The impact of blood pressure variability on cognition: current limitations and new advances

Abstract

 

Dementia is the most common neurodegenerative disease in the aging population. Emerging evidence indicates that blood pressure (BP) variability is correlated with cognitive impairment and dementia independent of mean BP levels. The state-of-the-art review summarizes the latest evidence regarding the impact of BP variability on cognition in cognitively intact populations, patients with mild cognitive impairment, and different dementia types, focusing on the important confounding factors and new advances. This review also summarizes the potential mechanisms underlying the relationship between BP variability and cognitive impairment, and dementia, briefly discussing sex differences in the relationship. At last, current limitations and future perspectives are discussed to optimize BP management in preventing cognitive impairment and dementia.

INTRODUCTION

Dementia impairs cognitive functions that severely interfere with daily activities. It is the most common neurodegenerative disease in older adults, with continuing growth due to the increased aging population with longer life expectancy ^[1]. Currently, there is no effective treatment for dementia. Thus, preventing dementia by identifying some modifiable risk factors in the early phase is an urgent need.

Hypertension is known as a modifiable risk factor for cognitive impairment and dementia ^[2]. However, there is controversy about the relationship between blood pressure (BP) and cognitive dysfunction. Although midlife hypertension was linked to an increased risk for dementia, late-life BP is more complicated, with both high SBP and low DBP associated with dementia ^[3]. Recently, emerging evidence indicated that BP variability (BPV), that is, fluctuation of BP, was related to cognitive impairment and dementia independent of mean BP levels ^[4–15]. Furthermore, the contribution of BPV to the risk of cognitive impairment and dementia may be beyond the BP value ^[13–15]. However, there are limitations in clinical studies regarding the relationship between BPV and dementia. Moreover, the mechanisms underlying this relationship are unclear.

The current review aims to summarize the latest evidence of BPV correlating with cognitive impairment and dementia in cognitively intact populations, patients with mild cognitive impairment (MCI), and different dementia types, introducing the new advances and critical confounding factors in the research. A second objective is to summarize the potential mechanisms underlying the relationship between BPV and cognitive impairment and dementia and briefly discuss sex differences in the relationship. At last, this review discusses the current challenges in the clinical trials and future directions to optimize BP management at an early stage to prevent cognitive impairment and dementia in later life.

MEASUREMENT OF BLOOD PRESSURE VARIABILITY

BP oscillates in response to external stimulation (environment), behavioral factors, and internal cardiovascular regulatory mechanisms ^[10,16]. BPV can be evaluated within different time frames: very short-term (beat-to-beat), short-term [within 24 h, usually measured by ambulatory BP (ABP) monitoring], mid-term (day-to-day, usually measured by home BP monitoring), or long-term (visit-to-visit, between clinic visits over weeks, months, and years). There are four types of indices for overall BPV measurement ^[16], including dispersion [such as SD, coefficient of variation (CV), and variability independent of the mean], sequence (such as average real variability), instability [such as range (maximum–minimum BP), peak size (maximum BP), and trough size (mean–minimum BP)], and frequency (such as residual variability). The most widely used indices are demonstrated and compared below (Table 1).

TABLE 1 - Blood pressure variability indices

Index	Equation	Type of BPV measured	Advantage	Disadvantage
Standard deviation (SD)	$\sqrt{\frac{\sum _{i=1}^n{(x_i-\overline{x})}^2}{(n-1)}}$	Very short-term BPV Short-term BPV Mid-term BPV Long-term BPV	Most used; independent of measurement order	Correlated with mean value; influenced by outliers and night-time BP fall
Residual standard deviation (RSD)	$\sqrt{\frac{\sum _{i=1}^n{(x_i-{\stackrel{\circ }{x}}_i)}^2}{(n-2)}}$	Long-term BPV	Less influenced by BP change over time compared with SD	The assumption of a linear trend may not accurately reflect the nature of changes over time
Coefficient of variance (CV)	100 × SD/ $\overline{\text{x}}$	Short-term BPV Mid-term BPV Long-term BPV	Weakly correlated with mean levels; correct correlations between SD and mean BP values	Not sufficient for visit-to-visit BPV
Average real variability (ARV)	$\frac{1}{n-1}\sum _{i=1}^{n-1}|x_{i+1}-x_i|$	Short-term BPV Mid-term BPV Long-term BPV	Weight for the between-reading time intervals	Partially dependent on the overall BP level and change in mean BP levels overtime; takes the order of the BP measurements into account
Variation independent of mean (VIM)	kxSD/ $\overline{\text{x}}$ m	Long-term BPV	No correlation with mean BP level over visits	Cannot be compared across populations
Range	Maximum–minimum	Short-term BPV Mid-term BPV Long-term BPV	Widely used	Influenced by extreme values

$\overline{x}$

, mean; ∑, sum of; N, number of values in the population; x, each value. ARV, average real variability; BP, blood pressure; BPV, blood pressure variability; CV, coefficient of variance; RSD, residual SD; VIM, variation independent of mean.

SD

SD is the most used index for measuring BPV across studies. SD is correlated with mean BP values independent of measurement order and affected by extreme BP values triggered by environmental stressors ^[17] as well as by day-night changes in BP (e.g. night-time BP fall) ^[18] (Table 1). The weighted SD (for short-term BPV measurement only) could remove the influence of night-time BP fall on 24-h SD by weighting daytime and night-time BP–SD, respectively, and by averaging them ^[18].

Residual SD

A trend may exist when measuring BP over a long period (i.e. weeks or months). For example, the trend of BP will decrease over time with antihypertensive treatment in clinical trials. Under this situation, the extent of variability measured by SD may be exaggerated. If there is a linear relationship between time and BP, variability can be defined as the residual SD (RSD), which is calculated as the root-mean-square error of the differences between predicted BP and observed BP from the regression ^[19] (Table 1). RSD is less affected by changes in BP levels over time compared to SD ^[19]. The limitation of this measurement is the assumption of a linear trend, which may not apply to the nature of changes.

Coefficient of variation

As absolute values of BPV might be positively related to mean BP values, a mathematical correction made by the CV (CV = SD × 100/mean) is often applied to correct correlations between SD and mean BP values ^[16] (Table 1). However, in the case of visit-to-visit BPV, CV might still not be sufficient, as it was reported to be positively related to mean BP values in some cohorts ^[17,20].

Variation independent of mean

Variation independent of mean (VIM) is a transformation of SD ^[17,20], which removes the influence of mean BP on BPV with nonlinear regression analysis through a plot of SD (y-axis) against mean BP value (x-axis), for all individuals in the cohort. (i.e. proportional to SD/meanx, with x derived from curve fitting) ^[16] (Table 1). There is no agreement on the gold-standard approach to visit-to-visit BPV measurement. The goal of visit-to-visit BPV research is to determine the causal effects, and VIM is an ideal approach based on the previous studies. However, as parameter x is specific to each cohort, VIM cannot be compared across populations ^[19].

Average real variability

In addition to adjusting SD, indices unaffected by day–night changes or mean BP values are preferred. Average real variability (ARV) measures the overall variability based on the recording sequence, calculated as the mean absolute difference between consecutive measurements ^[19] (Table 1). It is an alternative for SD to measure variability in mean BP value ^[18]. ARV has been suggested to be more appropriate in measuring 24-h BPV and be more useful in predicting outcomes than SD. For example, evidence has shown that SD is similar in participants with different 24-h ABP profiles while ARV shows a difference ^[21]. Moreover, ARV offers a computationally simple way to assess variation with a trend ^[20]. For instance, ARV will be greater than SD if there is a tendency with an alternating pattern of increases and decreases in BP values between consecutive measurements ^[20].

Range

Range is calculated as maximum minus minimum BP values (Table 1), which is quantifying for short-term, mid-term, and long-term BPV ^[16,22]. Range is influenced by extreme BP values ^[22], and thus, is more varied. It is also highly related with SD and CV.

