The Association Between 24-Hour Blood Pressure Profiles and Dementia

Abstract

Midlife hypertension increases risk for dementia. Around one third of adults have diagnosed hypertension; however, many adults are undiagnosed, or remain hypertensive despite diagnosis or treatment. Since blood pressure (BP) follows a circadian rhythm, ambulatory BP monitoring allows for the assessment of BP over a 24-hour period and provides an important tool for improving the diagnosis and management of hypertension. The measurement of 24-hour BP profiles, especially nocturnal BP, demonstrate better predictive ability for cardiovascular disease and mortality than office measurement. However, few studies have examined 24-hour BP profiles with respect to dementia risk. This is an important topic since improvements in BP management could facilitate the primary prevention of vascular cognitive impairment and dementia. Therefore, this review discusses the evidence linking BP to dementia, with a focus on whether the implementation of 24-hour BP measurements can improve risk prediction and prevention strategies. Pathways linking nocturnal BP to dementia are also discussed as are risk reduction strategies. Overall, limited research suggests an association between 24-hour BP elevation and poorer cognition, cerebral small vessel disease, and dementia. However, most studies were cross-sectional. Further evidence is needed to substantiate 24-hour BP profiles, over and above office BP, as predictors of vascular cognitive impairment and incident dementia.

Keywords

Alzheimer’s disease ambulatory monitoring blood pressure dementia hypertension

INTRODUCTION

Worldwide, an estimated 1.3 billion people aged 30–79 years (approximately one third) have diagnosed hypertension [1]. Hypertension remains an important public health concern for major cardiovascular disease and mortality [2]. Midlife hypertension is also a known dementia risk factor [3]. The number of individuals with dementia is expected to almost triple from 57.4 million in 2019 to 152.8 million by 2050 [4]. Management of hypertension in midlife represents a potential modifiable risk factor for dementia prevention. However, there remains a gap in both the detection and control of hypertension. Globally, 41–51% of adults remain undiagnosed and while 35–51% of hypertensive individuals receive treatment, less than half of those treated achieve hypertension control [1]. Considering global trends in population aging, better understanding of blood pressure (BP) management as a potential and meaningful protective factor in brain health is thereforecritical.

BP is most typically measured during the day, in a clinical setting using a brachial cuff. Measurement of BP in this manner is known as office BP. Basing clinical decisions on office BP assumes that the obtained BP reading is representative of a patient’s habitual BP levels. However, BP is not static, it is highly dynamic and can change rapidly in response to environmental and physiological demands. Moreover, BP exhibits a strong circadian (24 h) rhythm. Ambulatory BP monitoring allows the assessment of BP over the course of the day and night and provides an important tool for improving the diagnosis and management of hypertension [5]. Despite these advantages, the value of 24-h BP monitoring in the management of hypertension and risk prevention of dementia remains unclear. There is growing evidence that 24-h BP measures are associated with cognitive impairment and dementia [3] and are more strongly related to vascular brain injury compared to office BP [6 –15]. Therefore, this review discusses the evidence linking BP to dementia, with a focus on whether the implementation of 24-h BP measurements can improve risk prediction and prevention strategies. For context, we first provide a brief review of the relationship between hypertension and risk of dementia, possible mechanisms involved and effect of treatment. With this background, we then outline the literature on circadian variation in BP and the links between 24-h BP and dementia risk. Finally, the review discusses the potential benefit of screening and targeted treatment of 24-h BP to improve brain health.

HYPERTENSION AND DEMENTIA

Incidence of dementia in hypertensive individuals

Dementia has a long preclinical phase, with Alzheimer’s disease (AD) patients exhibiting neuropathological changes decades prior to the onset of clinical impairment [16]. Similarly, hypertension can cause the insidious accumulation of cerebral small vessel disease [17]. Therefore, longitudinal and retrospective cohort studies are well suited to examining the relationship between BP and the incidence of dementia due to the likely length of time between occurrence of hypertension and onset of dementia. There is a consistent association between midlife hypertension and AD dementia or all-cause dementia reported in meta-analyses of longitudinal studies [18 –21], where risk increased by 20-75% with history of midlife hypertension (Fig. 1). Studies differ in BP cut-offs used (i.e., systolic BP > 140 or > 160). There is evidence to suggest that risk of dementia increases linearly with systolic BP values over 130 [18]. Meta-analytic results with systolic cut-offs are noted in Fig. 1. Cohort studies considering multiple midlife vascular risk factors in addition to elevated BP, such as hypercholesterolemia and diabetes, demonstrate that the risk of dementia is greater for individuals with multiple vascular risk factors as compared to just hypertension [22 –26].

Fig. 1

A summary of meta-analytic findings on midlife hypertension and dementia risk. Some studies appeared in multiple meta-analyses. Risk statistics reported include hazard ratio (HR), odds ratio (OR), or risk ratio (RR). *Systolic blood pressure≥160 mmHg, **systolic blood pressure = 140-160mmHg, all else systolic blood pressure≥140 mmHg. Lennon (2019) and Norton (2014), Alzheimer’s disease dementia; Sharp (2011), Vascular dementia; all else all cause dementia.

Trajectory of mid to late life hypertension

Whilst there is a demonstrated positive association between midlife hypertension and dementia incidence, the association between late-life hypertension and dementia has been mixed [18 , 28]. It is possible that the trajectory of BP from mid to late life explains these mixed findings with two longitudinal studies demonstrating increased risk of dementia for participants with specific BP change patterns from mid to late life [29, 30]. Predominately, sustained hypertension from mid to late life and a steep decline in BP to late life hypotension were associated with increased risk of dementia compared to mid to late life normotensives [29, 30]. Sustained hypertension from mid to late life has also been associated with greater total brain and grey matter atrophy and subsequent impaired cognitive functioning [31], as well as smaller brain volumes in regions affected in early AD [32].

POTENTIAL MECHANISMS

There are many possible mechanisms that may explain the association between hypertension and dementia. An exhaustive consideration of all mechanisms is beyond the scope of this review. Here we focus on AD pathology, small vessel disease, impaired cerebral blood flow and promotion of oxidative stress and neuroinflammation (Fig. 2). These mechanisms commonly intersect through cerebral hypoperfusion, vascular brain injury (e.g., cerebral microbleeds), impaired autoregulation, blood-brain barrier disruption, and inflammatory pathways. Hypertension is often accompanied by several common comorbidities meaning that hypertension likely affects the development and progression of dementia in conjunction with other vascular risk factors. For example, hypertension increases risk of atrial fibrillation, heart failure, chronic kidney disease, diabetes, and carotid artery stenosis [33 –35]. Further, repeated alcohol consumption, diabetes, and chronic kidney disease are also shown to promote hypertension [36 –38]. Therefore, hypertension presents as one component of the relationship between cardiovascular health and dementia.

Fig. 2

Key potential mechanisms of the hypertension to dementia relationship. Sustained hypertension can directly promote changes to cerebral blood flow, small vessel disease and oxidative stress (white boxes). These changes promote cerebral hypoperfusion and white matter damage, infarcts and haemorrhage (grey boxes). These elements promote key drivers of dementia (white boxes below hypertension) which have multiple causes in addition to factors induced by hypertension, not pictured. The dashed lines represent some of the interconnected relationships between factors that can further accelerate damage.

Alzheimer’s disease pathology

Midlife hypertension may contribute to the development of AD pathology. In mice models, induced hypertension associates with increases in cerebral vascular amyloid deposits, amyloid plaque load and phosphorylated tau levels [39 –42] as well as dysregulated hippocampal gene expression involved in AD [43]. In humans, autopsy research demonstrated that the brains of individuals who had a history of midlife hypertension had increased AD pathology compared to normotensive individuals, including a higher number of neurofibrillary tangles [44] and amyloid plaques [44 –46]. Emerging in vivo research indicates that midlife [47] and late life hypertension [48] are associated with higher CSF pTau181. However, there are conflicting findings for the relationship between BP andin vivo markers of amyloid-β measured with positron emission tomography (PET) [49 –54].

Small vessel disease

Cerebral small vessel disease refers to chronic pathological conditions that damage arterioles and capillaries in the brain and result in microinfarcts, microhemorrhages, and white matter damage including axonal loss and demyelination [55]. Imaging markers include white matter hyperintensities, lacunes, microbleeds, and enlarged perivascular space. Cerebral small vessel disease is a well-established consequence of hypertension [56, 57] and is manifested by reduced cerebral blood flow, blood-brain barrier disruption, inflammation, secondary neurodegeneration, myelin damage, and brain injury itself [58, 59]. Small vessel disease increases risk of dementia [60 –62]. For example, in hypertensive individuals demonstrating marked progression of periventricular white matter hyperintensities, risk of incident dementia was 6.2 times greater than those without white matter hyperintensity progression (95% CI 1.5–25.4) [62]. Small vessel disease may also relate to dementia through contributing to the pathogenesis of AD, where it has been demonstrated that white matter hyperintensities and cerebral microbleeds negatively correlate to CSF amyloid, and positively correlate to cortical amyloid, neurofibrillary tangles, and cortical atrophy in the majority of studies, although limited longitudinal research is available [59].

Cerebral blood flow

Due to the hemodynamic stress, chronic hypertension can lead to vascular wall remodeling and consequent stiffening and narrowing of arterioles [63 –67]. These changes can result in reduced cerebral blood flow and cerebral hypoperfusion [68]. Cerebral blood flow autoregulation is a homeostatic mechanism that acts to maintain consistent perfusion pressure despite changes in arterial BP. In chronically elevated BP and subsequent vascular remodeling, the autoregulation curve is shifted to the right, meaning that the blood vessels require a higher BP to maintain the same level of blood flow to the brain [63]. Individuals with a history of hypertension therefore may also be more susceptible to hypoperfusion in periods of low or normal BP. Chronic hypoperfusion is also closely linked to impaired blood-brain barrier integrity [69] which subsequently promotes neuroinflammation processes and allows permeability of plasma proteins (including amyloid-β) [70 –72]. Additionally, research utilizing mice models have also demonstrated cerebral hypoperfusion as accelerating amyloid-β production and accumulation [73 –78].

