight increase in Mini Mental State Examination (MMSE) score compared to the control group185. This study also revealed that AD patients supplemented with folic acid demonstrated lower Aβ40, Presenilin 1, and TNFα-mRNA levels185. A study conducted in 2019 involved MCI patients treated with only folic acid, only vitamin B12, folic acid and vitamin B12, or a placebo186. Compared to the control group and the groups treated with folic acid alone or vitamin B12 alone, MCI patients supplemented with both folic acid and vitamin B12 demonstrated significant decreases in blood IL6, TNFα, and MCP-1 levels as well as improved cognitive performance on the Wechsler Adult Intelligence Scale, specifically improved overall IQ, verbal IQ, information scores and digit span scores186. An even more recent study involving AD patients either supplemented with folic acid and vitamin B12 or a placebo revealed that AD patients supplemented with folic acid and vitamin B12 had improved Montreal Cognitive Assessment (MoCA) Test scores (specifically naming and orientation scores) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) domain score of attention as well as decreased serum TNFα levels compared to control subjects187. The studies mentioned above demonstrate that supplementation with folate and vitamins that improve Hcy metabolism and treat Hhcy, also have positive cognitive effects and can combat some aspects of dementia pathology, but a few conflicting studies exist. A study conducted in 2010 found no improvement in cognitive function and did not find a reduced risk of cognitive impairment or dementia from daily vitamin B12, vitamin B6, and folic acid supplementation, but this study only contained hypertensive men that were older than 75 years of age thus the results may be swayed due to only considering men for the study and starting this supplementation later in life188. Similarly, a more recent study involving MCI patients aged 65 years or older supplemented with either Methylcobalamin, which is used to treat vitamin B12 deficiency, and folic acid or placebo found no significant reduction in cognitive decline in MCI patients supplemented with vitamins compared to the placebo group189. Again, this study utilized individuals that were well past midlife, a period of time in which intervention would likely be the most optimal, since AD pathology begins to accumulate decades prior to disease manifestation. This study also acknowledges that the cognitive decline level within the placebo group was very minimal and the sample size utilized was likely too small to detect small differences in cognitive function between the treated and placebo groups, thus justifying why this study found no cognitive benefit of vitamin supplementation189. Overall, the majority of clinical trials reveal promising results of vitamin supplementation on slowing the development or progression as well as severity of dementia pathology and cognitive decline. Preventative dementia medicine would benefit from future clinical trials that start vitamin supplementation prior to the average age of onset of the prodromal phase of dementia in order to determine if early vitamin supplementation could prevent dementia onset or pathological severity.

Biofluid Biomarkers Associated to Vascular Risk in AD

It’s now known that the prodromal asymptomatic phase of AD starts many years before the onset of symptoms. In a majority of AD patients, age-related vascular changes can also precede Aβ and tau pathology19,190,191. If these vascular changes could be detected early within the progression of pathology, both patients and physicians would be able to implement preventative measures to slow pathology progression and reduce risk and severity of dementia. A major key to detecting vascular damage earlier in time is the identification of novel biofluid biomarkers, beyond Aβ, tau pathology, and neurodegeneration (ATN). In recent years, more vascular specific fluid biomarkers have been identified, with some having the capability to differentiate AD from vascular dementia. Platelet-derived growth factor receptor-β (PDGFRβ), which is associated with pericytes, capillaries, and BBB integrity, has recently received more attention as a novel vascular-related cerebrospinal fluid (CSF) biomarker. A recent study has shown that increased levels of soluble CSF PDGFRβ, indicative of cerebral capillary and pericyte damage and BBB breakdown, was associated with more advanced cognitive impairment192,193. Additionally, this study demonstrated that patients with early cognitive decline had cerebral capillary damage and BBB breakdown within the hippocampus regardless of Aβ and/or tau biomarker changes, further suggesting that PDGFRβ could be an early biomarker of cognitive decline192,193. Elevated serum C-Reactive Protein (CRP), which is associated with inflammation and heart disease, has been found to be correlated with lower cognitive functioning levels in patients under 80 and also has been associated with an increased dementia risk of about 55%194,195. Vascular dementia-specific biomarkers are also starting to be unveiled, opening avenues to differentiate between heterogeneous forms of dementia and AD using fluid biomarkers. For example, increased CSF levels of lipocalin 2 (LCN2), a secreted glycoprotein that helps mediate neuronal damage within vascular cerebral injuries, has been found specifically in vascular dementia patients compared to controls, AD patients, neurodegenerative dementia patients, and cerebrovascular disease patients196. Another recent study demonstrated that brevican and neurocan peptides, which are CNS-specific extracellular matrix proteoglycans that are degraded by metalloproteinases, are decreased significantly in vascular dementia patients compared to controls and AD patients197. Additionally, glial fibrillary acidic protein (GFAP; marker of astrocytes and neuroinflammation), vascular endothelial growth factor A (VEGF-A; angiogenesis), placental growth factor (PIGF) were plasma biomarkers positively associated with elevated level of AD neuropathological change198.