Some argue that BPV indices convey redundant and overlapping information ^[22]. For example, the most used indices in the BPV studies, such as SD, CV, and VIM, are correlated with a high agreement in measuring visit-to-visit BPV. Indeed, all three indices belong to the dispersion type, which assesses the variability around the mean BP value across visits. Thus, calculating one of these indices is sufficient, and repeating three does not add information but would give a false sense of pseudo-consistency ^[22], thereby should be avoided. Although in the stability type, indices, including range, maximum, peak size, and trough size are more varied and are influenced by extreme values. Recently, one study has introduced a new index, random slope, which measures BPV at unequal intervals between visits ^[8]. Random slope showed consistent correlations with traditional BPV indices in assessing associations between BPV and cognitive functions, validating it as an effective index of BPV. In addition, because traditional BPV indices are limited to BP measurements at specific predetermined intervals, the introduction of random slope could allow clinical studies assessing BPV utilizing data collected at irregular intervals and account for the varying intervals of measurements across patients ^[8]. Lacking consensus on optimal BPV indices and measurement methods, such as the number and the interval time of measurements, leads to great heterogeneity in exploring the relationship between BPV and cognitive impairment and dementia. Thus, it is critical to determine the most reliable indices and record BP values accurately and consistently among studies.

THE IMPACT OF BLOOD PRESSURE VARIABILITY ON COGNITION IN COGNITIVELY NORMAL PEOPLE

Mounting evidence has shown that elevated BPV (mostly systolic) is a risk factor for cognitive decline and dementia in cognitively normal people ^{[4,6–7,9,11–12,23–41]}. Although a few studies showed contradictory results ^[8,42–43]. For example, one retrograde study with 94 African-American reported that BPV did not correlate with global cognitive function, while higher DBP variability (DBPV) correlated with poorer verbal and incidental memory ^[8]. Another study reported that higher BPV contributed to better cognitive performance in older adults with cardiovascular disease (CVD) than those with stable BP ^[8]. However, these two studies have relatively small sample sizes of 94 and 97 participants. In addition, Tsang et al.^[8] only measured the BPV with the three most recent clinic visits in African-American community-dwelling elderly. Another larger trial (Prevention of Dementia by Intensive Vascular Care, preDIVA trial with sample sizes of 2305 participants) found that high visit-to-visit BPV was associated with cognitive decline but not incident dementia among older people ^[43]. The inconsistent findings on the influence of BPV on cognitive impairment and dementia may be due to the insufficient attention to confounding factors, such as sex, age, race, and ethnicity, type of BPV, timeframes, and follow-up lengths. These abovementioned factors will be discussed below. Summary of the studies please see Table 2.

TABLE 2 - Summary of the relationship of blood pressure variability and cognitive function in cognitive normal individuals.