Oxidative stress and inflammation

There is a large body of evidence that reports oxidative damage early in the course of AD [79]. Oxidative stress causes an alteration of BACE1, an enzyme involved in the β-secretase cleavage of the amyloid-β protein precursor, resulting in an accumulation of amyloid-β, which in turn promotes further oxidative stress [80]. Hypertension reduces antioxidant capacity and increases concentrations of reactive oxygen species [81], which results in both neuroinflammation and cell death [82, 83]. Neuroinflammation is a key pathological feature of AD and other neurodegenerative diseases [84, 85]. In animal models, hypertension can trigger adverse glial activation and neuroinflammation, followed by increased amyloid-β deposition and tau levels [39, 40]. Taken together, both oxidative stress and neuroinflammation arising from exposure to high pressure can have detrimental impact to brain tissue and formation of plaques. Oxidative stress may also exhibit a bidirectional relationship with hypertension as vascular oxidative stress is shown to also precede hypertension onset [86].

BLOOD PRESSURE LOWERING TO PREVENT DEMENTIA

There have been several meta-analyses that have demonstrated treatment of elevated office BP with anti-hypertensive medication as reducing dementia risk. In a meta-analysis of 14 randomized control trials (n = 96,158), individuals with lowered BP through anti-hypertensives, had a slightly lower risk of dementia or cognitive impairment (OR = 0.93, 95% CI 0.88-0.98) and cognitive decline (OR = 0.93, 95% CI, 0.88-0.99) compared to controls either receiving placebo (10 studies), an alternative antihypertensive agent (1 study), or higher BP targets (3 studies) [87]. Recent additional analyses of randomized controlled trials (RCTs) [88] and observational studies [89] demonstrate a 12-16% reduced risk of all cause dementia or AD dementia from anti-hypertensive use compared to non-use [89]. The effect sizes of anti-hypertensive treatment on dementia are small across studies and while there is good emerging evidence to support their use, most RCTs naturally have a short follow-up duration and therefore the efficacy of BP lowering specifically in midlife in reducing late life dementia or AD is not determined.

Alzheimer’s disease pathology

Lowering BP through anti-hypertensive medication may also limit AD neuropathology and slow progression of mild cognitive impairment. In a recent autopsy study, individuals with a history of anti-hypertensive medication use were compared to those with hypertension who were unmedicated [90]. While there was no difference in the number of amyloid-β and tau proteins, there was a reduction in spread of these proteins across the brain in those with a history of anti-hypertensive use. For example, medicated individuals had a 7.4 times greater chance of being in the less severe amyloid-β group as opposed to the most severe group than someone who was not medicated for hypertension. In an additional postmortem study, individuals who used anti-hypertensive medication had significantly lower mean neuritic plaques and neurofibrillary tangles, compared to unmedicated hypertensive individuals and even lower levels compared to those without history of hypertension [91]. Several studies suggest the possibility that anti-hypertensives that either act on the renin angiotensin system [92, 93] or reduce neuroinflammation [84] may serve neuroprotective effects [84 , 93]. However, as meta-analytical results report no differences by class of medication in risk of dementia [89, 94], managing elevated BP may be more important than any specific anti-hypertensive medication use.

HYPERTENSION AND DEMENTIA CONCLUSIONS

There is strong epidemiological evidence to suggest hypertension in midlife relates to an increased risk of dementia. Therefore, management of hypertension is currently purported as a modifiable strategy for dementia prevention [3]. While there is good public awareness of hypertension as a major health risk factor, there are still a substantial number of individuals that remain undiagnosed, untreated, or with persistent hypertension despite treatment [1]. One potential opportunity for improvement in the way hypertension is detected, managed, and researched is 24-h BP monitoring.

BLOOD PRESSURE OVER 24 HOURS

Research on the relationship between BP and dementia largely ignores that BP follows a 24-h circadian rhythm (see Fig. 3) [95]. During the first half of nocturnal sleep, systolic BP (and to a lesser extent diastolic BP) falls 10-20% compared to daytime BP. This is followed by a slow rise during late sleep eventually leading to a morning surge where BP peaks upon awakening. BP falls mildly during the afternoon and rises mildly before sleep. 24-h BP changes are measured and quantified in a variety of ways including: dippers/non-dippers (i.e., nocturnal BP fall/non-fall), average day and night BP, BP variability ratio (24-h systolic BP standard deviation (SD) over diastolic SD), and coefficient of variation. There are four distinct patterns in nocturnal BP variation: an extreme dipper demonstrated a decline in BP by > 20%; a dipper, between 10 and 20% reduction; non-dipper < 10% reduction, and riser or reverse dipper, where BP increases during sleep [96]. However, these cut-off values are arbitrary [97].

Fig. 3

Simplified 24 h systolic blood pressure patterns. A simplified demonstration of four key systolic blood pressure patterns over a 24 h period. The duration of nocturnal BP (i.e., when the individual is asleep) is highlighted in the light grey box. From top to bottom, the lines within the grey box represent the following: rising blood pressure (grey dashed line), non-dipping blood pressure (black dashed line), normal dipping blood pressure (solid red line), and extreme differs (dark grey dashed line).

Measuring BP over 24 h can identify masked hypertension, where individuals present with a normal in office BP but an elevated out of office BP [98]. Individuals with masked hypertension may make up around 10% of the general population and are not identified by routine clinical examination yet still present with adverse lifetime effects of hypertension [98]. Of note, in a study of nearly 6,000 individuals not using anti-hypertensives, one in six had elevated office BP, yet one in three had elevated 24-h, daytime, or nocturnal average BP [99]. Further, in hypertensive individuals (n = 42,947), 41% of those untreated were found to have non-dipping BP and 53% who were treated with anti-hypertensive medication had non-dipping BP [100]. Measuring out of office 24-h BP can therefore identify hypertensive individuals unable to be detected during standard office BP assessments.

Why blood pressure changes over 24 hours

The circadian regulation of BP occurs through neurohormonal factors, vascular tone, the autonomic nervous system (ANS), and the renal system [95]. Vagal parasympathetic activity dominates during sleep and sympathetic nervous system activity dominates during wakefulness [95]. BP dipping occurs during the shift from sympathetic to parasympathetic activity. It is believed that autonomic dysfunction, via sympathetic overactivity primarily underlies non-dipping patterns [101 –105]. Impaired ANS activity at age 65 (especially lower sympathetic tone) measured by 24-h heart rate variability, has also demonstrated to precede shifting to non-dipping status two years later [106]. Sleep disruption including obstructive sleep apnea (OSA), short sleep, insomnia, and poor sleep quality are associated with non-dipping BP patterns [107 –110], as well as cognitive impairment and dementia [111 –113]. These sleep pathologies are associated with increased sympathetic activity [114 –117] which is known to be involved in the development of hypertension [118].

24-hour blood pressure, cerebrovascular and cardiovascular outcomes

24-h BP compared to office BP suggest better predictive ability for cardiovascular events, and all-cause, cardiovascular, and stroke mortality [6 –15], and night-time BP as superior to daytime measures in predicting outcomes [6 , 119]. Those who do not demonstrate nocturnal BP fall, non-dippers, risers, and also extreme dippers, experience greater cardiovascular risk and target organ damage compared to normal dippers [6 , 121]. Specifically, non-dipping was related to a 1.5-3.3 times greater risk of developing cardiovascular disease [122]. Controlling nocturnal BP has also demonstrated to protect against stroke and cardiovascular events, with hypertensive individuals treated for nocturnal BP demonstrating significantly lower relative risk of total cardiovascular events than those treated for daytime hypertension (RR = 0.39, 95% CI 0.3–0.5; number of events 187 versus 68; p < 0.001) [122]. Much of the research to date on 24-h BP however has focused on cardiovascular disease outcomes rather than dementia.

24-HOUR BLOOD PRESSURE RELATIONSHIP TO DEMENTIA

While elevated 24-h BP profiles may be a stronger predictor of cardiovascular events than office BP, the literature on 24-h BP as predictive of dementia is less defined. However, there are several small community-based studies that have demonstrated links between elevated and abnormal 24-h BP profiles and dementia, AD, cognitive impairment, or small vessel disease (see Tables 1–3). This evidence is summarized below.

Table 1

24-hour Blood Pressure, Dementia, and Alzheimer’s Disease

Citation	Country	Participants (clinical diagnosis, n)	Baseline Age; Sex	24-h Blood Pressure Outcome	Key Findings
Cross-Sectional Studies
[174]	China	310 participants (AD = 130, CU = 188)	65-80 y; 46% Female	Dipping status Mean 24-h BP Mean nocturnal BP	Compared to controls, AD participants more likely to be reverse dippers and non-dippers, less likely to be normal or extreme dippers. Compared to controls, AD participants had significantly higher 24-h BP. Compared to controls, AD participants had significantly higher nocturnal systolic BP.
[175]	Romania	90 participants (AD = 30, VaD = 30, CU = 30)	69.8 – 80.2 y; 52% Female	Dipping Status Mean nocturnal BP	Compared to controls, DU participants more likely to be reverse dippers and non-dippers. Compared to controls, VaD participants had significantly higher nocturnal systolic BP.
[176]	Korea	100 participants (AD = 37, MCI = 24, SMI = 17, CU = 25)	70 y (mean); 73% Female	Mean Dipping Dipping Status	Compared to controls, AD participants had reduced nocturnal BP dipping. Compared to controls, AD participants more likely to be reverse dippers.
[177]	Japan	31 hospitalized participants (8 = AD, CU = 23)	80-86 y, unknown sex	Dipping status	AD patients experienced no dipping.
[178]	Japan	137 participants with PD (PDD = 27, PD without dementia = 110)	64.1 y (mean), 54% Female	Dipping status	Compared to PD without dementia, PDD participants were more likely to be reverse dippers and have orthostatic hypotension.
[179]	Japan	200 participants with first-time symptomatic lacunar infarcts (DU = 26, MCI = 15)	68.8 y (mean), 39% Female	Dipping status	Compared to controls, DU, and MCI participants more likely to be reverse dippers and non-dippers.
Longitudinal Studies
[123]	Venezuela	1,320 participants from the Maracaibo Aging Study (CU at baseline),≤5.3 y	57-85.4 y (at follow-up), 70% Female	Mean nocturnal BP Treated nocturnal BP	Higher nocturnal systolic BP was associated with AD incidence, only among participants carrying APOE-4. Nocturnal systolic BP successfully treated by anti-hypertensives was associated with lower AD risk.
[124]	Sweden	611 participants (CU at baseline),≤24 y	71 y (mean), 0% Female	Dipping status	Reverse dippers but not reduced dipping was association with higher DU and AD risk but not VaD.

AD, Alzheimer’s disease; CU, Cognitive unimpaired; DU, dementia unspecified; MCI, mild cognitive impairment; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; SMI, subjective memory impairment; VaD, vascular dementia; y, years.