Considering the risk that cardiovascular risk factors, such as hypertension and hyperhomocystenemia, pose on the neurovascular unit, causing individuals to become more likely to develop dementia later in life, it is important to consider that cardiovascular disease biomarkers can also be repurposed to predict the risk of dementia development. One study following 1456 non-hypertensive patients, of which 232 participants developed hypertension, looked at 9 biomarkers, including C-reactive protein (inflammation; found to be a dementia related biomarker), fibrinogen (inflammation/thrombosis), plasminogen activator inhibitor-1 (fibrinolytic potential), aldosterone, renin, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide (neurohormonal functions), homocysteine (oxidant stress; increases both AD and hypertension risk), and urinary albumin/creatinine ration (glomerular endothelial function) in order to understand which biomarkers were associated with hypertension development199. The biomarker panel as a whole was significantly associated with the development of hypertension, in particular C-reactive protein, plasminogen activator inhibitor-1, and urinary albumin/creatinine ratio. Indeed, the incidence of hypertension was higher when the number of elevated biomarkers increased199. Biofluid biomarkers, in addition to Hcy itself, have also been identified for Hhcy. A recent study looking at blood and CSF samples from 72 patients examined several potential Hhcy biomarkers, finding not only that Hcy can be detected within the CSF of patients but also that CSF Hcy concentrations correlated with CSF folate, S-adenosylhomocysteine (SAH), and albumin indicating that these may serve as additional biomarkers to detect Hhcy200. Similarly, another study has demonstrated that cerebral Hcy concentrations significantly related to circulating B vitamin levels and CSF albumin201. Interestingly, this study also demonstrated that higher CSF SAH concentrations and lower CSF folate concentrations were correlated to increased levels of CSF phosphorylated tau201. Since there is strong evidence to suggest that both hypertension and Hhcy exacerbate dementia risk, future studies should consider investigating how hypertension and Hhcy biomarkers correlate to dementia incidence, risk, and canonical AD biomarkers. These new biomarkers, many of which are easily detectable in blood, may eventually be used to pinpoint subjects with increased dementia risk and apply preventive measures before significant pathology accumulates, or include these “high risk” asymptomatic subjects in clinical trials.

Genetic Risk Biomarkers

In addition to fluid biomarkers, recent studies have begun to look at how gene polymorphisms that are related to hypertension and Hhcy relate to dementia pathology and risk. In terms of hypertension, it is known that ACE contributes to elevated blood pressure levels and as previously mentioned, this enzyme is targeted to control hypertension and in turn decrease dementia risk. ACE2 protein expression levels have been found to be upregulated within AD brains and positive correlations between ACE2 protein expression and oxidative stress levels in AD brains have also been revealed202,203. Interestingly, a recent metanalysis including 82 cohorts from 65 individual studies revealed significant associations between the rs1799752 ACE polymorphism and increased AD risk204. Another recent study comparing AD patients to age and gender matched cognitively healthy controls demonstrated that the rs4646994 ACE gene polymorphism was also associated with increased AD risk205. Gene polymorphisms within the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes a protein necessary for homocysteine metabolism, have been found to increase circulating Hcy levels and promote memory impairment and cognitive dysfunction, decrease cortical and hippocampal volumes, increase cerebral atrophy, and increase hippocampal apoptosis in mice206,207. In humans, the MTHFR gene polymorphism C677T (rs1801133), as well as MTHFR A1298C, were associated with increased late-onset AD risk208211. Interestingly the prevalence of MTHFR 677CT gene polymorphism was increased in patients carrying APOEɛ4, which has long been accepted as an AD genetic risk factor208.