Author year	Age, year avg ± SD	sample size	Male%	Region	Ethnics	Health status (database)	HT treatment %	BP index	BP time point	Follow-up duration	Cognition Methods	Cognition time point	Adjustment comorbidity factors	Results
Alpérovitch 2014 [6]	73.7 ± 5.2	6506	38	France	NA	Well functioning volunteers, the three-city study	No dementia group: 52.8; Incident dementia group: 47.1	CV	2 years, 4 years	Median 6.8 years; 8 years (1999–2001–2008)	MMSE, IST, DSM-IV	2,4 and 7–8 years	Sex, study center, education, diabetes, history of vascular diseases, antihypertensive drug use, mean BP	BPV was associated with an increased risk of incident dementia, whereas mean BP was not
Böhm 2015 [7]	≥55	24 593	NA	Worldwide	NA	W.o. demntia and CVD. ONTARGET and TRANSCEND trials	NA	CV	6 weeks, 6 months, and every 6 months thereafter	56 months	MMSE	Baseline, after 2 years, and 3–5 years	Baseline MMSE, DBPV, age, BMI, estimated glomerular filtration rate, sex, ethnicity, physical activity, formal education, alcohol consumption, stroke, diabetes mellitus, and concomitant medications	SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk
Cho 2018 [23]	77.7 ± 8.3	232	33.6	Japan	Asian	Ambulatory patients with one or more CV risk factors	85.3	wSD	Every 30 min for 24 h	24 h	MoCA-J	NA	Age and 24-h SBP	In elderly patients with well ambulatory BP control, higher BP variability but not average ambulatory BP level was associated with cognitive impairment
de Havenon 2021 [58]	67.9 ± 9.3	8379	64.9	US	White 58.6%, Black 29.3%, Hispanic 10.4%	SPRINT MIND trial	NA	SD	First 600 d, 7.8 measurements	3.2 ± 1.4 years	NA	2 years, 4 years, then 1 year thereafter	Age, sex, race/ethnicity, history of CVD, hypertension, education, level of physical activity, smoking, SPRINT randomization arm, No. of BP measurements, and mean SBP	Higher BPV was associated with the development of probable dementia with excellent BP control
Dore 2018 [24]	62.0 ± 12.8	980	41.4	US	White, black	Community-dwelling individuals, the Maine-Syearacuse Longitudinal Study	51.2	SD	15 times (5 times each sitting, reclining, and standing) in 2001–2006	5 years	Neuropsychological test battery	Following BP assessment	Age, sex, education, ethnicity, mean BP, diabetes, BMI, TC, smoking, and alcohol consumption	BPV is an important predictor of cognition with advancing age
Ernst 2021 [25]	≥65	19 114	NA	Australia and US	White, black, Hispanic	ASPREE trial (community-dwelling free of dementia and CVD)	NA	SD, CV, ARV	Annually	4.7 years	MMSE	Annually	Age, SBP, AHT medications, education, diabetes, depression, BMI, and statin medications.	High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline
Fujiwara 2018 [26]	83.2 ± 3.2	497	44.3	Japan	Asian	W.o. CVD	Working memory impairment: 60.6; without working memory impairment: 66.8	Short-term: SD, CV, wSD of 24-h SBP and DBP; long-term: SD, CV, MMD	Office: baseline and each office visits for 1 year; Ambulatory: every 30 min for 24 h	1 year	MMSE	NA	Age	Exaggerated BPV was significantly associated with working memory impairment in very elderly individuals
Godai 2020 [27]	85–87	111	47.7	Japan	Asian	SONIC study, community-dwelling oldest-old population	64	CV	HBP every morning	30 days	MoCA-J	Entry and 30 d	Sex, the corresponding mean HBP, antihypertensive medication, diabetes mellitus, history of arrhythmia, WHO-5, and gait speed	In the community-dwelling oldest-old population, higher day-to-day HBPV, but not the value of HBP, was associated with cognitive impairment
Keary 2007 [42]	69.8 ± 7.5	97	57.7	US	NA	Nondemented older adults with CVD	NA	SD	NA	NA	MMSE	NA	Age, education	Greater BPV was associated with better, not poorer, cognitive test performance
Li 2021 [28]	HRS cohort: 66.3 ± 8.0; ELSA cohort: 62.4 ± 8.9	12 298	HRS cohort: 40.4; ELSA cohort: 43.8	NA	White	Dementia free, HRS & ELSA study	NA	SD, CV, VIM	Wave 1 (2002–2003), to wave 9 (2018–2019), at least 3 waves	HRS cohort: 8–12 years; ELSA cohort: 10–14 years	Standardized Z score of cognitive function	NA	Age, sex, race, education, cohabitation status, smoking, alcohol consumption, physical activity, BMI, mean BP, depressive symptom, history or presence of CVD, diabetes, lung disease and cancer, AHT medication	Higher long-term BPV was associated with accelerated cognitive decline among general adults aged ≥50 years, with nonlinear dose-response relationship
Ma 2019 [9]	67.6 ± 8	5273	41.9	Netherland	NA	Dementia-free	29.3	CV, SD, ARV	Every 4 years	Median 14.6 years	MMSE, geriatric mental schedule, DSM-III-R, ADRDA, AIREN	5, 10, or 15 years	Age, sex, education, APOE genotype, vascular risk factors, and history of CVD	A large BPV over a period of years was associated with an increased long-term risk of dementia. The association between BPV and dementia appears most pronounced when this variation occurred long before the diagnosis. An elevated long-term risk of dementia was observed with both a large rise and fall in BP
Ma 2021 [29]	71.4 ± 6.4	1835	37	Netherland	NA	Adults from The Rotterdam Study	31.2	BP complexity: sample entropy; BPV: CV of beat-to-beat BP	NA	20 years	MMSE, GMS, DSM-III-R, ADRDA	NA	Age, sex, APOE genotype, mean SBP, and other confounding factors.	Lower complexity and higher beat-to-beat SBPV are potential novel risk factors or biomarkers for dementia
Matsumoto 2014 [30]	63.3 ± 4.7	485	28	Japan	Asian	Ohasama study w.o. cognitive decline at the enrollment	30	SD	HBP, every morning for 4 weeks	7.8 years	MMSE	4 years apart	Sex, age, history of CVD, low level of education, baseline MMSE score <27, and follow-up duration	A significant association between day-to-day HBPV and cognitive decline independent of SBP
McDonald 2017 [31]	72	353	58	England	NA	Community-dwelling cohort	NA	CV	ABP	5 years	MMSE, Cambridge Cognitive Examination	Baseline and at 5 years	Age, sex, and education	Greater daytime BPV was associated with poorer cognitive function while night-time BPV was not associated with cognitive function at baseline or cognitive decline
Nagai 2012 [4]	79.9 ± 6.4	201	25	Japan	Asian	Elderly patients at high risk of CVD	71.2	SD, CV, max BP, min BP, delta BP	12 visits once a month	12 months	MMSE, GDS	3 months after Apr 2007	Age, calcium channel blockade use, low density lipoprotein, SBP	In the high-risk elderly, exaggerated visit-to-visit BPV was significant indicators for cognitive impairment
Nagai 2014 [32]	79.9 ± 6.4	201	24	Japan	Asian	3SCO study, high risk of CVD	71.2	CV, delta BP	Monthly	12 months	MMSE, GDS	3 months after Apr 2007	Age, calcium channel blockade use, low density lipoprotein, average HR, and average SBP	Exaggerated visit-to-visit SBPV and advanced carotid artery remodeling (high IMT and high stiffness parameter b) have a synergetic association with cognitive dysfunction
Ogliari 2016 [33]	75.2 ± 3.3	4745	47.4	Netherland	NA	High CV risk, In PROspective Study of Pravastatin in the Elderly at Risk	40.2	SD	Every 3 months during the first 18 month	3.2 years	The Lawton-Brody activities of daily living scale, instrumental activities of daily living	First at 18 months and then during follow-up until 48 months	Age, sex, country, education, CV risk factors (smoking, BMI, hypertension and diabetes), CV morbidities (myocardial infarction, stroke/transient ischemic attack, claudication and glomerular filtration rate), use of AHT, statin treatment, mean SBP or DBP, No. of measurements of BP	Higher visit-to-visit SBPV but not DBPV was associated with steeper functional decline in older adults at high cardiovascular risk
Oishi 2017 [34]	71 ± 7	1674	44.1	Japan	Asian	Community-dwelling elderly w.o. dementia, Hisayama study	43.3	CV	HBP, every morning for 4 weeks	5.3 years	MMSE, HDS, HDS-R	2005–2006, 2012–2013	Age, sex, low education, use of AHT agents, ECG abnormalities, diabetes, serum total cholesterol, BMI, history of CVD, smoking, alcohol, and regular exercise	Increased day-to-day BPV is an independent significant risk factor for the development of all-cause dementia, vascular dementia, and AD in the general elderly Japanese population
Qin 2016 [35]	64 ± 6	976	48	China	Asian	Community-dwelling older adults, prospective cohort study, China Health and Nutrition Survey	12	SD, CV, VIM	3 or 4 visits	3.2 years	Cognitive screening test	≥2 visits in 1997, 2000, or 2004	Age, sex, education, time, smoking physical activity, ever used antihypertensive treatment, mean SBP	Higher long-term visit-to-visit BPV is associated with a faster rate of cognitive decline among older adults
Rouch 2020 [11]	77.7 ± 6.2	3319	43.5	France	NA	Noninstitutionalized patients from S.AGES cohort	70.8	SD, CV, ARV, VIM, RSD	Every 6 months	3 years	MMSE, DSMMD	Every 6 months	Age, sex, educational level, SBP or DBP or MAP or pulse pressure, AHT drug use, coronary artery disease, type 2 diabetes, chronic heart failure, AF, transient ischemic attack or stroke, smoking and dyslipidemia at baseline	Higher BPV is associated with poorer cognitive function and incident dementia, independent of mean BP
Sabayan 2013 [36]	75.3 ± 3.3	5461	48.3	Netherland	NA	At risk of CVD	NA	SD	Every 3 months	3.2 years	Selective attention, processing speed, immediate and delayed memory	Every 3 months	Age, sex, BMI, statin treatment, smoking, cholesterol level, history of vascular diseases, history of hypertension, history of diabetes mellitus, and average BP measures	Higher visit-to-visit BPV independent of average BP was associated with impaired cognitive function in old age
Sakakura 2007 [37]	Younger elderly: 71.9 ± 4.5; very elderly: 84 ± 3.9	202	Younger elderly: 22.8; very elderly: 18.8	Japan	Asian	101 very elderly (≥80) & 101 younger elderly (61–79)	Younger Elderly: 78.2; Very Elderly: 73.3	SD	24-h ABP	24 h	MMSE, short-form 36 items health survey	NA	NA	Very elderly had larger BPV than younger elderly. Exaggerated ABPV was related to cognitive dysfunction in the elderly, especially in the very elderly, and was related to lower QOL in the younger elderly
Tadic 2019 [38]	63 ± 5.7	471	53	Italy	NA	PAMELA study	31.4	SD	ABP: every 20 min for 24 h; Long-term: NA	10 years	MMSE	Entry and at the end	NA	Individual residual SBPV and DBPV gradually decreased with the increase in MMSE score
Tsang 2017 [8]	69.2 ± 6.8	94	62.7	US	Black	Normal African Americans	NA	Range, SD, CV, random slope	3 most recent clinic visits	NA	MMSE, computer assessment of MCI	NA	Age, sex, education, medical conditions (diabetes, hypercholesterolemia, obesity, and stroke)	In a sample of cognitively intact older African American adults, BP variability did not correlate with global cognitive function, as measured by the MMSE. However, higher diastolic BP variability correlated with poorer verbal and incidental memory
Van Middelaar 2018 [43]	74.2 ± 2.5	2305	44.8	Netherland	White	Community preDIVA trial	54.1	CV, SD, ARV, delta BP	Every 2 years	6.4 years	MMSE, DSM-IV	Every 2 years	Sex, age, education level, obesity, low-density-lipoprotein, smoking and diabetes	Among older people, high BPV is not associated with incident all-cause dementia. It is associated with stronger cognitive decline and incident CVD
Yano 2014 [39]	25.3 ± 3.5	2326	43	US	White, 40% black	Healthy young adults (18–30 years), data from CARDIA	NA	SD, ARV	8 visits for 25 years	25 years	DSS, RAVL, MS	At year 25	Age, sex, race, educational attainment, and study site	Long-term BPV for 25 years beginning in young adulthood was associated with worse psychomotor speed and verbal memory tests in midlife, independent of BP
Yano 2018 [40]	54.35.7	11 408	44	US	White, 21% black	ARIC study	27	ARV	4 BP measures from 1987–1989 (visit 1) through 1996–1998 (visit 4)	25 years	Global z score: delayed word recall test, digit symbol substitution test, word fluency test	1996–1998 (visit 4), 2011–2013 (visit 5)	Age, sex, race, education, APOE ε4 alleles, study center, BMI, smoking, alcohol, total cholesterol, HDL, diabetes, and prevalent stroke	1. Greater visit-to-visit SBPV or DBPV from midlife on is modestly associated with lower cognitive function, whereas higher mean SBP and lower DBP levels from midlife to later life are modestly associated with cognitive decline in later life; 2. No differences in sex, race, apolipoprotein E e4 allele, or antihypertensive medication use
Yoo 2020 [12]	55.5 ± 10.2	7844 814	52.5	Korea	Asian	W.o.dementia, population-based restrospective cohort study, from Korean National Health Insurance System database	NA	VIM, CV, SD	3 examinations	6.2 years	MMSE, ICD-10	End point	Age, sex, BMI, smoking, alcohol, regular exercise, income status, diabetes and dyslipidemia, mean SBP, or DBP at baseline, use of AHT drugs, ischemic heart disease, stroke	A dose–response relationship was noted between higher BPV and incidence of all-cause dementia, AD and vascular dementia
Zhou 2019 [41]	59.8 ± 8.0	1804	51.9	France	NA	The Maastricht Study	39.1	SD, ARV,	Within-visit, 24 h, 7 days	NA	Neuropsychological test battery	NA	Age, sex, educational level, 24-h SBP, DBP, and cardiovascular risk factors	Greater very short-term to mid-term DBPV and, to a lesser extent, SBPV may be a modifiable risk factor for cognitive deterioration in 40- to 75-year-old, community-dwelling individuals