Table 2

24-hour blood pressure and cognitive impairment

Citation	Country	Participants (clinical diagnosis, n)	Baseline Age; Sex	Cognitive Testing	24-h Blood Pressure Outcome	Key Findings
Cross-sectional Studies
[125]	Japan	144 participants from the J-SHIPP study	68 y (mean); 34% Female	Mild Cognitive Impairment Screen	Mean 24-h BP Dipping status	24-h BP did not differ between MCI participants and CU controls.Frequency of MCI was significantly higher in the extreme dippers, non-dippers and risers than dippers.
[129]	Venezuela	435 participants from the Maracaibo Aging Study	59 y (mean), 69% Female	Cambridge Neuropsychological Test Automated Battery	Dipping Status	Dipping status moderated the effect of hypertension on learning scores.
[130]	US	121 participants from The 90 + Study.	93 y (mean), 70% Female	Assorted neuropsychological testing*	Dipping status	CU participants had greater nocturnal dips compared to impaired individuals. Below norm performance in cognitive testing was associated with smaller nocturnal dips.
[131]	Spain	699 participants from ISSYS project (MCI = 71, CU = 628)	62.8 y (mean); 50.1% Female	Dementia Rating Scale 2^nd Version	Mean nocturnal pulse pressure	Higher nocturnal pulse pressure measurements were associated with MCI
[134]	US	199 participants from the INFINITY trial	81.2 y, 54.3% Female	Mini-Mental State Exam, Trail Making Test, Stroop	Mean 24-h BP Mean nocturnal BP Dipping status	Worse cognitive performance was associated with greater 24-h systolic BP and nocturnal diastolic BP. Cognitive testing was comparable in dippers and non-dippers, but trail making test times were slightly longer in dippers compared to non-dippers.
[180]	Sweden	999 men	70 y; 0% Female	Mini-Mental State Exam, Trail Making Test	Mean 24-h BP, Mean nocturnal BP Dipping status	High 24-h BP was related to worse cognitive scores. Mean nocturnal diastolic BP exhibited the strongest linear relationship to poorer cognitive performance. Non-dippers had lower mean cognitive scores than dippers.
[181]	Netherlands	115 participants in the Maastricht Aging Study	28-82 y, 41% Female	Word Learning Task, Concept Shifting Task, Stroop	Day to night BP ratio	Absolute and relative differences in day– night BP were positively correlated with memory performance.
[182]	Japan	148 treated hypertensives	75.5 y (mean), 70% Female	Mini-Mental State Exam	Mean nocturnal BP Dipping status	High nocturnal systolic BP was related to lower cognitive scores. Cognitive scores were related to less dipping.
Longitudinal Studies
[126]	US	224 participants from CARDIA study, 20-y follow up	30 y (mean), 55% Female	Stroop, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test	Mean nocturnal BP Dipping status	Only Stroop scores at follow-up were associated with reduced systolic BP dipping and increased nocturnal diastolic BP at baseline.
[127]	China	305 participants CU at baseline (MCI at follow up = 130), 2-y follow up	80.6 y (mean), 31% Female	Mini-Mental State Exam	Dipping status Mean nocturnal BP	Reverse dipping was associated with MCI. Higher nocturnal systolic BP was associated with MCI.

ISSYS project, Investigating Silent Strokes in hypersensitive individuals, a magnetic resonance imaging Study; INFINITY, INtensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional DeclINe In The ElderlY; Stroop, Stroop Color Word Test; MCI, mild cognitive impairment; CU, cognitively unimpaired; y, years. *Completed a battery of 10 neuropsychological tests and neurological exam.

Table 3

24-hour blood pressure and cerebral small vessel disease markers

Citation	Country	Participants (clinical diagnosis, n)	Baseline Age; Sex	Imaging Marker	24-h Blood Pressure Outcome	Key Findings
Cross-Sectional Studies
[129]	Venezuela	435 participants from the Maracaibo Aging Study (CU)	59 y (mean), 71% Female	WMH	Dipping status	Reverse dipping BP was associated with WMH volume.
[130]	US	121 participants from the 90 + Study	93 y (mean), 70% Female	WMH and Cerebral Microbleeds	Dipping status	Diastolic reverse dippers had greater proportion of WMH and cerebral microbleeds compared to extreme dippers, dippers and non-dippers.
[131]	Spain	699 participants from ISSYS project (MCI = 71, CU = 628)	62.8 y (mean), 50.1% Female	WMH	Mean nocturnal pulse pressure	Higher nocturnal pulse pressure measurements were associated with WMH.
[132]	China	188 participants with HTN (SCI = 111, non-SCI=77)	64 y (mean), 57% Female	SCI	Dipping status	Compared to dippers, non-dippers were more likely to have SCI.
[134]	US	199 participants from the INFINITY trial (CU)	81.2 y, 54.3% Female	WMH	Mean 24-h BP Dipping status	Mean systolic BP was positively associated with WMH burden. WMH volume was significantly lower in dippers compared to non-dippers.
[183]	Canada	345 participants (CU)	69.9 y (mean), 60% Female	Brain Volume	Dipping status	Systolic dipping was negatively associated with right and total hippocampal volume.
[184]	US	80 participants (stroke history = 37, non-stroke=43)	66.4 y (mean), 51% Female	Brain Volumes and Perfusion	Dipping status Mean 24-h BP	Blunted systolic nocturnal dipping was associated with greater brain atrophy. Higher mean 24-h BP was associated with lower cerebral perfusion but not atrophy.
Longitudinal Studies
[127]	China	305 participants (CU at baseline), 2-y follow up	80.6 y (mean), 31% Female	WMH	Dipping status	Nocturnal BP rise was associated with increased white matter hyperintensities.
[128]	US	72 participants (CU at baseline), 2-y follow up	82.1 y (mean), 60%	WMH	Mean 24-h BP	Increased WMH from baseline to follow up was associated with changes in 24-h systolic BP but not changes in office BP.
[133]	US	67 participants (CU at baseline), 4-y follow up	81.7 y (mean), 61% Female	WMH	Mean 24-h BP	Average 24-h BP at 2 and 4 y, but not office BP at any time point, was associated with total WMH at 4 y.
[185]	China	2,091 participants (CU), 5-y average follow up	67.8 y (mean), 55.3% Female	WMH, lacunes, microbleeds	Dipping status.	Extreme dippers, non-dippers and reverse dippers had greater WMH volume compared with dippers. Non-dippers and reverse dippers had higher rates of new-incident lacunes and microbleeds than dippers.

MCI, mild cognitive impairment; CU, cognitively unimpaired; HTN, hypertension; WMH, white matter hyperintensities; SCI, silent cerebral infarct; y, years; INFINITY, INtensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional DeclINe In The ElderlY.

24-hour blood pressure and risk of dementia

Cross-sectional research has indicated that dementia patients have higher BP during sleep, including significantly more incidences of non-dipping BP and rising BP profiles compared to healthy older adults across six studies of 845 individuals (see Table 1). In our literature search, no research to date has investigated the prospective association between midlife 24-h BP profiles and dementia risk. Limited longitudinal data available supports a relationship with late life 24-h BP profiles and development of dementia and AD [123, 124]. In a cohort of 1,283 men without dementia at baseline (aged 71 or 77 years) followed for up to 24 years, 286 later developed dementia [124]. Compared with normal BP dipping, those with reverse systolic BP dipping (i.e., rising but not reduced dipping) were more likely to be later diagnosed with all cause dementia (HR = 1.64, 95% CI 1.14–2.34, n = 286), AD dementia (HR = 1.67, 95% CI 1.01–2.76, n = 141), but not vascular dementia (HR = 1.29, 95% CI 0.55–3.06, n = 48), although the number of individuals with vascular dementia was considerably small. A similar study included 1,320 adults aged 57-85 years without dementia at baseline followed for an average of 5.3 years [123]. Those who were later clinically diagnosed with AD had significantly higher 24-h average BP and nocturnal systolic BP compared to those free from dementia, but only if they were also carrying the APOE4 allele. Additionally, in this study, individuals who were using anti-hypertensives had a reduced risk of AD dementia compared to untreated hypertensive individuals.

24-hour blood pressure, mild cognitive impairment, and cognitive functioning

Elevated nocturnal BP, non-dipping, elevated 24-h BP, and elevated nocturnal pulse pressure in adults is associated with mild cognitive impairment and worse cognitive functioning in mostly cross-sectional analyses (see Table 2). For example, in 144 older adults, mild cognitive impairment occurred more in extreme dippers (32%), non-dippers (30%), and risers (50%) than in normal dippers (13.2%, p = 0.018), even after adjusting for the APOE4 allele [125]. Moreover, in younger adults (mean age = 30 years), reduced nocturnal systolic dipping and higher diastolic BP levels were associated with worse executive functioning at follow-up 20 years later, independent of office BP [126]. Additionally, the relationship between abnormal 24-h BP profiles and poorer cognitive functioning also appeared to be mediated by MRI markers of small vessel disease [127 –132].

24-hour blood pressure and cerebral small vessel disease

High 24-h BP and abnormal dipping are also associated with imaging markers of cerebral small vessel disease across multiple studies (see Table 3). 24-h BP measurement may also be a better predictor of WMH than office BP. That is, studies that include both office and 24-h BP measures, demonstrate significant associations with WMH for 24-h BP but not office BP [128 , 134]. The effect of lowering 24-h BP on WMH outcomes has been conducted in a single clinical trial of older adults (the INFINITY trial; M = 80.5 years, n = 199) [135]. Mean 24-h BP lowering was achieved at either a standard (systolic BP≤145 mm Hg) or intensive (≤130 mm Hg) level. Followed for 3 years, participants with intensive BP lowering had greater reduction in WMH volumes (-0.48%) compared to standard BP lowering (-0.29%), p = 0.03) and less cardiovascular events (RR = 0.24, 95% CI, 0.08 – 0.68), although no significant changes in cognition.