Conclusions

As extensively outlined within this review, midlife hypertension has been found to cause pathologies that affect the cerebrovascular environment, and by consequence the whole neurovascular unit, similarly to AD and CAA. Hypertension has been found to cause the loss of cerebral autoregulation, increasing transmission of pressure to cerebral vessels, to induce cerebral endothelial cell dysfunction, namely decreased barrier and vasodilatory function as well as increased cerebral endothelial cell apoptosis. As depicted in Figure 1, damage to endothelial cell integrity and function thus results in increased BBB permeability, leading to increased presence of micro-hemorrhages and increased infiltration of blood borne toxins and peripheral immune cells, which causes neuroinflammation and oxidative stress. Additionally, hypertension can impair perivascular Aβ clearance and promote capillary rarefaction and decreased microvessel density, leading to hypoperfusion and a hypoxic and nutrient deficient cerebral environment. Since hypertension begins to negatively impact the cerebral environment during midlife, a time in which Aβ also begins to accumulate in prodromal asymptomatic AD, we hypothesize that hypertension can exacerbate and/or accelerate the onset and accumulation of AD pathology, leading to worsened disease outcome. Hhcy, on the other hand, not only promotes, similarly to hypertension, endothelial cell dysfunction and death, oxidative stress, Aβ accumulation and vascular inflammation, but can also increase individuals’ risk for other cardiovascular diseases such as hypertension. This sheds light on the phenomenon that cardiovascular risk factors can both be contemporaneous comorbidities, and also independently and additively increase AD risk and pathology.

Figure 1. Graphical hypothesis:

Figure 1.

Hypertension and HHcy cause BBB permeability, endothelial cell stress, microhemorrhages, ROS production, inflammation, and cerebrovascular dysfunction, resulting in hypoperfusion, synaptic and neuronal loss, and cognitive impairment.

Major gaps in knowledge include dissecting the specific initiators and pathways contributing to neuronal loss besides Aβ and tau. Among these, we propose that cerebral hypoperfusion, neurovascular unit impairment, neuroinflammation, and mitochondrial dysfunction, will need to be thoroughly assessed to define and understand diverse dementia endophenotypes and how each of these endophenotypes results in neuronal dysfunction, synaptic loss, cognitive impairment, and in the development of the “AD syndrome”. We propose that it is vital for future studies to better elucidate the specific molecular mechanisms responsible for hypertension and Hhcy’s contribution to amyloid-related AD pathology and cognitive impairment, particularly in regard to cerebral endothelial cell death, impaired BBB function, neuroinflammation, effects on cerebral angiogenesis, cerebral hypoperfusion, oxidative stress, dysfunctional Ca2+ signaling and regulation, all of which lead to synaptic loss, a cerebral energy crisis, and eventually, cognitive impairment. It is also of great importance that future studies work to understand if comorbid cardiovascular risk factors work together to exacerbate amyloid-related pathology through common cellular and molecular mechanisms or if different cardiovascular risk factors work through separate pathways to promote AD pathology, particularly focusing on pathways involved in mitochondrial function, ROS production, BBB integrity and function, cerebrovascular cell death, and cerebral angiogenesis. The field of AD is greatly lacking research on tau-related cerebrovascular pathology, so future studies should also begin to elucidate how the presence of cardiovascular risk factors impacts tau-specific vascular pathologies. As mentioned within this review, female sex is not only the second greatest risk factor for AD development, but females are also at higher risk for hypertension development, thus demonstrating the multiple angles at which female sex can heighten risk for AD and worsened dementia syndromes. Future studies need to consider sex-specific and longitudinal interactions between cardiovascular risk factors, AD risk and tau/Aβ pathology. We postulate that understanding through which molecular mechanisms different cardiovascular risk factors operate to promote specific aspects of Aβ and tau related pathologies and considering how the variables of sex and age differentially promote cardiovascular risk factor-associated dementia risk will stimulate the generation of new preventive therapies and treatment options for AD able to address its multifactorial pathology before the disease progresses to the symptomatic stage.