AD, Alzheimer's disease; ADAS-COG, the modified Alzheimer's Disease Assessment Scale Cognitive Component; ADRDA, Alzheimer's Criteria Definite Alzheimer's disease; AHT, antihypertensive; APOE, apolipoprotein E; avg, average; CDR, Clinical Dementia Rating Sum of Boxes; CN, cognitive normal; CVD, cardiovascular disease; DSM-III-R, the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DST, HRS, Health and Retirement Study; ELSA, English Longitudinal Study of Ageing; HBP, home BP; HDS-R, the revised Hasegawa's Dementia Scale; HT, hypertension; IS, ischemic stroke; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; MoCA-J, Japanese version of the Montreal Cognitive Assessment; NIHSS, National Institutes of Health Stroke Scale; PSCI, poststroke cognitive impairment; RAVL, Rey Auditory Verbal Learning; TMT B, the Trail-Making Test Part B; WMH, white matter hyperintensity; wSD, weighted SD.

Sex differences

Some evidence showed that men had higher mean BP values while women had higher BPV ^[6]. However, one study found that men had significantly higher levels of all BPV measures than women ^[44]. This difference may be due to measuring BPV at different ages. Li et al.^[44] measured BPV starting at 14 years old with a follow-up of 15 years, while Alpérovitch et al.^[6] enrolled the participants at an average of 73.7 ± 5.2 years old, a long period after women's menopause, losing the protection of estrogen. Furthermore, although these studies indicated sex differences in BPV, little attention was paid to the sex-specific effects on the association between BPV and cognitive impairment ^[25]. Some studies adjusted the results for sex and found no sex differences in the association ^[6,33,40]. In addition, a systematic review with a meta-analysis of 16 longitudinal studies (>7 million participants) did not find sex differences in the influence of visit-to-visit SBP variability (SBPV) on dementia and cognitive impairment in the older population ^[14]. In contrast, other studies reported contradictory results. Evidence indicated that the association between SBPV and dementia appeared stronger in men ^[9,12,25,44], and men had a greater degree of CVD with higher BPV ^[44]. For example, Ernst et al.^[25] found that men in the highest tertile of BPV had significantly higher risks for both cognitive decline and dementia than those in the lowest tertile, while women did not have an association between BPV and cognitive decline or dementia, no matter the baseline cognitive scores were similar among all BPV tertiles for both sexes. Furthermore, antihypertensive treatments in men but not women, impacted the association between BPV and cognitive decline and dementia, with increased risk in the middle and highest tertiles using antihypertensives ^[25]. Due to the limited and inconsistent findings, sex differences in the relationship between BPV and cognitive function warrant further investigation.

Age differences

The findings are complicated regarding the influence of BPV on cognitive function at different life stages. For example, some studies indicated the relationship between BPV and cognitive impairment in the aged population over 60 years old ^{[4,6,24–27,31–32,36–37,45]}. For example, one large systematic review with twenty cohort studies of around eight million persons found the effect of SBPV on all-cause dementia was more prominent among the older age (>65 years) ^[45]. In addition, exaggerated ambulatory BPV was associated with cognitive dysfunction in the elderly, especially in the very elderly (≥80 years old) and lower quality of life in the younger elderly (61–79 years old) ^[37]. However, another systematic review with a meta-analysis of 16 longitudinal studies (>7 million participants) found a trend but no statistical significance in the effect of visit-to-visit SBPV on dementia and cognitive impairment between older age (≥65 years old) and younger age (<65 years old) ^[14]. In a prospective cohort study of 976 community-dwelling older adults, higher visit-to-visit SBPV was associated with a faster cognitive decline, and higher visit-to-visit of DBPV was associated with a faster cognitive decline among individuals aged 55–64 years but not those at least 65 years ^[35]. The inconsistent findings may be due to multiple methods, including the number and interval of BP measurements, duration of the follow-up, participants’ characteristics (i.e. sex, ethnicity, and race), and cognitive function measurements. Moreover, associations between cognitive function and BPV are not limited to older adults. Data from the CARDIA study showed that young adults (18–30 years old) with long-term BPV over 25 years of follow-up had worse verbal memory and psychomotor speed in midlife than those with stable BP ^[39]. Another study showed that greater visit-to-visit BPV starting from midlife was associated with cognitive decline ^[40]. Importantly, these two studies of the healthy young population with extended follow-up indicate the BPV measured in young adulthood is a risk factor for cognitive impairment or even dementia in later life and could provide the critical time window for BPV management to prevent cognitive impairment or dementia.

Racial and ethnic differences

One systematic review with meta-analysis recently found the increased risk of cognitive impairment and dementia was associated with greater BPV, and participants from the United States and Europe had higher risks than those from Asia ^[14]. However, this systematic review only included a limited number of Asian studies ^[14]. Another larger systematic review, containing original studies from Asia (10), Europe (nine), North America (seven), and Americans with Japanese ancestry (one), showed distinct differences in BPV between non-Asian and Asian populations ^[46]. It demonstrated that SBPV-induced risk for cerebral small vascular disease, a contributor to cognitive impairment and dementia, was higher in Asian groups ^[46]. The higher BPV in Asian may be due to their higher morning surge in BP ^[47], a pressor component of BPV. In contrast, one study containing 24 593 participants worldwide reported no ethnic differences in the influence of SBPV on cognitive impairment ^[7]. More research with diverse samples will help understand the role of BPV in cognitive impairment and dementia among different ethnic groups.