Mechanisms linking 24-h blood pressure to dementia

The mechanisms previously discussed to explain the relationship between hypertension and dementia are still applicable for elevated 24-h BP. Monitoring 24-h BP provides a more complete picture of an individual’s BP profile and abnormal nocturnal BP patterns may cause further stress on the vasculature. In addition to the outlined mechanisms, elevated nocturnal BP offers a potential additional mechanism in promoting AD through disruption of the glymphatic transport system. The glymphatic system facilitates the clearance of amyloid and other toxic proteins primarily during sleep [136]. This system is shown to be impaired in early and advanced hypertension in rodents [137]. Inducing hypertension in mice resulted in a reduction in flow of cerebrospinal fluid through perivascular space [138]. It is possible the nocturnal BP dip may play an essential role in the glymphatic system’s efficacy, and when disrupted could result in amyloid-β accumulation and subsequent development of AD. In patients with amnestic mild cognitive impairment, reduced BP dipping was associated with increased amyloid-β burden (captured through PET imaging) in the posterior cingulate and altered cerebral blood flow (n = 35) [139]. Additionally, the majority of OSA patients (around 80%) experience non-dipping BP patterns [107 , 140]. It has been demonstrated in longitudinal studies that OSA is associated with increases in amyloid burden [141 –143] and in emerging evidence hypertension (as indicated by office measures) strengthened this relationship (n = 98, M_age = 69.6 years; B = 23.11; 95% CI: 23.71 - 22.51; p = 0.01) [144]. It is expected, but not yet identified, that nocturnal hypertension would exhibit similar or stronger effects. Though there appears to be a role of nocturnal BP dipping in glymphatic clearance of amyloid-β, alternatively, disturbed nocturnal BP may also be a sign of amyloid accumulation and an early indicator of AD progression. Several studies of mice have demonstrated that amyloid deposition in the brain can also lead to the disruption of normal sleep architecture, often prior to the appearance of amyloid plaques [145].

IMPROVING 24-HOUR BLOOD PRESSURE PROFILES

Despite advances in understanding the role of 24-h BP in cardiovascular and brain health, to date, research on BP lowering to prevent dementia is limited to office BP measures. Individuals who successfully lower office BP but remain with undetected nocturnal hypertension could attenuate the effect size of anti-hypertensive use on dementia risk. However, as trials using anti-hypertensive medications target office BP and not 24-h BP, this remains unclear. Research is needed to determine if targeting 24-h BP profiles has the potential to demonstrate similar or stronger effects to office BP lowering on risk of dementia. There are multiple successful treatment strategies for reducing BP across 24 h and restoring normal dipping patterns, including medication timing, lifestyle modification and sleep disorder treatment. Utilizing 24-h BP monitoring in treatment strategies has the capacity to better identify and treat hypertension and therefore could be an important avenue for research and clinical practice in the prevention of dementia. For example, chronotherapy, the administration of medication at times determined by circadian rhythms, is a treatment method to improve 24-h BP profiles. Taking at least one anti-hypertensive medication before bed (compared to morning) has shown to help restore normal BP dipping and/or reduce nocturnal systolic BP in the short term [146 –148] and demonstrates reduced risk of major cardiovascular disease events in longitudinal studies [149].

Lifestyle modification

Treatment of hypertension additionally includes lifestyle modification, some of which has also shown to improve 24-h BP profiles. Many kinds of exercise programs have demonstrated as being effective in restoring normal dipping BP patterns and reducing 24-h BP [150 –154]. Salt restriction and increased dietary potassium in salt-sensitive individuals has also shown to restore the dipping BP profile [155].

Treatment of sleep disorders

As sleep plays a key role in BP dipping, treatment of sleep disorders offers a potential method to improve BP profiles. Small clinical trials have repeatedly demonstrated that in hypertensive patients with OSA, treatment with continuous positive airway pressure (CPAP) led to a reduction in mean 24-h BP [156 –161], 24-h pulse pressure [162], and restored normal dipping patterns [163]. Further, CPAP treatment was also lowered BP in patients with treatment resistant hypertension [164, 165]. There is a lack of research on whether restoring normal sleep amongst other sleep disorders demonstrates a similar effect to CPAP as it relates to reducing nocturnal BP.

FUTURE DIRECTIONS

Hypertension is one of the most established risk factors for dementia. Better screening and management of hypertension would likely prove to be beneficial in prevention of dementia. Ambulatory BP monitoring is one such strategy that is not only markedly more effective than office BP in determining masked hypertension, white coat hypertension and treatment resistant hypertension [99 , 167], but also is the only way to identify blunted nocturnal BP dipping of which there is a high prevalence [99, 100]. Further, use of 24-h monitoring for medication timing strategies has the potential to help manage elevated nocturnal BP. Use of 24-h BP monitoring provides a stepping-stone towards improved screening and effective treatment of hypertension and therefore may have an important role in helping to curtail the rising burden of dementia.

Recommendations for use of ambulatory BP monitoring have emerged within the past decade. The latest international clinical guidelines across Europe, the US and Australia recommend ambulatory BP monitoring for better diagnosis of hypertension [168 –170]. Data of ambulatory BP monitoring use in primary care settings suggests that uptake is limited [171 –173]. More evidence is needed to support the use of 24-h BP monitoring in dementia prevention strategies.

This review has identified many research gaps in our knowledge of 24-h BP and dementia (see Fig. 4). Specifically, there is a dearth of longitudinal research that examines effects of elevated 24-h BP profiles over the life course and dementia outcomes. Cohort studies would also provide more detailed analysis of the mechanisms linking 24-h BP profiles to dementia through brain imaging and fluid biomarkers. Furthermore, for 24-h BP lowering to be used as a prevention strategy, intervention trials are much needed, including chronotherapy trials and anti-hypertensive use with nocturnal BP targets. Research is also needed to further understand the role of sleep disorders on nocturnal dipping and dementia risk, including sleep treatment intervention trials.

Fig. 4

Summary of review findings including what is known and future research questions.

CONCLUSION

Persistent elevated BP harms the brain in a way that increases risk for dementia. Addressing the future public health burden of dementia means improving the way we identify, treat, and manage elevated BP, as there are major gaps in clinical practice and research. It is suggested that 24-h BP monitoring will help bridge some of these gaps. Elevated 24-h BP patterns are well researched as being better predictors of cardiovascular and mortality outcomes in comparison to office BP; similar studies are needed with dementia as an outcome. The limited research conducted to date with 24-h BP suggests that abnormal 24-h BP, especially blunted nocturnal dipping, is associated with higher dementia incidence, along with markers of brain injury. Although persistent knowledge gaps raise uncertainties in the relationship between 24-h BP and dementia, 24-h BP measurement has good clinical utility for identifying and treating the large number of individuals experiencing nocturnal hypertension and consequently could have a key role in risk reduction for dementia.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

MPP is supported by a National Health and Medical Research Council of Australia Emerging Leader 2 Investigator Grant Fellowship (GTN2009264). SY is supported by an Alzheimer’s Association Research Grant – New to the Field (AARG-NTF-22-971405). MG is supported by an Australian Government Research Training Program (RTP) Scholarship.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

References

NCD Risk Factor Collaboration (NCD-RisC) (2021) Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: A pooled analysis of 1201 population-representative studies with 104 million participants. Lancet 398, 957–980.

Zhou

, Perel

, Mensah

, Ezzati

(2021) Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nat Rev Cardiol 18, 785–802.

Livingston

, Huntley

, Sommerlad

, Ames

, Ballard

, Banerjee

, Brayne

, Burns

, Cohen-Mansfield

, Cooper

, Costafreda

, Dias

, Fox

, Gitlin

, Howard

, Kales

, Kivimäki

, Larson

, Ogunniyi

, Orgeta

, Ritchie

, Rockwood

, Sampson

, Samus

, Schneider

, Selbæk

, Teri

, Mukadam

(2020) Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413–446.

GBD Dementia Forecasting Collaborators (2022) Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health 7, e105–e125.

Kario

, Hoshide

, Chia

, Buranakitjaroen

, Siddique

, Shin

, Turana

, Park

, Tsoi

, Chen

, Cheng

, Fujiwara

, Li

, Huynh

, Nagai

, Nailes

, Sison

, Soenarta

, Sogunuru

, Sukonthasarn

, Tay

, Teo

, Verma

, Wang

, Zhang

, Wang

(2021) Guidance on ambulatory blood pressure monitoring: A statement from the HOPE Asia Network. J Clin Hypertens 23, 411–421.

Fagard

, Thijs

, Staessen

, Clement

, De Buyzere

, De Bacquer

(2009) Night-day blood pressure ratio and dipping pattern as predictors of death and cardiovascular events in hypertension. J Hum Hypertens 23, 645–653.

Staessen

, Thijs

, Fagard

, O’brien

, Clement

, De Leeuw

, Mancia

, Nachev

, Palatini

, Parati

, Tuomilehto

, Webster

(1999) Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. JAMA 282, 539–546.

Shen

, Li

, He

, Deng

, Liu

, Shen

(2017) Comparison of ambulatory blood pressure and clinic blood pressure in relation to cardiovascular diseases in diabetic patients. Medicine (Baltimore) 96, e7807.

Kikuya

, Ohkubo

, Asayama

, Metoki

, Obara

, Saito

, Hashimoto

, Totsune

, Hoshi

, Satoh

, Imai

(2005) Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: The Ohasama study. Hypertension 45, 240–245.

10.

Dolan

, Stanton

, Thijs

, Hinedi

, Atkins

, McClory

, Hond

E Den

, McCormack

, Staessen

, O’Brien

(2005) Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: The Dublin outcome study. Hypertension 46, 156–161.

11.

Verdecchia

, Porcellati

, Schillaci

, Borgioni

, Ciucci

, Battistelli

, Guerrieri

, Gatteschi

, Zampi

, Santucci

, Reboldi

(1994) Ambulatory blood pressure an independent predictor of prognosis in essential hypertension. Hypertension 24, 793–801.

12.

Clement

, De Buyzere

, De Bacquer

, de Leeuw

, Duprez

, Fagard

, Gheeraert

, Missault

, Braun

, Six

, Van Der Niepen

, O’Brien

; Office versus Ambulatory Pressure Study Investigators (2003) Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 348, 2407–2415.

13.

Sega

, Facchetti

, Bombelli

, Cesana

, Corrao

, Grassi

, Mancia

(2005) Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: Follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 111, 1777–1783.

14.

Hansen

, Kikuya

, Thijs

, Björklund-Bodegård

, Kuznetsova

, Ohkubo

, Richart

, Torp-Pedersen

, Lind

, Jeppesen

, Ibsen

, Imai

, Staessen

; IDACO Investigators (2007) Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: A meta-analysis of 7030 individuals. J Hypertens 25, 1554–1564.

15.

Yano

, Tanner

, Sakhuja

, Jaeger

, Booth

, Abdalla

, Pugliese

, Seals

, Ogedegbe

, Jones

, Muntner

, Shimbo

(2019) Association of daytime and nighttime blood pressure with cardiovascular disease events among African American individuals. JAMA Cardiol 4, 910–917.

16.