This review has provided a vast array of evidence to demonstrate that utilization of various classes of anti-hypertensive drugs can reduce AD risk and pathological severity, with some classes being more effective compared to other. Based on the data we complied, strong evidence points to ARBs and diuretics to most significantly reduce AD risk, AD pathology and symptomology. Even more recently, strong evidence has begun to accumulate in favor of carbonic anhydrase inhibitors being promising novel AD treatments due their ability to be neuroprotective and prevent several aspects of AD pathology, including mitochondrial dysfunction, ROS production, cerebrovascular cell death, and neuroinflammation, as well as to promote cerebrovascular reactivity, cerebral blood flow, and reduce hypertension. It is becoming increasingly clear that AD is a multifactorial disease with many risk factors and that development of AD pathology is caused by much more than just Aβ or tau. Most of the available treatments and therapies for AD and dementia focus on targeting amyloid, but there has been a high failure rate of amyloid-only targeting therapies. Although amyloid is an important player in AD pathology, it is vital that we expand our pathological targets and acknowledge the multifactorial nature of dementia and AD syndromes. It is vital that multi-target therapies for AD begin to be developed, including some that focus on targeting the impact that the CV risk factors that we discussed. Carbonic anhydrase inhibitors not only can reduce hypertension, but also target the vascular cells and specifically the mitochondria to combat AD pathology, including the detrimental effects of Aβ, and possibly improve clearance through the stimulation of cerebral blood flow. MTZ and ATZ are also FDA approved, safe, and they are known to pass the BBB. Additional animal studies by our group and collaborators are in progress with very promising results, and if confirmed, clinical trials should be designed to test these compounds in MCI or even SCI subjects.

In conclusion, both midlife hypertension and hyperhomocystenemia, which also increases the risk for hypertension, play a prominent role in increasing AD risk and cerebrovascular pathology in the aging population. This review clearly demonstrates that regardless of Aβ and tau pathology levels, the consequences of cardiovascular risk factors, such as increased oxidative stress and reactive oxygen species, cerebral hypoperfusion, dysregulation of Ca2+ signaling, lead to increased synaptic loss and eventually cognitive impairment. It is likely that the presence of cardiovascular risk factors leaves individuals more susceptible to synaptic loss and dysfunction and cognitive impairment and primes individuals for the negative cerebral effects that Aβ and tau accumulation confer. Hence, just as proposed in the Berlin Manifesto regarding stroke and dementia risk, and based on the evidence outlined here, it is likely that a potential roadmap to combating dementia can be achieved by preventing other cardiovascular risk factors besides stroke, including hypertension and Hhcy44. Future studies should continue to explore which drugs could most effectively reduce midlife hypertension and thus be used as a prevention strategy to reduce individual’s risk for AD development and cognitive decline. Drugs able to treat both disorders in people presenting with comorbid AD/CAA and hypertension, or other cardiovascular risk factors, should also be explored. To reduce the impact of cardiovascular risk factors, such as hypertension and hyperhomocystenemia, on risk of AD pathology, AD clinical treatment should strive to be more preventative rather than only focusing on symptoms reduction. The increased investigation and development of drugs targeting simultaneously multiple pathways responsible for AD, such as cardiovascular/cerebrovascular compromise, synaptic loss, Ca2+ signaling dysregulation as well as inflammatory, mitochondrial stress and cell death pathways, will be likely to produce more effective therapeutic strategies for this extremely devastating and multifactorial neurodegenerative disease. Additionally, the identification of novel biofluid and genetic biomarkers that have the capability of differentiating AD from vascular forms of dementia as well as pin-pointing specific vascular comorbidities, can be repurposed to also detect the risk for developing AD and vascular dementia. This will allow for earlier detection of dementia risk and thus earlier clinical intervention to delay disease onset and reduce severity of pathology, thus paving the way for preventive dementia medicine.

1. Systematic review:

The authors reviewed the literature using PubMed. Cerebrovascular dysfunction is a major contributor to Alzheimer’s Disease (AD) and dementia. Recent evidence suggests that cardiovascular (CV) risk factors, such as mid-life hypertension and blood pressure variability, as well as late-life hypotension and hyperhomocysteinemia, increase risk for dementia and AD as well as contributing to similar causal molecular mechanisms responsible for the disease pathology.

2. Interpretation:

Our findings led to an integrated hypothesis describing the importance of these CV risk factors in the etiology of AD and dementia, as well as pointing to novel potential biomarkers and therapeutic strategies for CV/AD comorbid conditions.

3. Future directions:

The manuscript defines research gaps and proposes that future studies should consider hypertension and HHcy as potential contributors to increased dementia risk, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of subjects who will profit from preventive strategies against dementia.

Acknowledgements

This work was supported by NIH R01NS104127 and R01AG062572 grants, the Edward N. and Della L. Thome Memorial Foundation Awards Program in Alzheimer’s Disease Drug Discovery Research, the Alzheimer’s Association (AARG), the Pennsylvania Department of Heath Collaborative Research on Alzheimer’s Disease (PA Cure) Grant, awarded to SF, and by the Karen Toffler Charitable Trust, and the Lemole Center for Integrated Lymphatics research.

Footnotes

Competing interest: We declare no conflict of interest. SF has US Patent 10780094 for the use of CAIs in Alzheimer’s disease and CAA.

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