The differences between SBP variability and DBP variability

Most studies report SBPV to be more closely correlated with cognitive function, especially in aged people ^{[7,16,25,30,33]}. For example, in a prospective study of Pravastatin in the Elderly at Risk, higher visit-to-visit SBPV but not DBPV was associated with faster functional decline in older adults at high cardiovascular risk ^[33]. Similar results were also found in patients with high cardiovascular risk but without preexisting cognitive dysfunction ^[7]. Although other studies found that the association with dementia was comparable between SBPV and DBPV ^[6,9,34,40]. Moreover, if both are increased, there may be a synergistic effect ^[12]. Yoo et al.^[12] found that both higher SBPV and DBPV had a greater impact on the risk for dementia than only increased SBPV or DBPV. Other studies showed that higher visit-to-visit DBPV instead of SBPV was correlated with poorer cognitive function ^[48]. Furthermore, evidence indicates that SBPV and DBPV impact different domains of cognitive functions. For example, Zhou et al.^[41] found that increased SBPV was associated with lower memory function while increased DBPV was associated with information processing speed and executive function in 40–75-year-old community-dwelling individuals. Although the pathophysiological mechanisms underlying the differences are still unclear, SBPV is correlated with arterial stiffness, which is related to aging and high BP (SBP but not DBP) levels ^[16,49]. For example, Schillaci et al.^[49] found that higher short-term SBPV significantly increased carotid–femoral velocity, an indicator of aortic stiffness, in patients with hypertension. In contrast, DBPV predicts lower hippocampal volume ^[50] and is related to endothelial dysfunction and impaired autonomic function with increased sympathetic activity ^[16]. Diaz et al.^[51] found that African-Americans with higher visit-to-visit DBPV had impaired endothelial function measured by the flow-mediated/nitroglycerin-mediated dilation ratio or the 5-min time-course under the curve of flow-mediated dilation. They also found that increased visit-to-visit or 24-h DBPV had lower circulating endothelial microparticles, the biomarker of endothelium status ^[51]. In addition, higher DBPV was associated with the risk of cerebral microbleeds ^[36], greater white matter hyperintensity (WMH) volume starting from midlife, potential risk factors for cognitive decline in later life ^[52]. The differences between SBPV and DBPV are important for determining the potential mechanisms underlying the relationship between BPV and cognitive impairment and dementia, especially in later life.

Different timeframes of blood pressure variability

Most studies reported the relationship between long-term (visit-to-visit) BPV and cognitive impairment and dementia ^{[4,6–7,9,11–12,24–26,30–32,35–36,39–40,53]}. In addition to visit-to-visit BPV, mid-term (day-to-day) SBPV is associated with cognitive decline ^[27,41], poststroke cognitive impairment ^[54], and all-cause dementia ^[34] in the elderly. Mid-term (day-to-day) SBPV also correlates with cerebral small vascular disease burden in memory clinic patients ^[55]. Regarding short-term (hour-to-hour) BPV, evidence showed that participants with increased hour-to-hour BPV measured within 24 h had a cognitive decline. For example, in elderly patients with one or more cardiovascular risk factors and well BP control, higher 24-h ambulatory BPV was associated with cognitive impairment ^[23]. Another study showed that both hour-to-hour and visit-to-visit BPV, not BP values, were significantly higher in patients with working memory impairment compared to those cognitively normal individuals ^[26]. Moreover, there is a risk of very short-term (beat-to-beat) BPV for dementia, with a hazard ratio of 1.57, comparing the highest quintile to the lowest BPV ^[14]. However, due to the lack of standard measurements and few studies, it is challenging to draw a definitive conclusion about the association between very short-term (beat-to-beat) or short-term (hour-to-hour) BPV and cognitive function ^[14].

Different follow-up lengths

High SBPV was reported to be correlated with an increased risk for dementia, which was more prominent with longer intervals between SBPV measurement and the diagnosis of dementia ^[9]. Ma et al.^[9] reported that SBPV at lag 0 year was not significantly related to the risk of dementia. It reached statistical significance starting from 1 year lag period, and there was an upward trend with every 1-year increase in the lag period from 0 to 15 years, with the hazard ratio with the highest quintile of BPV increasing from 1.08 within 5 years of SBPV measurement to 3.13 after 15 years for dementia risk ^[9]. Moreover, the growing long-term risk was related to both significant rises and falls in SBP, while the increased risk at shorter follow-up length was moderate and only related to significant falls in SBP ^[9]. Similar findings were observed for DBPV ^[9]. Moreover, a cohort study with a follow-up of 20 years observed that higher SBPV and reduced SBP complexity (the adaptive capacity of dynamic BP processes) were associated with a higher risk of dementia ^[29]. Another two studies with even longer follow-up lengths of 25 years also reported the association of long-term BPV with worse cognitive function in later life ^[39]. However, higher visit-to-visit BPV from middle-life was modestly related to worse cognitive function during a 20-year follow-up but not over 25 years ^[40]. Currently, most prospective studies only investigated the impact of BPV on cognition within a short period of follow-up. It is essential to extend the follow-up lengths so that it is long enough to detect the pathophysiology changes, such as white matter lesions (WMLs).

THE IMPACT OF BLOOD PRESSURE VARIABILITY ON COGNITION IN MILD COGNITIVE IMPAIRMENT PATIENTS

MCI is a transition phase between healthy cognition and dementia ^[56]. There are two subtypes of MCI. One is amnestic MCI, which progresses to Alzheimer's disease preferentially. The other one is the multiple domains MCI, which progresses to different types of dementia, including Alzheimer's disease and vascular dementia ^[56]. Long-term SBPV was elevated in amnestic MCI compared to age-matched cognitively normal participants ^[57]. In a post-hoc analysis of the Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT MIND) cohort study of 9361 participants, visit-to-visit BPV increased the risk for dementia in participants diagnosed with MCI, with comparable mean BP levels ^[58]. In the lowest quartile of SBPV-SD, the rate of dementia was 8.5%, while it rose to 21.7% in the highest quartile. The findings were similar for DBPV ^[58]. In another more extensive study using longitudinal data of 13 284 individuals from the National Alzheimer's Coordinating Center, higher visit-to-visit BPV was also associated with cognitive deterioration (odds ratio of 2.64, comparing extreme quintiles) ^[59]. This association was linked to neurofibrillary tangle and vascular pathology, including WMH, microinfarcts, and atherosclerosis ^[59]. Furthermore, the association with vascular pathology and cognitive decline appeared stronger in participants with normal cognition than those with MCI at baseline ^[59]. In a most recent study, higher visit-to-visit BPV was correlated with cerebrospinal fluid (CSF) Alzheimer's disease biomarkers, increased phosphorylated Tau (pTau), total Tau, and decreased amyloid-beta levels in older adults with either normal cognition or MCI, independent of BP levels ^[60]. Evidence indicated that CSF pTau was a more potent marker for Alzheimer's disease neuropathology, such as neurofibrillary tangles, compared to CSF total Tau ^[60]. As mentioned above, BPV was associated with neurofibrillary tangle ^[59] but not with amyloid plaques. In addition, deterioration in cognition is more relevant to CSF Tau than amyloid-beta levels beyond vascular pathology ^[60]. These findings imply that reducing BPV might be beneficial for patients with MCI as a novel approach to prevent the progression to dementia. Moreover, it greatly impacts on the pathophysiology mechanisms to help us better understand the conversion from MCI to dementia. Summary of the studies please see Table 3.