Bateman

, Xiong

, Benzinger

TLS

, Fagan

, Goate

, Fox

, Marcus

, Cairns

, Xie

, Blazey

, Holtzman

, Santacruz

, Buckles

, Oliver

, Moulder

, Aisen

, Ghetti

, Klunk

, McDade

, Martins

, Masters

, Mayeux

, Ringman

, Rossor

, Schofield

, Sperling

, Salloway

, Morris

(2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367, 795–804.

17.

Petrea

, O’Donnell

, Beiser

, Habes

, Aparicio

, Decarli

, Seshadri

, Romero

(2020) Mid to late life hypertension trends and cerebral small vessel disease in the Framingham Heart Study. Hypertension 76, 707–714.

18.

, Tan

, Shen

, Xu

, Hou

, Dong

, Tan

, Yu

(2020) Blood pressure and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 209 prospective studies. Hypertension 76, 217–225.

19.

Lennon

, Makkar

, Crawford

, Sachdev

(2019) midlife hypertension and Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 71, 307–316.

20.

Sharp

, Aarsland

, Day

, Sønnesyn

, Ballard

(2011) Hypertension is a potential risk factor for vascular dementia: Systematic review. Int J Geriatr Psychiatry 26, 661–669.

21.

Norton

, Matthews

, Barnes

, Yaff

, Brayne

(2014) Potential for primary prevention of Alzheimer’s disease: An analysis of population-based data. Lancet Neurol 13, 788–794.

22.

Kivipelto

, Helkala

, Laakso

, Hänninen

, Hallikainen

, Alhainen

, Soininen

, Tuomilehto

, Nissien

(2001) Midlife vascular risk factors and Alzheimer’s disease in later life: Longitudinal, population based study. BMJ 322, 1447–1451.

23.

Whitmer

, Sidney

, Selby

, Claiborne Johnston

, Yaffe

(2005) Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64, 277–281.

24.

Gottesman

, Albert

, Alonso

, Coker

, Coresh

, Davis

, Deal

, McKhann

, Mosley

, Sharrett

, Schneider

ALC

, Windham

, Wruck

, Knopman

(2017) Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) cohort. JAMA Neurol 74, 1246–1254.

25.

Virta

, Heikkilä

, Perola

, Koskenvuo

, Räihä

, Rinne

, Kaprio

(2013) Midlife cardiovascular risk factors and late cognitive impairment. Eur J Epidemiol 28, 405–416.

26.

Malik

, Georgakis

, Neitzel

, Rannikmäe

, Ewers

, Seshadri

, Sudlow

CLM

, Dichgans

(2021) Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank. Alzheimers Dement 17, 1422–1431.

27.

Power

, Weuve

, Gagne

, McQueen

, Viswanathan

, Blackera

(2011) The association between blood pressure and incident alzheimer disease: A systematic review and meta-analysis. Epidemiology 22, 646–659.

28.

, Rhew

, Shofer

, Kukull

, Breitner

JCS

, Peskind

, Bowen

, McCormick

, Teri

, Crane

, Larson

(2007) Age-varying association between blood pressure and risk of dementia in those aged 65 and older: A community-based prospective cohort study. J Am Geriatr Soc 55, 1161–1167.

29.

Walker

, Sharrett

, Wu

, Schneider

ALC

, Albert

, Lutsey

, Bandeen-Roche

, Coresh

, Gross

, Windham

, Knopman

, Power

, Rawlings

, Mosley

, Gottesman

(2019) Association of midlife to late-life blood pressure patterns with incident dementia. JAMA 322, 535–545.

30.

McGrath

, Beiser

, DeCarli

, Plourde

, Vasan

, Greenberg

, Seshadri

(2017) Blood pressure from mid- to late life and riskof incident dementia. Neurology 89, 2447–2454.

31.

Muller

, Sigurdsson

, Kjartansson

, Aspelund

, Lopez

, Jonnson

, Harris

, van Buchem

, Gudnason

, Launer

; Age, Gene/Environment Susceptibility-Reykjavik Study Investigators (2014) Joint effect of mid-and late-life blood pressure on the brain: The AGES-Reykjavik Study Neurology 82, 2187–2195 .

32.

Power

, Schneider

ALC

, Wruck

, Griswold

, Coker

, Alonso

, Jack

Jr , Knopman

, Mosley

, Gottesman

(2016) Life-course blood pressure in relation to brain volumes. Alzheimers Dement 12, 890–899.

33.

Verdecchia

, Angeli

, Reboldi

(2018) Hypertension and atrial fibrillation. Circ Res 122, 352–368.

34.

Fuchs

, Whelton

(2020) High blood pressure and cardiovascular disease. Hypertension 75, 285–292.

35.

Greco

, Egorova

, Moskowitz

, Gelijns

, Kent

, Manganaro

, Zwolak

, Riles

(2013) A model for predicting the risk of carotid artery disease. Ann Surg 257, 1168–1173.

36.

Fuchs

, Chambless

, Whelton

, Nieto

, Heiss

(2001) Alcohol consumption and the incidence of hypertension. Hypertension 37, 1242–1250.

37.

Epstein

, Sowers

(1992) Diabetes mellitus and hypertension. Hypertension 19, 403–418.

38.

Schiffrin

, Lipman

, Mann

(2007) Chronic kidney disease. Circulation 116, 85–97.

39.

Shih

, Wu

, Yu

, Huang

, Lee

, Jiang

, Lin

, Yang

, Kuo

(2018) Hypertension accelerates Alzheimer’s disease-related pathologies in pigs and 3xTg mice. Front Aging Neurosci 10, 73.

40.

Carnevale

, Mascio

, D’Andrea

, Fardella

, Bell

, Branchi

, Pallante

, Zlokovic

, Yan

, Lembo

(2012) Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension 60, 188–197.

41.

Kruyer

, Soplop

, Strickland

, Norris

(2015) Chronic hypertension leads to neurodegeneration in the TgSwDI mouse model of Alzheimer’s disease. Hypertension 66, 175–182.

42.

Carnevale

, Mascio

, Ajmone-Cat

, D’Andrea

, Cifelli

, Madonna

, Cocozza

, Frati

, Carullo

, Carnevale

, Alleva

, Branchi

, Lembo

, Minghetti

(2012) Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging 33, 205.e19–29.

43.

Csiszar

, Tucsek

, Toth

, Sosnowska

, Gautam

, Koller

, Deak

, Sonntag

, Ungvari

(2013) Synergistic effects of hypertension and aging on cognitive function and Hippocampal expression of genes involved in β-amyloid generation and Alzheimer’s disease. Am J Physiol Heart Circ Physiol 305, H1120–H1130.

44.

Petrovitch

, White

, Izmirilian

, Ross

, Havlik

, Markesbery

, Nelson

, Davis

, Hardman

, Foley

, Launer

(2000) Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: The HAAS. Neurobiol Aging 21, 57–62.

45.

Ashby

, Miners

, Kehoe

, Love

(2016) Effects of hypertension and anti-hypertensive treatment on Amyloid-β (Aβ) plaque load and Aβ-synthesizing and Aβ-degrading enzymes in frontal cortex. J Alzheimers Dis 50, 1191–1203.

46.

Shah

, Vidal

, Masaki

, Petrovitch

, Webster Ross

, Tilley

, DeMattos

, Tracy

, White

, Launer

(2012) Midlife blood pressure, plasma β-amyloid, and the risk for Alzheimer disease: The Honolulu Asia Aging Study. Hypertension 59, 780–789.

47.

, Meng

, Bi

, Zhang

, Xu

, Shen

, Ou

, Ma

, Dong

, Tan

, Yu

(2022) Tau pathologies mediate the association of blood pressure with cognitive impairment in adults without dementia: The CABLE study. Alzheimers Dement 18, 53–64.

48.

Kester

, van der Flier

, Mandic

, Blankenstein

, Scheltens

, Muller

(2010) Joint effect of hypertension and APOE genotype on CSF biomarkers for Alzheimer’s disease. J Alzheimers Dis 20, 1083–1090.

49.

Rabin

, Schultz

, Hedden

, Viswanathan

, Marshall

, Kilpatrick

, Klein

, Buckley

, Yang

, Properzi

, Rao

, Kirn

, Papp

, Rentz

, Johnson

, Sperling

, Chhatwal

(2018) Interactive associations of vascular risk and β-amyloid burden with cognitive decline in clinically normal elderly individuals findings from the Harvard Aging Brain Study. JAMA Neurol 75, 1124–1131.

50.

Gottesman

, Wu

, Coresh

, Knopman

, Jack

, Rahmim

, Sharrett

, Spira

, Wong

, Wagenknecht

, Hughes

, Walker

, Mosley

(2022) Associations of vascular risk and amyloid burden with subsequent dementia. Ann Neurol 92, 607–619.

51.

Lane

, Barnes

, Nicholas

, Sudre

, Cash

, Parker

, Malone

, Lu

, James

, Keshavan

, Murray-Smith

, Wong

, Buchanan

, Keuss

, Gordon

, Coath

, Barnes

, Dickson

, Modat

, Thomas

, Crutch

, Hardy

, Richards

, Fox

, Schott

(2019) Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): An epidemiological study. Lancet Neurol 18, 942–952.

52.

Rodrigue

, Rieck

, Kennedy

, Devous

, Diaz-Arrastia

, Park

(2013) Risk factors for β-amyloid deposition in healthy aging: Vascular and genetic effects. JAMA Neurol 70, 600–606.

53.

Jeon

, Byun

, Yi

, Lee

, Choe

, Ko

, Sohn

, Choi

, Lee

(2019) Influence of hypertension on brain amyloid deposition and Alzheimer’s disease signature neurodegeneration. Neurobiol Aging 75, 62–70.

54.

Langbaum

JBS

, Chen

, Launer

, Fleisher

, Lee

, Liu

, Protas

, Reeder

, Bandy

, Yu

, Caselli

, Reiman

(2012) Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiol Aging 33, 827.e11–827.e19.

55.

Chojdak-Łukasiewicz

, Dziadkowiak

, Zimny

, Paradowski

(2021) Cerebral small vessel disease: A review. Adv Clin Exp Med 30, 349–356.

56.

Hilal

, Mok

, Youn

, Wong

, Ikram

, Chen

(2017) Prevalence, risk factors and consequences of cerebral small vessel diseases: Data from three Asian countries. J Neurol Neurosurg Psychiatry 88, 669–674.

57.

Huang

, Zhou

, Yuan

, Zhang

, Li

, You

, Zhu

, Sun

(2022) Contribution of inflammation and hypoperfusion to white matter hyperintensities-related cognitive impairment. Front Neurol 12, 786840.

58.

