1. Introduction

The world population is ageing. The proportion of people aged over 65 years currently represents 15% of the global population, and it is predicted to grow to 22% by 2050 ^[1]. As a consequence, more people are expected to work and contribute to their communities for longer. However, for this to be possible, ageing individuals need to remain physically and cognitively fit. It is, thus, important to identify the risk factors for premature ageing so preventative actions can be implemented. A large body of evidence demonstrating a link between cardiovascular and physical health exists ^[2]. However, the association between cardiovascular health and brain health has received less attention, particularly in those who are not clinically impaired, and needs to be more precisely characterised.

Hypertension is a major risk factor for cerebral health. Midlife hypertension is associated with a two- to five-fold increased risk of stroke ^[3], and up to 50% greater risk of developing vascular dementia ^[4]. Moreover, hypertension is also linked to the development of amyloid angiopathy, the progression of white matter lesions (WMLs), and a reduction in global ^[5] and regional brain volumes ^[6]. Hippocampal atrophy, in particular, has been consistently reported in individuals with hypertension. This is significant as the hippocampal region plays a fundamental role in memory and overall cognition ^[7].

In recent times, increasing research has demonstrated that, not only hypertension, but elevated BP in the pre-hypertensive or even the upper normal range, may be detrimental to cerebral health ^[8]. However, the extent to which variation in BP across its full range impairs cerebral health is not fully understood. It has been long known that BP rises steadily with increasing age from early adulthood into older age ^[9]. Therefore, even small harmful effects experienced over decades could lead to a substantial deterioration of cerebral health. The importance of BP for cerebral health has also been acknowledged in a recent communication from the American Heart Association, which indicated that hypertension-related symptomatic clinical conditions, including cognitive dysfunction, could be avoided through primary prevention of BP elevations ^[10]. Consequently, it is important to develop a better understanding of the progressive impact of rising BP levels and brain structure and function, which will help promote and justify prevention earlier in life rather than in mid-life when hypertension typically develops.

2. Higher Blood Pressure is Associated with Greater White Matter Lesions and Brain Atrophy

The key finding of this recent meta-analysis is that the vast majority of published articles (93.7% of the 52 articles included) reporting on the association between BP and brain volumes found that higher BP was associated with poorer brain health. The effect of BP varied across brain regions, but consistent evidence suggested particularly strong associations for WMLs and the hippocampus. The magnitude of these effects were large and dose-dependent, with every one-SD higher SBP being associated with an 11.2% larger WMLs volume in cross-sectional studies. However, the association between SBP and WMLs was substantially weaker in longitudinal analyses, which were based on a very small number of studies. Consistent with these findings, similar associations, albeit weaker, were also found in relation to TBV with 91.3% of studies reporting higher BP to be associated with lower volume. This effect may have been substantially driven by smaller white matter and higher WMLs, as consistent associations between BP and these measures were observed across all studies.

Since the existing literature is inconclusive on whether SBP or DBP has a greater impact on brain health, we contrasted the effect of SBP and DBP on HCV. We found that higher SBP was more strongly associated with lower volume than DBP, but only in the hippocampus. This may suggest that SBP has a somewhat greater impact on brain health. However, it must be noted that the studies included in this analysis mostly consisted of individuals who were on average in their mid-fifties, which may indicate that this difference might be due to changes in SBP and DBP patterns at this point in life, as DBP tends to decline after the age of 50–60, while SBP continues to increase with age ^[11].

These findings have significant clinical implications since TBV, but particularly HCV, are implicated in the onset and progression of Alzheimer’s disease (AD). HCV is strongly predictive of conversion to AD and therefore, any additional shrinkage in this brain regions attributable to higher BP is likely to hasten conversion. Hippocampal shrinkage in normal aging is estimated to be slightly over 1% per/year above 70 ^[12], and twice this amount in the pre-clinical stage of the disease ^[13]. Thus, we estimate that the additional 2.6% shrinkage experienced by somebody with hypertension (SBP = 140 mmHg), compared to somebody with normal SBP (120 mmHg), might lead to premature AD conversion by a year or more ^[13]. Consequently, since the mean age of the samples included in the meta-analysis was 52 years and above, it is critical that prevention efforts be directed at younger adults, not only to protect brain health in general, but also to decrease future risk of developing dementia.

Another important finding was that increased BP was associated with a poorer brain health across its full range, and not exclusively in individuals with hypertension or pre-hypertension. Indeed, the meta-regression testing the effect of the proportion of participants with hypertension across different studies, which ranged from 23.9% to 69%, revealed no significant effect of hypertension on brain health. This indicates that associations between BP and brain measures are not mainly driven by those individuals with hypertension and further emphasizes the need for risk reduction before hypertension develops. Additionally, these findings suggest that more systematic BP and overall health monitoring, as well as the promotion of a healthier lifestyle, should be implemented at a younger age and supported through educational campaigns.

The pathological mechanisms linking BP to overall and localized brain atrophy and cognitive decline are not fully understood. Several mechanisms, including neuroinflammation, oxidative stress, dendritic shrinkage, and apoptosis, are thought to be implicated in the pathophysiology linking elevated BP and neurodegeneration. Indeed, higher BP levels have been shown to up-regulate the production of pro-inflammatory cytokines ^[14][15][16]. In turn, chronic systematic inflammation produces higher levels of oxidative stress, which leads to DNA damage and impairment of cellular structure and function ^[15]. Thus, through these mechanisms, elevated BP is likely to contribute to dendritic shrinkage, decreased neurogenesis, demylination, and neuronal loss ^[17] which are detectable at a macroscopic level as brain atrophy, particularly in the hippocampus.

In addition, the etiology of WMLs is of particular significance, as they impact cognitive function across all domains, and generally to a greater extent than brain atrophy ^[18]. While the pathophysiological mechanisms reviewed above are also implicated in the development of WMLs, cardio-vascular factors are thought to be the main contributors. Good evidence suggests that BP increases the risk of arthrosclerosis by 50% or more ^[19]. This is likely to lead to lower blood perfusion in capillaries, endothelia dysfunction ^[20], impaired vasoreactivity, increased pulsatility, vessel stiffening, and changes to the blood brain barrier (BBB) integrity. Resulting small vessel disease in conjunction with ischemia, inflammation, and myelin loss are then likely to contribute to the development of WMLs ^[21].

The progression of WMLs may also contributes to worse global and regional brain atrophy. Although the precise nature of this relationship is not fully clear, advanced neuroimaging methods suggest that WMLs particularly affect white matter networks connecting remote brain regions and thus lead to gray matter shrinkage, for example through Wallerian degeneration ^[22]. This makes it particularly important to assess an individual’s brain health profile with both WMLs and tissue loss, ^[18] so we can develop a better understanding of their inter-relationship and underlying pathological mechanisms ^[18].

A somewhat surprising result is that the association between BP and brain volume was, as demonstrated in the sensitivity analyses of WMLs, somewhat stronger in mid-life individuals although it remained significant into old age. The reasons for this effect are not completely clear but may be due to sample or study characteristics. Alternatively, it has been shown that vascular structure changes with advanced age. Therefore, it is possible that endothelial sensitivity to increasing BP varies across age groups ^[23][24]. In contrast, no moderating effect of sex was detected despite several previous reports suggesting differential effects of BP in men and women ^[6]. This may be due to the approximate nature of the sex analyses, which were based on the sex ratio of each sample, rather than on individual-centered data. Therefore, future studies should aim to report separate estimates for men and women so more precise syntheses can be conducted.