TABLE 3 - Summary of the relationship of blood pressure variability and cognitive function in patients with mild cognitive impairment, and different types of dementia

Author year	Age, year avg ± SD	Sample size	Male%	Region	Ethnics	Health status (database)	HT treatment %	BP index	BP time point	Follow-up duration	Cognition Methods	Cognition time point	Adjustment comorbidity factors	Results
de Havenon 2021 [53]	73.8 ± 8.7	9361	66.2	US	47.1% white	Post-hoc analysis of SPRINT MIND with MCI, CVD risk factors	NA	SD, CV, RSD, ARV, SV	At least 4 BP measurements	2.6 ± 1.2 years	NA	Year 2, year 4, then 1 year thereafter	Age, sex, race, education, SPRINT randomization arm, history of CVD, HTN, diabetes, and mean BP	Increased BPV after MCI diagnosis was associated with incident probable dementia during subsequent follow-up
Epstein 2013 [5]	75.2 ± 6.4	626	59.8	US	NA	ADNI (400 MCI, 184 AD, 226 healthy)	47.7	Mean, max, SD, CV	Every 6 months	36 months	CDR, MMSE, ADAS-COG, trail making test-B, Fluency, digital symbol test, RAVL	Every 6 months	Baseline scores, years of education, age, BMI at 36 months, sex, APOEe4, depression, and vascular disease at 36 months	1. Greater variability in systolic but not diastolic BP was associated with worse global and executive function and episodic memory (RAVL Total Score); 2. Female sex was significantly associated with higher Rey, Digit Symbol, and executive z-score
Sible and Nation 2020 [57]	CN: 73.9 ± 6.8; MCI: 73.6 ± 7.2; AD: 75.4 ± 7.6	1421	CN: 52.6; MCI: 61.6; AD: 55.6	US	NA	681 cognitively normal, 479 MCI, 261AD	CN: 18.8; MCI: 22.3; AD: 29.5	VIM	At 0, 6, 12 months	Over 12 months	NA	NA	NA	Long-term SBPV is elevated in cognitive impairment due to AD
de Heus 2019 [63]	72.1 ± 8.1	460	37.6	Europe	NA	NILVAD trial, patients with mild-to-moderate AD	34.6	SD, CV, VIM	At baseline and 6, 13, 26, 39, 52, 65, and 78 weeks thereafter; D-D (46 patients), HBP, day and night duplicate, for 7 consecutive days	Long-term: 78 weeks; HBP: 7 days	ADAS-COG, DAD	After 1 and 1.5 years	Mean BP, age, sex, intervention group, baseline ADAS-COG or DAD score, AHT use, memantine use, cholinesterase inhibitor use, cholesterol lowering drug use, history of CVD and diabetes	Higher visit-to-visit and day-to-day BPV might be associated with progression of AD
Lattanzi 2014 [61]	79.1 ± 8.7	210	NA	Italy	NA	70 AD, 140 healthy	NA	SD, CV, Max, Min	Monthly	6 months	NA	NA	NA	AD patients have a greater variability of both SBP and DBP in comparison with age-matched cognitive normal controls, suggesting potential implication in the pathogenesis or progression of the disease
Lattanzi 2014 [62]	76.0 ± 7.4	240	30.4	Italy	NA	AD	52.9	CV	Every 3 months	12 months	MMSE	Entry and end	Sex, age, education, BMI, APOE genotype, baseline MMSE score, severity of dementia, vascular risk factors (hypertension, diabetes, smoking habits, and hyperlipidemia), burden of white matter disease and treatments (antihypertensives, statins, antiplatelets)	Only SBPV explained the decrease in the MMSE score
Lattanzi 2015 [66]	76.0 ± 7.3	329	NA	Italy	NA	248 AD, 81 frontotemporal dementia	NA	CV	Every 3 months	12 months	MMSE	Entry and end	NA	SBPV was associated with the rate of cognitive impairment in AD, but not in frontotemporal dementia patients. No relationship emerged between any other BP index and cognitive decline
O’Caoimh 2019 [65]	77.9 ± 7.1	392	51	Ireland	NA	Mild-to-moderate AD in the Doxycycline and Rifampicin for AD study	94	CV	≥3 BP readings	1 year	ADAS-COG, MMSE, CDR, QMCIS, the Lawton-Brody activities of daily living scale	Entry and end	Sex, age, education, randomization group, Geriatric Depression Scale, Standardized MMSE, AHT, cholinesterase inhibitors and memantine, average SBP	Visit-to-visit BPV did not predict cognitive decline in AD
Geng 2017 [54]	63.1 ± 10.0	796	54.1	China	Asian	Ischemic stroke patients	NA	SD, CV	7 days of symptom onset, 5 times	1 Year	MoCA	14 days, 3, 6, and 12 months after onset	Age, sex, education, hypertension, SBP, DBP, location of infarction, NIHSS, and thrombolytic therapy	Midterm BPV during the early phase of acute ischemic stroke is independently associated with PSCI, especially in the visuoperceptual, executive, and delayed recall domains. male sex, low education levels, high NIHSS scores, cortical–subcortical infarction, and subcortical infarction are risk factor for PSCI
Hilkens 2021 [71]	No dementia: 65.5 ± 8.3; Dementia: 70.1 ± 8.5	17 064	No dementia: 65; Dementia: 59	35 countries	White, black, Asian, and other	PRoFESS trial, noncardioembolic ischemic stroke	No dementia: 67; Dementia: 71	CV	1, 3, 6 months, and every 6 months thereafter	2.4 years	NA	At final visit	Age, sex, baseline NIHSS, HTN, diabetes, smoking, hypercholesterolemia, obesity, history of stroke, mean SBP and AHT treatment	High BPV is associated with an increased risk of poststroke dementia
Kim 2021 [15]	64.6 ± 10.8	746	64.1	South Korea, Hong Kong	Asian	PICASSO ischemic stroke patients	NA	SD, CV, VIM	Median: 11 readings; 1 month later, and every 3 months thereafter	Mean 2.6 years ≥5 reading	MMSE, MoCA	Apr 2010-Aug 2015; 1-months, 4-months, annual (13,25, 37, 49 months) and final	Age, sex, educational, probucol treatment, baseline NIHSS score, baseline cognition test scores, diabetes, intracerebral hemorrhage and mean SBP	Higher BPV was independently associated with faster cognitive decline over time

THE IMPACT OF BLOOD PRESSURE VARIABILITY ON COGNITION IN ALZHEIMER'S DISEASE PATIENTS

Higher long-term BPV (both visit-to-visit SBPV and DBPV) has been found in Alzheimer's disease patients compared to cognitively normal participants ^[61]. Greater visit-to-visit SBPV was associated with a significant cognitive decline in 240 mild-to-moderate Alzheimer's disease patients after 12 months of follow-up ^[62]. Moreover, a randomized trial (European multicenter, double-blind placebo-controlled Phase III trial of nilvadipine in Mild to Moderate Alzheimer's Disease) containing 460 mild-to-moderate Alzheimer's disease patients, increased day-to-day and visit-to-visit BPV were found to be associated with Alzheimer's disease progression ^[63]. In addition, postmortem cerebrovascular lesion related to elevated BPV was reported in autopsy confirmed Alzheimer's disease, independent of mean BP value and Alzheimer's disease neuropathology ^[64]. However, a smaller study did not find statistically significant associations between visit-to-visit BPV and cognitive decline in Alzheimer's disease ^[65]. The inconsistent findings may be due to the lack of a gold standard for BPV measurement, suggesting the need for integrated methods for analyzing pooled data ^[63]. Furthermore, increased BPV may play different roles according to the stages and types of dementia ^[66]. For example, SBPV is associated with the faster progression of cognitive impairment in Alzheimer's disease but not in frontotemporal dementia patients ^[66]. Summary of the studies please see Table 3.

THE IMPACT OF BLOOD PRESSURE VARIABILITY ON COGNITION IN POSTSTROKE DEMENTIA

Besides the disability caused by a focal ischemic lesion, emotional dysfunction, and cognitive impairment in the later phase of stroke receive less attention. Existing data showed that approximately 10–30% of stroke patients had poststroke dementia, and poststroke cognitive impairment (PSCI) ranged from 35 to 80% ^[67–68]. Studies suggest no correlation between BP and poststroke cognitive function ^[69], whereas increased BPV predicts PSCI ^[54]. For example, mid-term BPV measured within 7 days of stroke onset was independently associated with PSCI, especially in late recall memory, visuoperceptual, and executive domains ^[54]. The incidence of PSCI began to rise at 14 days, peaked at 3 months, decreased at 6 months, and reached the baseline level at 12 months after stroke onset ^[54]. In addition, higher BPV in the early phase of lacunar infarction predicted poor cognitive outcomes, especially frontal lobe dysfunction, 3 months after stroke ^[70]. Moreover, a subanalysis of the PICASSO study containing 746 participants with a mean of follow-up 2.6 years indicated that BPV, not mean BP value, was correlated with faster cognitive decline after stroke, adjusted for sex, age, and other confounders ^[15], consistent with the findings of another large PRoFESS clinical trial containing 17 064 participants from 35 countries ^[71]. It should be noted that high BPV was reported to be associated with a significant cognitive decline only in the stroke patients with Mini-Mental State Examination (MMSE) scores more than 24, suggesting that BPV was more likely to affect cognitive function in patients with a relatively preserved baseline ^[15]. BPV may contribute to the mechanisms underlying PSCI, including hypoperfusion, small cerebral vessel disease, arterial remodeling, and neurodegeneration pathologies. For example, BPV independently predicts cerebral microbleeds, not WMLs, in deep and infratentorial regions of ischemic stroke patients within 1–6 months after onset ^[72]. Although most studies reported no sex differences in the relationship between BPV and poststroke dementia or PSCI ^[15,70–72], there is one study indicating male sex is a risk factor for PSCI ^[54]. Summary of the studies please see Table 3. Further large studies are needed to confirm the influence of BPV on cognitive function at both the early and late phases of stroke onset and its underlying mechanisms.