Wardlaw

, Smith

, Dichgans

(2019) Small vessel disease: Mechanisms and clinical implications. Lancet Neurol 18, 684–696.

59.

Kim

, Hong

, Jeon

(2020) Cerebral small vessel disease and Alzheimer’s disease: A review. Front Neurol 11, 927.

60.

Rensma

, van

Sloten TT

, Launer

, Stehouwer

CDA

(2018) Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-analysis. Neurosci Biobehav Rev 90, 164–173.

61.

Vermeer

, Prins

, den Heijer

, Hofman

, Koudstaal

, Breteler

, Sev

(2003) Silent brain infarcts and the risk of dementia and cognitive decline from the departments of epidemiology. N Engl J Med 13, 1215–1237.

62.

Jiménez-Balado

, Riba-Llena

, Abril

, Garde

, Penalba

, Ostos

, Maisterra

, Montaner

, Noviembre

, Mundet

, Ventura

, Pizarro

, Delgado

(2019) Cognitive impact of cerebral small vessel disease changes in patients with hypertension. Hypertension 73, 342–349.

63.

Pires

, Dams

Ramos CM

, Matin

, Dorrance

(2013) The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol 304, H1598–H1614.

64.

Humphrey

(2021) Mechanisms of vascular remodeling in hypertension. Am J Hypertens 34, 432–441.

65.

Laurent

, Boutouyrie

(2015) The structural factor of hypertension: Large and small artery alterations. Circ Res 116, 1007–1021.

66.

Levy

, Schiffrin

, Mourad

, Agostini

, Vicaut

, Safar

, Struijker-Boudier

(2008) Impaired tissue perfusion a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 118, 968–976.

67.

Iadecola

, Davisson

(2008) Hypertension and cerebrovascular dysfunction. Cell Metab 7, 476–484.

68.

Muller

, van der Graaf

, Visseren

, Mali

, Geerlings

; SMART Study Group (2012) Hypertension and longitudinal changes in cerebral blood flow: The SMART-MR study. Ann Neurol 71, 825–833.

69.

, Bai

, Dong

, Guo

, Cui

(2022) Blood-brain barrier dysfunction and the potential mechanisms in chronic cerebral hypoperfusion induced cognitive impairment. Front Cell Neurosci 16, 870674.

70.

Shekhar

, Liu

, Travis

, Roman

, Fan

(2017) Cerebral autoregulation in hypertension and ischemic stroke: A mini review. J Pharm Sci Exp Pharmacol 2017, 21–27.

71.

Kinnecom

, Lev

, Wendell

, Smith

, Rosand

, Frosch

, Greenberg

(2007) Course of cerebral amyloid angiopathy-related inflammation. Neurology 68, 1411–1416.

72.

Takata

, Nakagawa

, Matsumoto

, Dohgu

(2021) Blood-brain barrier dysfunction amplifies the development of neuroinflammation: Understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front Cell Neurosci 15, 661838.

73.

Koizumi

, Wang

, Park

(2016) Endothelial dysfunction and amyloid-β-induced neurovascular alterations. Cell Mol Neurobiol 36, 155–165.

74.

Shang

, Yamashita

, Tian

, Li

, Liu

, Shi

, Nakano

, Tsunoda

, Nomura

, Sasaki

, Tadokoro

, Sato

, Takemoto

, Hishikawa

, Ohta

, Abe

(2019) Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse. Brain Res 1723, 146379.

75.

Kitaguchi

, Tomimoto

, Ihara

, Shibata

, Uemura

, Kalaria

, Kihara

, Asada-Utsugi

, Kinoshita

, Takahashi

(2009) Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice. Brain Res 1294, 202–210.

76.

Okamoto

, Yamamoto

, Kalaria

, Senzaki

, Maki

, Hase

, Kitamura

, Washida

, Yamada

, Ito

, Tomimoto

, Takahashi

, Ihara

(2012) Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol 123, 381–394.

77.

Koike

, Green

, Blurton-Jones

, LaFerla

(2010) Oligemic hypoperfusion differentially affects tau and amyloid-β. Am J Pathol 177, 300–310.

78.

Yang

, Hou

, Wang

, Luo

, Yan

, Jia

(2018) The effect of chronic cerebral hypoperfusion on amyloid-β metabolism in a transgenic mouse model of Alzheimer’s disease (PS1V97L). J Alzheimers Dis 62, 1609–1621.

79.

Luca

, Luca

, Calandra

(2015) The role of oxidative damage in the pathogenesis and progression of Alzheimer’s disease and vascular dementia. Oxid Med Cell Longev 2015, 504678.

80.

Cheignon

, Tomas

, Bonnefont-Rousselot

, Faller

, Hureau

, Collin

(2018) Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14, 450–464.

81.

Zhu

, Smith

, Honda

, Aliev

, Moreira

, Nunomura

, Casadesus

, Harris

PLR

, Siedlak

, Perry

(2007) Vascular oxidative stress in Alzheimer disease. J Neurol Sci 257, 240–246.

82.

Popa-Wagner

, Mitran

, Sivanesan

, Chang

, Buga

(2013) ROS and brain diseases: The good, the bad, and the ugly. Oxid Med Cell Longev 2013, 963520.

83.

Hussain

, Tan

, Yin

, Blachier

, Tossou

MCB

, Rahu

(2016) Oxidative stress and inflammation: What polyphenols can do for us? Oxid Med Cell Longev 2016, 7432797.

84.

Bajwa

, Klegeris

(2022) Neuroinflammation as a mechanism linking hypertension with the increased risk of Alzheimer’s disease. Neural Regen Res 17, 2342–2346.

85.

Guzman-Martinez

, Maccioni

, Andrade

, Navarrete

, Pastor

, Ramos-Escobar

(2019) Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol 10, 1008.

86.

Nabha

, Garbern

, Buller

, Charpie

(2009) Vascular oxidative stress precedes high blood pressure in spontaneously hypertensive rats. Clin Exp Hypertens 27, 71–82.

87.

Hughes

, Judge

, Murphy

, Loughlin

, Costello

, Whiteley

, Bosch

, O’Donnell

, Canavan

(2020) Association of blood pressure lowering with incident dementia or cognitive impairment: A systematic review and meta-analysis. JAMA 323, 1934–1944.

88.

Peters

, Xu

, Fitzgerald

, Aung

, Beckett

, Bulpitt

, Chalmers

, Forette

, Gong

, Harris

, Humburg

, Matthews

, Staessen

, Thijs

, Tzourio

, Warwick

, Woodward

, Anderson

(2022) Blood pressure lowering and prevention of dementia: An individual patient data meta-analysis. Eur Heart J 43, 4980–4990.

89.

Ding

, Davis-Plourde

, Sedaghat

, Tully

, Wang

, Phillips

, Pase

, Himali

, Gwen Windham

, Griswold

, Gottesman

, Mosley

, White

, Guðnason

, Debette

, Beiser

, Seshadri

, Ikram

, Meirelles

, Tzourio

, Launer

(2020) Antihypertensive medications and risk for incident dementia and Alzheimer’s disease: A meta-analysis of individual participant data from prospective cohort studies. Lancet Neurol 19, 61–70.

90.

Affleck

, Sachdev

, Stevens

, Halliday

(2020) Antihypertensive medications ameliorate Alzheimer’s disease pathology by slowing its propagation. Alzheimers Dement 6, e12060.

91.

Hoffman

, Schmeidler

, Lesser

, Beeri

, Purohit

, Grossman

, Haroutunian

, Baldwin McGonagle

, Saul Foundations

(2009) Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology 72, 1716–1727.

92.

Deng

, Jiang

, Wang

, Pan

, Zhu

, Li

, Zhang

, Liu

, Xu

, Li

, Tang

(2022) Angiotensin receptor blockers are associated with a lower risk of progression from mild cognitive impairment to dementia. Hypertension 79, 2159–2169.

93.

Wharton

, Goldstein

, Zhao

, Steenland

, Levey

, Hajjar

(2015) Modulation of renin-angiotensin system may slow conversion from mild cognitive impairment to Alzheimer’s disease. J Am Geriatr Soc 63, 1749–1756.

94.

Peters

, Yasar

, Anderson

, Andrews

, Antikainen

, Arima

, Beckett

, Beer

, Bertens

, Booth

, van Boxtel

, Brayne

, Brodaty

, Carlson

, Chalmers

, Corrada

, DeKosky

, Derby

, Dixon

, Forette

, Ganguli

, van Gool

, Guaita

, Hever

, Hogan

, Jagger

, Katz

, Kawas

, Kehoe

, Keinanen-Kiukaanniemi

, Kenny

, Köhler

, Kunutsor

, Laukkanen

, Maxwell

, Peggy McFall

, van Middelaar

, Moll van Charante

, Ng

, Peters

, Rawtaer

, Richard

, Rockwood

, Rydén

, Sachdev

, Skoog

, Staessen

, Stephan

BCM

, Sebert

, Thijs

, Trompet

, Tully

, Tzourio

, Vaccaro

, Vaaramo

, Walsh

, Warwick

, Anstey

(2020) An investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis. Neurology 94, e267–e281.

95.

Smolensky

, Hermida

, Portaluppi

(2017) Circadian mechanisms of 24-hour blood pressure regulation and patterning. Sleep Med Rev 33, 4–16.

96.

Ohkubo

, Hozawa

, Yamaguchi

, Kikuya

, Ohmori

, Michimata

, Matsubara

, Hashimoto

, Hoshi

, Araki

, Tsuji

, Satoh

, Hisamichi

, Imai

(2002) Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: The Ohasama study. J Hypertens 20, 2183–2189.

97.

Birkenhäger

, van

den Meiracker AH

(2007) Causes and consequences of a non-dipping blood pressure profile. Neth J Med 65, 127–131.

98.

Thakkar

, Pope

, Anpalahan

(2020) Masked hypertension: A systematic review. Heart Lung Circ 29, 102–111.

99.

Lin

, Lampa

, Fall

, Engström

, Sundström

(2021) Blood pressure phenotypes based on ambulatory monitoring in a general middle-aged population. Blood Press 30, 237–249.

100.

De La Sierra

, Redon

, Banegas

, Segura

, Parati

, Gorostidi

, De La Cruz

, Sobrino

, Llisterri

, Alonso

, Vinyoles

, Pallarés

, Sarría

, Aranda

, Ruilope

(2009) Prevalence and factors associated with circadian blood pressure patterns in hypertensive patients. Hypertension 53, 466–472.

101.

Kanbay

, Turgut

, Erkmen Uyar

, Akcay

, Covic

(2008) Causes and mechanisms of nondipping hypertension. Clin Exp Hypertens 30, 585–597.