POTENTIAL MECHANISMS UNDERLYING THE RELATIONSHIP BETWEEN BLOOD PRESSURE VARIABILITY AND COGNITIVE IMPAIRMENT AND DEMENTIA

Although increasing evidence shows that BPV is related to cognitive impairment and dementia, the potential mechanisms underlying this relationship are not fully elucidated. The overall pathophysiology process may be hemodynamic instability causing cerebral hypoperfusion and subsequent endothelial damage and inflammatory processes. These changes led to the thickening of blood vessels, arterial stiffness, arterial remodeling, amyloid-beta deposition, cerebral small vessel diseases, and brain atrophy (Fig. 1). In addition, studies of sex differences in the underlying mechanisms are limited and warrant further investigation. This review summarizes here those above putative pathogenic factors, with brief discussion of sex differences.

FIGURE 1: Potential mechanisms underlying the relationship between blood pressure variability and cognitive impairment and dementia. CMB, cerebral microbleeds; CSVD, cerebral small vessel diseases; WMH, white matter hyperintensities.

Hypoperfusion

As a delicate organ with high metabolic and perfusion demands, the brain has the autoregulation mechanism to maintain steady cerebral blood flow across a wide range of BP levels ^[73]. However, this autoregulation mechanism is affected by aging and chronic hypertension, with a rightward shift of the plateau stage, rendering the brain frailer to low BP levels ^[73], and is associated with hypoperfusion leading to ischemic brain injury ^[74]. Recently, high BPV with extreme high and low BP levels has been reported to hamper cerebral perfusion, causing recurrent episodes of cerebral hypoperfusion in older adults ^[75]. Cerebral hypoperfusion contributes to cognitive decline and the progression and severity of dementia in the general population ^[76]. As reviewed thoroughly ^[77], cerebral hypoperfusion is related to ischemic neuronal damage, neuroinflammation, oxidative stress, WMLs, and blood–brain barrier (BBB) dysfunction, leading to cognitive impairments. Notably, these changes occur in the vulnerable regions, such as the hippocampus, affected at the early stage of Alzheimer's disease ^[12]. Studies assessing sex differences in cerebral hypoperfusion caused by BPV are lacking. One study reported no statistical differences in the relationship between BPV and cerebral hypoperfusion after adjusting the sex ^[75].

Endothelial dysfunction and inflammation

Cerebral blood vessel dilation contributes to cerebral blood flow (CBF) maintenance via smooth muscle autoregulation and vasoactive factors (e.g. nitric oxide, NO) produced by endothelial cells ^[78]. Long-term hemodynamic instability in the circulation puts stress on the vascular endothelium, causing microvascular and endothelial damage, vascular smooth muscle dysfunction, and inflammation ^[79]. Indeed, emerging data have shown that both short-term and long-term BPV increase shear stress on the vessel wall, leading to endothelial injury, smooth muscle dysfunction, and vascular inflammation ^[51,79]. High BPV increased endothelial activation and inflammatory biomarkers, such as IL-6 ^[79]. Moreover, anti-inflammatory treatments alleviated the impairment of end-target organs secondary to BP fluctuation ^[80]. Early inflammation is known as a long-term risk for dementia ^[81]. Moreover, experimental study suggested that great BPV suppressed NO production, impaired endothelial function, and raised the secretion of proinflammatory cytokines, resulting in neurovascular unit damage, BBB abnormality, and dementia pathology ^[82].

Cerebral small vessel disease

Accumulating data have implicated that BPV is related to cerebral small vessel disease (CSVD), including WMH, microbleeds, and silent infarcts, leading to cognitive impairment and dementia ^{[36,46,74,83–85]}. For example, greater home BPV is associated with faster deterioration of cognitive impairment and WMLs in community-dwelling oldest old ^[86]. Increased SBPV in midlife may contribute to developing WMLs and ventricular atrophy in late life ^[84]. More recently, in a meta-analysis of 27 clinical studies and 12 309 individual brain scans, BPV was confirmed to be associated with CSVD independent of mean BP value ^[46]. Several lines of evidence from experimental and clinical studies indicated that microvascular damage disturbed the BBB, resulting in neuronal loss and brain atrophy ^[36]. While most studies highlighted the importance of SBPV in CSVD ^[7,17,27,55], Liu et al.^[72] found that DBPV, instead of SBPV, was significantly associated with deep cerebral microbleeds progression, independent of mean DBP in the elderly. The varied results from studies of associations between BPV and CSVD may be related to different population cohorts and study designs. Higher DBPV was associated with greater WMH volume starting from midlife and was a potential risk factor for cognitive decline in later life ^[52]. Moreover, a clinical study with a cohort of nondemented elderly demonstrated that WMH volume and infarction frequency increased with higher BPV across three visits at 24-month intervals ^[83]. The results are inconsistent regarding sex differences in the relationship between BPV and WMH. Some studies found no sex differences in the association of BP and long-term BPV with WMH volume ^[83,87]. In contrast, one study meta-analyzed 27 papers consisting of 12 309 brain scans and found that the difference between CSVD groups in DBPV was associated with the female sex ^[46].

Arterial stiffness, arterial remodeling, and amyloid-beta deposits

High BPV increased shear stress to the vascular endothelium, the expression of adhesion molecules, and reduced NO, ultimately leading to arterial stiffness with increased carotid intima–media thickness (IMT) and stiffness parameter β ^[32]. For example, in high-risk elderly (79.9 ± 6.4 years old), max-IMT was significantly correlated with CV, delta (maximum-minimum) in SBP, and CV in DBP; while stiffness parameter β is significantly associated with SD, CV, maximum, and delta in SBP, and SD, CV, and delta in DBP ^[88]. In addition, long-term BPV is significantly associated with arterial stiffness assessed by brachial-ankle pulse wave velocity in a longitudinal study of 3994 participants with 4 years of follow-up ^[89]. Moreover, greater 24-h SBPV is correlated with arterial stiffness not only in the elderly but also in young, healthy participants ^[90]. In one Cohort study, patients with high delta SBP and high arterial stiffness indices (i.e. IMT and stiffness parameter β) had significantly lower MMSE scores than those with low delta SBP and low indices of arterial stiffness ^[32]. Furthermore, others reported the association between higher BPV and arterial remodeling in cognitive decline and all-cause death ^[9,32]. Cerebral arterial remodeling disrupted hemodynamics and caused hypoperfusion, leading to increased production and decreased clearance of amyloid-beta ^[91]. The relationships between IMT and 24-h SBPV were more evident in male than female participants, indicating that 24-h ARV of SBPV was the independent factor for increased carotid IMT in males but not in females ^[92]. However, in another larger clinical study of 957 healthy individuals, 24-h weighted SD of BPV is related to arterial stiffness in middle-aged and older adults and more correlated in females ^[93]. The inconsistent findings may be due to the different measurement indices for BPV and the limited studies.