102.

Dubielski

, Zamojski

, Wiechecki

, Mozenska

, Petelczyc

, Kosior

(2016) The current state of knowledge about the dipping and non-dipping hypertension. Arterial Hypertens 20, 33–43.

103.

Ragot

, Herpin

, Siché

, Ingrand

, Mallion

(1999) Autonomic nervous system activity in dipper and non-dipper essential hypertensive patients. What about sex differences? J Hypertens 17, 1805–1811.

104.

Kohara

, Nishida

, Maguchi

, Hiwada

(1995) Autonomic nervous function in non-dipper essential hypertensive subjects: Evaluation by power spectral analysis of heart rate variability. Hypertension 26, 808–814.

105.

Arita

, Minami

, Nakamura

, Ueno

, Nishio

, Masuyama

(1996) Role of the sympathetic in the nocturnal fall in nervous system blood pressure. Hypertens Res 19, 195–200.

106.

Dauphinot

, Gosse

, Kossovsky

, Schott

, Rouch

, Pichot

, Gaspoz

, Roche

, Barthelemy

(2010) Autonomic nervous system activity is independently associated with the risk of shift in the non-dipper blood pressure pattern. Hypertens Res 33, 1032–1037.

107.

Ashram

, Abdel Wahab

, Diab

(2013) Non-dipping pattern of nocturnal blood pressure in obstructive sleep apnea syndrome: Possible role of oxidative stress and endothelin-1 precursor. Alex J Med 49, 153–161.

108.

Wolf

, Hering

, Narkiewicz

(2010) Non-dipping pattern of hypertension and obstructive sleep apnea syndrome. Hypertens Res 33, 867–871.

109.

Yalım

, Yalım

(2020) Relationship of non-dipper andreverse-dipper pattern with sleep quality in normotensive patients. J Sleep Med 17, 58–65.

110.

Yilmaz

, Yalta

, Turgut

, Yilmaz

, Yucel

, Bektasoglu

, Tandogan

(2007) Sleep quality among relatively younger patients with initial diagnosis of hypertension: Dippers versus non-dippers. Blood Press 16, 101–105.

111.

Shi

, Chen

, Ma

, Bao

, Han

, Wang

, Shi

, Vitiello

, Lu

(2018) Sleep disturbances increase the risk of dementia: A systematic review and meta-analysis. Sleep Med Rev 40, 4–16.

112.

Fulda

, Schulz

(2001) Cognitive dysfunction in sleep disorders. Sleep Med Rev 5, 423–445.

113.

Stranks

, Crowe

(2015) The cognitive effects of obstructive sleep apnea: An updated meta-analysis. Arch Clin Neuropsychol 31, 186–193.

114.

Venkataraman

, Vungarala

, Covassin

, Somers

(2020) Sleep apnea, hypertension and the sympathetic nervous system in the adult population. J Clin Med 9, 591.

115.

Pressman

, Fry

(1989) Relationship of autonomic nervous system activity to daytime sleepiness and prior sleep. Sleep 12, 239–245.

116.

Grimaldi

, Goldstein

, Carter

(2019) Insomnia and cardiovascular autonomic control. Auton Neurosci 220, 102551.

117.

Huang

, Mai

, Hu

, Wu

, Song

, Qiu

, Dong

, Kuang

(2011) Poor sleep quality, stress status, and sympathetic nervous system activation in nondipping hypertension. Blood Press Monit 16, 117–123.

118.

Elser

(2000) The sympathetic system and hypertension. Am J Hypertens 13, S99–S105.

119.

Hansen

, Li

, Boggia

, Thijs

, Richart

, Staessen

(2011) Predictive role of the nighttime blood pressure. Hypertension 57, 3–10.

120.

Hermida

, Crespo

, Otero

, Domınguez-Sardina

, Moya

, Rios

, Castineira

, Callejas

, Pousa

, Sineiro

, Salgado

, Duran

, Sanchez

, Fernandez

, Mojon

, Ayala

(2018) Asleep bloodpressure: A target for cardiovascular event reduction? EurHeart J 39, 4172–4174.

121.

Hermida

, Ayala

, Portaluppi

(2007) Circadian variation of blood pressure: The basis for the chronotherapy of hypertension. Adv Drug Deliv Rev 59, 904–922.

122.

Hermida

, Ayala

, Mojón

, Fernández

(2010) Influence of circadian time of hypertension treatment on cardiovascular risk: Results of the MAPEC study. Chronobiol Int 27, 1629–1651.

123.

Melgarejo

, Aguirre-Acevedo

, Gaona

, Chavez

, Calmon

, Silva

, De Erausquin

, Gil

, Mena

, Terwilliger

, Arboleda

, Scarmeas

, Lee

, Maestre

(2020) Nighttime blood pressure interacts with APOE genotype to increase the risk of incident dementia of the Alzheimer’s type in Hispanics. J Alzheimers Dis 77, 569–579.

124.

Tan

, Sundström

, Lind

, Franzon

, Kilander

, Benedict

(2021) Reverse dipping of systolic blood pressure is associated with increased dementia risk in older men: A longitudinal study over 24 Years. Hypertension 77, 1383–1390.

125.

Guo

, Tabara

, Igase

, Yamamoto

, Ochi

, Kido

, Uetani

, Taguchi

, Miki

, Kohara

(2010) Abnormal nocturnal blood pressure profile is associated with mild cognitive impairment in the elderly: The J-SHIPP study. Hypertens Res 33, 32–36.

126.

Yano

, Ning

, Muntner

, Reis

, Calhoun

, Viera

, Levine

, Jacobs

, Shimbo

, Liu

, Greenland

, Lloyd-Jones

(2015) Nocturnal blood pressure in young adults and cognitive function in midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Am J Hypertens 28, 1240–1247.

127.

Xing

, Sun

, Wang

, Feng

, Zhang

, Li

(2021) Nocturnal blood pressure rise as a predictor of cognitive impairment among the elderly: A retrospective cohort study. BMC Geriatr 21, 462.

128.

White

, Wolfson

, Wakefield

, Hall

, Campbell

, Moscufo

, Schmidt

, Kaplan

, Pearlson

, Guttmann

CRG

(2011) Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. Circulation 124, 2312–2319.

129.

Chesebro

, Melgarejo

, Leendertz

, Igwe

, Lao

, Laing

, Rizvi

, Budge

, Meier

, Calmon

, Lee

, Maestre

, Brickman

(2020) White matter hyperintensities mediate the association of nocturnal blood pressure with cognition. Neurology 94, e1803–e1810.

130.

Paganini-Hill

, Bryant

, Corrada

, Greenia

, Fletcher

, Singh

, Floriolli

, Kawas

, Fisher

(2019) Blood pressure circadian variation, cognition and brain imaging in 90+year-olds. Front Aging Neurosci 11, 54.

131.

Riba-Llena

, Nafría

, Filomena

, Tovar

, Vinyoles

, Mundet

, Jarca

, Vilar-Bergua

, Montaner

, Delgado

(2016) High daytime and nighttime ambulatory pulse pressure predict poor cognitive function and mild cognitive impairment in hypertensive individuals. J Cereb Blood Flow Metab 36, 253–263.

132.

, Sun

, Zhao

, Wei

, Wang

, Fu

(2010) Relationship between nocturnal blood pressure variation and silent cerebral infarction in Chinese hypertensive patients. J Neurol Sci 294, 67–69.

133.

Wolfson

, Wakefield

, Moscufo

, Kaplan

, Hall

, Schmidt

, Guttmann

CRG

, White

(2013) Rapid buildup of brain white matter hyperintensities over 4 years linked to ambulatory blood pressure, mobility, cognition, and depression in old persons. J Gerontol A Biol Sci Med Sci 68, 1387–1394.

134.

White

, Jalil

, Wakefield

, Kaplan

, Bohannon

, Hall

, Moscufo

, Fellows

, Guttmann

CRG

, Wolfson

(2018) Relationships among clinic, home, and ambulatory blood pressures with small vessel disease of the brain and functional status in older people with hypertension. Am Heart J 205, 21–30.

135.

White

, Wakefield

, Moscufo

, Guttmann

CRG

, Kaplan

, Bohannon

, Fellows

, Hall

, Wolfson

(2019) Effects of intensive versus standard ambulatory blood pressure control on cerebrovascular outcomes in older people (INFINITY). Circulation 140, 1626–1635.

136.

Buccellato

, D’Anca

, Serpente

, Arighi

, Galimberti

(2022) the role of glymphatic system in Alzheimer’s and Parkinson’s disease pathogenesis. Biomedicines 10, 2261.

137.

Mortensen

, Sanggaard

, Mestre

, Lee

, Kostrikov

, Xavier

ALR

, Gjedde

, Benveniste

, Nedergaard

(2019) Impaired glymphatic transport in spontaneously hypertensive rats. J Neurosci 39, 6365–6377.

138.

Mestre

, Tithof

, Du

, Song

, Peng

, Sweeney

, Olveda

, Thomas

, Nedergaard

, Kelley

(2018) Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun 9, 4878.

139.

Tarumi

, Harris

, Hill

, German

, Riley

, Turner

, Womack

, Kerwin

, Monson

, Stowe

, Mathews

, Cullum

, Zhang

(2015) Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment. Neurology 85, 1922–1929.

140.

Mansukhani

, Kolla

, Somers

(2019) Hypertension and cognitive decline: Implications of obstructive sleep apnea. Front Cardiovasc Med 6, 96.

141.

Sharma

, Varga

, Bubu

, Pirraglia

, Kam

, Parekh

, Wohlleber

, Miller

, Andrade

, Lewis

, Tweardy

, Buj

, Yau

, Sadda

, Mosconi

, Li

, Butler

, Glodzik

, Fieremans

, Babb

, Blennow

, Zetterberg

, Lu

, Badia

, Romero

, Rosenzweig

, Gosselin

, Jean-Louis

, Rapoport

, de Leon

, Ayappa

, Osorio

(2018) Obstructive sleep apnea severity affects amyloid burden in cognitively normal elderly: A longitudinal study. Am J Respir Crit Care Med 197, 933–943.

142.

Yun

, Lee

, Kim

, Seo

, Bang

, Kim

, Greve

, Au

, Shin

, Thomas

(2017) Amyloid burden in obstructive sleep apnea. J Alzheimers Dis 59, 21–29.

143.

Hogan

, Shim

, Umasabor-Bubu

, Fahad

, Bubu

(2019) Obstructive sleep apnea is associated with longitudinal increases in amyloid burden in elderly mild cognitive impairment individuals. Am J Undergrad Res 15, 71–77.

144.

Bubu

, Kaur

, Mbah

, Umasabor-Bubu

, Cejudo

, Debure

, Mullins

, Parekh

, Kam

, Osakwe

, Williams

, Turner

, Glodzik

, Rapoport

, Ogedegbe

, Fieremans

, de Leon

, Ayappa

, Jean-Louis

, Masurkar

, Varga

, Osorio

(2022) Obstructive sleep apnea and hypertension with longitudinal amyloid-β burden and cognitive changes. Am J Respir Crit Care Med 206, 632–636.

145.

Musiek

, Xiong

, Holtzman

(2015) Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med 47, e148.

146.

Hermida

, Ayala

, Mojón

, Fernández

(2011) Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol 22, 2313–2321.

147.

Kasiakogias

, Tsioufis

, Thomopoulos

, Andrikou

, Aragiannis

, Dimitriadis

, Tsiachris

, Bilo

, Sideris

, Filis

, Parati

, Stefanadis

(2015) Evening versus morning dosing of antihypertensive drugs in hypertensive patients with sleep apnoea. J Hypertens 33, 393–400.

148.

Almirall

, Comas

, Martinez-Ocana

, Roca

, Arnau

(2012) Effects of chronotherapy on blood pressure control in non-dipper patients with refractory hypertension. Nephrol Dial Transplant 27, 1855–1859.

149.

Hermida

, Hermida-Ayala

, Smolensky

, Mojón

, Crespo

, Otero

, Ríos

, Domínguez-Sardiña

, Fernández

(2020) Does timing of antihypertensive medication dosingmatter? Curr Cardiol Rep 22, 118.

150.

Boa Sorte Silva

, Gregory

, Gill

, McGowan

, Petrella

(2018) The impact of blood pressure dipping status on cognition, mobility, and cardiovascular health in older adults following an exercise program. Gerontol Geriatr Med 4, 233372141877033.

151.

Ling

, Diaz

, Kretzschmar

, Feairheller

, Sturgeon

, Perkins

, Veerabhadrappa

, Williamson

, Lee

, Grimm

, Babbitt

, Brown

(2015) Chronic aerobic exercise improves blood pressure dipping status in African American nondippers. Blood Press Monit 19, 353–358.

152.

Sturgeon

, Fenty-Stewart

, Diaz

, Brinkley

, Dowling

, Brown

(2009) The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press 18, 171–179.

153.

Park

, Jastremski

, Wallace

(2005) Time of day for exercise on blood pressure reduction in dipping and nondipping hypertension. J Hum Hypertens 19, 597–605.

154.

Ramirez-Jimenez

, Morales-Palomo

, Moreno-Cabañas

, Alvarez-Jimenez

, Ortega

, Mora-Rodriguez

(2022) Aerobicexercise training improves nocturnal blood pressure dipping inmedicated hypertensive individuals. Blood Press Monit 27, 272–275.

155.

Vij

, Peixoto

(2009) Management of nocturnal hypertension. Expert Rev Cardiovasc Ther 7, 607–618.

156.

Wilcox

, Grunstein

, Hedner

, Doyle

, Collins

, Fletcher

, Kelly

, Sullivan

(1993) Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea. Sleep, 16, 539–544.

157.

Suzuki

, Otsuka

, Guilleminault

(1993) Long-term nasal continuous positive airway pressure administration can normalize hypertension in obstructive sleep apnea patients. Sleep 16, 545–549.

158.

Becker

, Jerrentrup

, Ploch

, Grote

, Penzel

, Sullivan

, Peter

(2003) Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 107, 68–73.

159.

Dimsdale

, Loredo

, Profant

(2000) Effect of continuous positive airway pressure on blood pressure: A placebo trial. Hypertension 35(1 Pt 1), 144–147.

160.

Alves

AJA

, Garcia

, Lopes

, Ribau

, Ribeiro

, Viana

, Oliveira

, Bertoquini

, Mesquita-Bastos

, Polónia

, Ribeiro

(2019) Aerobic training decreases 24-hour and daytime ambulatory blood pressure in patients with resistant hypertension. J Hypertens 37, e90.

161.

Liu

, Cao

, Guo

, Dai

(2016) Continuous positive airway pressure in patients with obstructive sleep apnea and resistant hypertension: A meta-analysis of randomized controlled trials. J Clin Hypertens (Greenwich) 18, 153–158.

162.

Sanner

(2002) Effect of continuous positive airway pressure therapy on 24-hour blood pressure in patients with obstructive sleep apnea syndrome. Am J Hypertens 15, 251–257.

163.

Akashiba

, Minemura

, Yamamoto

, Kosaka

, Saito

, Horie

(1999) Nasal continuous positive airway pressure changes blood pressure “non-dippers” to “dippers” in patients with obstructive sleep apnea. Sleep 22, 81–84.

164.

Dernaika

, Kinasewitz

, Tawk

(2009) Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. J Clin Sleep Med 5, 103–107.

165.

Iftikhar

, Valentine

, Bittencourt

LRA

, Cohen

, Fedson

, Gíslason

, Penzel

, Phillips

, Yu-Sheng

, Pack

, Magalang

(2014) Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: A meta-analysis. J Hypertens 32, 2341–2350.

166.

Hamdidouche

, Gosse

, Cremer

, Lorthioir

, Delsart

, Courand

, Denolle

, Halimi

, Girerd

, Ormezzano

, Rossignol

, Pereira

, Azizi

(2019) Clinic versus ambulatory blood pressure in resistant hypertension: Impact of antihypertensive medication nonadherence: A post Hoc Analysis the DENERHTN Study. Hypertension 74, 1096–1103.

167.

Hameed

, Tebbit

, Jacques

, Thomas

, Dasgupta

(2016) Non-adherence to antihypertensive medication is very common among resistant hypertensives: Results of a directly observed therapy clinic. J Hum Hypertens 30, 83–89.

168.

Whelton

, Carey

, Aronow

, Casey

, Collins

, Dennison Himmelfarb

, DePalma

, Gidding

, Jamerson

, Jones

, MacLaughlin

, Muntner

, Ovbiagele

, Smith

, Spencer

, Stafford

, Taler

, Thomas

, Williams

, Williamson

, Wright

(2018) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 71, e127–e248.

169.

Stergiou

, Palatini

, Parati

, O’Brien

, Januszewicz

, Lurbe

, Persu

, Mancia

, Kreutz

(2021) 2021 European Society of Hypertension practice guidelines for office and out-of-office blood pressure measurement. J Hypertens 39, 1293–1302.

170.

National Heart Foundation of Australia (2016) Guideline for the diagnosis and management of hypertension in adults - 2016. National Heart Foundation of Australia, Melbourne. .

171.

Boyd

, Carter

, Moise

, Alcántara

, Valadares

, Anstey

, Kronish

(2021) Awareness, knowledge, and attitudes toward screening and treatment of masked hypertension in primary care. Am J Hypertens 34, 1322–1327.

172.

Setia

, Subramaniam

, Teo

, Tay

(2017) Ambulatory and home blood pressure monitoring: Gaps between clinical guidelines and clinical practice in Singapore. Int J Gen Med 10, 189–197.

173.

Mejzner

, Clark

, Smith

LFP

, Campbell

(2017) Trends in the diagnosis and management of hypertension: Repeated primary care survey in South West England. Br J Gen Pract 67, e306–e313.

174.

Chen

, Chang-Quan

, You

, Wang

, Hui

, Liu

, Si-Qing

(2013) The circadian rhythm of arterial blood pressure in Alzheimer disease (AD) patients without hypertension. Blood Press 22, 101–105.

175.

Daniela

, Grigoras

, Cuciureanu

, Constantinescu

(2021) The circadian rhythm of arterial blood pressure in Alzheimer’s disease and vascular dementia. Acta Neurol Belg 123, 129–137.

176.

Kim

, Park

, Oh

, An

, Park

, Han

, Park

, Yang

, Shim

, Lee

(2015) Blood pressure and heart rate variability in Alzheimer’s disease. Dement Neurocogn Disord 14, 128.

177.

Otsuka

, Mikami

, Katahira

, Nakamoto

, Minamitani

, Imaoka

, Nishide

, Ogihara

(1990) Absence of nocturnal fall in blood pressure in elderly persons with Alzheimer-type dementia. J AmGeriatr Soc 38, 973–978.

178.

Tanaka

, Shimo

, Yamashiro

, Ogawa

, Nishioka

, Oyama

, Umemura

, Hattori

(2018) Association between abnormal nocturnal blood pressure profile and dementia in Parkinson’s disease. Parkinsonism Relat Disord 46, 24–29.

179.

Yamamoto

, Akiguchi

, Oiwa

, Hayashi

, Ohara

, Ozasa

(2005) The relationship between 24-hour blood pressure readings, subcortical ischemic lesions and vascular dementia. Cerebrovasc Dis 19, 302–308.

180.

Kilander

, Nyman

, Boberg

, Hansson

, Lithell

(1998) Hypertension is related to cognitive impairment a 20-year follow-up of 999 men. Hypertension 31, 780–786.

181.

van Boxtel

MPJ

, Gaillard

, Houx

, Buntinx

, de Leeuw

, Jolles

(1998) Is nondipping in 24h ambulatory blood pressure related to cognitive dysfunction? J Hypertens 6, 1425–1432.

182.

Yano

, Inokuchi

, Hoshide

, Kanemaru

, Shimada

, Kario

(2011) Association of poor physical function and cognitive dysfunction with high nocturnal blood pressure level in treated elderly hypertensive patients. Am J Hypertens 24, 285–291.

183.

Boa Sorte Silva

, Gill

, Nagamatsu

, Owen

, Petrella

(2020) Systolic blood pressure dipping may be associated with mobility impairment and brain volume in community-dwelling older adults: An exploratory study. Exp Gerontol 141, 111100.

184.

Hajjar

, Zhao

, Alsop

, Abduljalil

, Selim

, Novak

(2010) Association of blood pressure elevation and nocturnal dipping with brain atrophy, perfusion and functional measures in stroke and nonstroke individuals. Am J Hypertens 23, 17–23.

185.

Zhang

, Cui

, Zhao

, Dong

, Wang

, Duan

, Ji

, Zhou

, Hu

, Chen

, Sun

, Gong

, Chai

, Liu

(2019) Association of circadian rhythm of blood pressure and cerebral small vessel disease in community-based elderly population. J Gerontol A Biol Sci Med Sci 74, 1322–1330.