Brain atrophy

Greater visit-to-visit BPV has been reported to increase brain atrophy and decrease white matter integrity ^[94]. Higher visit-to-visit BPV was associated with lower hippocampal volume ^[36,50], leading to cognitive impairment and dementia ^[36,50,94], especially when it begins in young adulthood ^[94]. Long-term BPV has also been associated with ventricular atrophy in prospective cohort studies ^[84]. These results indicate that hippocampal neurons are vulnerable to the disturbed cerebral circulation. The hippocampus size is larger in females than in males. Lower hippocampal volume is associated with worse verbal memory in women under 70 years old than those with higher hippocampal volumes, suggesting the importance of hippocampal volume in the memory function of women ^[95]. In a WHIMS-MRI clinical study containing 558 postmenopausal women, the group with the highest tertile of SBPV had lower hippocampal volumes and higher lesion volumes in later life than the lowest tertile ^[96]. However, there was no relationship between BPV and cognitive decline ^[96], highlighting the need to add more female data to investigate the relationship between BPV and cognition in females due to the lower hippocampal volume and whether sex differences exist in the relationship.

Furthermore, the association between BPV and pulse pressure and its effects on cognitive function should be noted. Evidence indicates that visit-to-visit, day-to-day, or beat-to-beat BPV proceeds over 55 years old in parallel with progression of aortic pulsatility ^[97]. The intensity of pulse pressure increases with age-related aorta and large arteries stiffening, damages the cerebral vasculature (microbleeds), and contributes to dementia ^[98]. Moreover, vascular pulsatile stretch increased cerebral amyloid-beta levels and expression and phosphorylation of endothelial nitric oxide synthase in brain vascular endothelial cells ^[99].

It is also worth noting that a reverse causal relationship between BPV and dementia might be possible. Increased BPV could be the consequence of dementia. At the subclinical stage of dementia, brain structure changes could affect the central autonomic regulation of BP, leading to increased BPV ^[100]. Moreover, baroreceptor sensitivity decreases during normal aging and in Alzheimer's disease ^[101]. However, one clinical study with a cohort of nondemented elderly demonstrated that higher BPV was related to worse silent infarcts and WMH ^[83], and the other study found that BPV is related to an increased risk of stroke ^[17]. Due to the decade-long prodromal stage of dementia, it is difficult to determine the temporal order of the relationship without sufficient follow-up time ^[10]. Further studies with experiments or interventions are warranted to confirm the causal arguments.

CURRENT LIMITATIONS

Although emerging data has shown that BPV plays a crucial role in the cause of cognitive impairment and dementia, their relationship and underlying mechanisms are still unclear due to methodological issues. This review discusses these issues usually seen in clinical studies: first, sex differences are lacking; second, ethnic differences are lacking; third, information of antihypertensive treatment is lacking. Different antihypertensive medicine has varied effects on BPV. For example, angiotensin-receptor blockers, β blockers, and angiotensin-converting enzyme inhibitors increase BPV while nonloop diuretics and calcium channel blockers decrease BPV ^[85]. Thus, the information on the types and doses of antihypertensive medication is needed to evaluate the influence of the poor adherence to antihypertensives on BPV; fourth, BPV indices used in clinical studies are redundant and overlapping. In addition, only BP measurements taken at regular intervals were included; fifth, sample sizes are small. The inconsistent results suggest that larger sample size is warranted to detect small effects; sixth, the follow-up period is short, not long enough to detect WMLs; seventh, cognition and dementia measurements are not sensitive enough; eighth, the time of the day when BP is measured is usually not recorded, which could lead to a random error in longitudinal measurement of BPV ^[6]; ninth, ignorance of death distorts the long-term relationship between BPV and dementia. Evidence indicates that BPV is correlated with all-cause death ^[10]. Survival bias is another concern regarding long-term BPV, which could be resolved by inverse probability weighting ^[10]; tenth, obstructive sleep apnea, associated with BPV and cognitive decline ^[5], is not measured; eleventh, evidence on short-term and mid-term BPV is lacking; twelfth, factors that affect mental health, such as depression and stress, should be noted; thirteenth, MRI markers indicating subsequent progression are limited.

FUTURE PERSPECTIVES

First, determine the most reliable indices and schedule appropriately to record BP value accurately. Calculating indices from each type, such as one from overall variability (SD, CV, or VIM), one from variability between consecutive visits (ARV), and one from extreme values (maximum), are recommended. In addition, most studies did not report if individuals were having hypertensive treatment or not. Moreover, controlling BP with antihypertensive treatment has been reported to reduce the risk of cognitive impairment, while poor adherence to antihypertensive treatment affects visit-to-visit BPV ^[25]. Thus, researchers should state the results of normotension and hypertension, respectively, and the use of antihypertensive treatments in future studies. Furthermore, as in most studies, BPV was measured with a limited number of BP recordings; home BP measurements could increase the accuracy of BPV, and BP monitoring regularly could shred more insights for people at advancing age with MCI or early symptoms of dementia.

Second, explore the sex, age, and ethnic differences in the relationship between BPV and dementia. In addition to the lack of sex difference studies on the relationship between BPV and dementia, studies exploring sex differences are even less. However, the sex difference is important because low education and low occupation history exist in women for a long time, which are well known risk factors for dementia. Nowadays, both educational and occupational situations for women are getting better, which have been found to cause changes in lifestyles of intellect in women and men, contributing to changes in epidemiologic patterns for cognitive decline and dementia worldwide. Some studies find differential mortality between men and women as early as mid-life, resulting in survival bias of men aged 60 years and older at lower risk for dementia ^[102]. However, most clinical studies enroll individuals aged 65 years or older, and thus the differential selection has already started. In addition, CVDs may already be too advanced to find a significant impact of BPV on dementia. Thereby, monitoring BP at mid-life or earlier is important to detect the influence of BPV on cognitive decline or dementia in later life and its sex differences. In addition, more research is needed to explore the influence of BPV on cognitive risk from different ethnic groups to assess ethnic differences.

Third, MMSE, the most used cognitive test in clinical studies, is developed as a screening tool for dementia and thereby is not sensitive enough to minor cognitive changes ^[43] and to different cognitive domains ^[11]. It is important to explore the impact of BPV on different dementia types, especially MCI and dementia. Thus, multiple testing (not only a single test, e.g. MMSE) and more sensitive testing are needed. Additionally, adding more neuroimaging markers in future studies to explore the contribution of cerebral structural changes in the relationship between long-term BPV and cognitive decline is necessary.

Fourth, the mechanisms underlying the relationship between BPV and dementia are still not clear, and whether the sex differences exist in the mechanisms is unknown. Some studies suggested that visit-to-visit and day-to-day BPV may have different underlying mechanisms ^[10,17]. Furthermore, no conclusion is yet to be drawn on the association between beat-to-beat or hour-to-hour BPV and cognitive function due to the limited numbers of studies and inconsistent measurement methods ^[14]. Thus, unraveling the mechanisms could provide insight into dementia prevention and help develop personalized, sex-specific treatments for dementia and other aging-related diseases. Besides controlling mean BP values, physicians need to pay more attention to stable BPV to prevent cognitive decline. Moreover, reducing large BP fluctuations is a potential target for developing novel drug candidates and combination therapy.

CONCLUSION

The current review indicated that BPV is a risk factor for cognitive decline and dementia independent of BP. A better understanding of the relationships between BPV and dementia could offer new mechanistic insights into cognitive function. This review also discusses current limitations and future perspectives to optimize BP management for dementia prevention.

ACKNOWLEDGEMENTS

The current work was supported by the Start-up Funding of Hangzhou Normal University, grant number 4255C50221204123.

Conflicts of interest

The authors declare no conflicts of interest.