2022 Volume 8 Pages 25-28
Hypertension (HTN) is known to be associated with cognitive decline and dementia. It causes cerebral vascular damage, which leads to pathological changes not only in vascular dementia but also in Alzheimer’s disease. Epidemiological evidence also suggests that HTN in midlife is probably a risk factor for dementia. Conversely, blood pressure variability or hypotension may also be associated with cerebral damage and cognitive decline. Blood pressure must be controlled for dementia prevention. We discuss the relationship between blood pressure dysregulation and cognitive decline and dementia with respect to current evidence and clinical research.
Hypertension (HTN), one of the most common disorders, is a leading risk factor for various diseases in elderly people. The NCD Risk Factor Collaboration noted that among people aged 30–79, the world prevalence of HTN in 2019 was 34% among men and 32% among women1). The high prevalence of HTN has resulted in a huge public health burden. HTN is known to be associated with cognitive decline and dementia. While poor quality of life is associated with cognitive impairment, the association between HTN and cognitive impairment and the effect of blood pressure control on cognitive decline must be considered.
Smoking and conditions such as HTN, diabetes mellitus, and hyperlipidemia are established risk factors for vascular dementia (VaD). On the other hand, recent studies have revealed that these vascular risk factors are associated with the progression of not only VaD but also Alzheimer’s disease (AD). In a previous review of several studies of dementia, the findings suggested that the outcomes of non- pharmacological intervention of vascular risk factors are comparable with those of treatment with acetylcholinesterase inhibitors2). A review article about blood pressure and dementia was published by Skoog in 19973). The association between pathological features of AD and HTN has also been extensively explored.
In this review, we focus on the effect of HTN and blood pressure dysregulation on cognitive function. Next, we discuss the current evidence and clinical research on the pathological mechanisms of cognitive decline.
VaD and AD are the most prevalent types of dementia. Some elderly people appear to have both types. Kalaria et al. noted pathological evidence of overlap between VaD and AD4). In their study, clinical criteria for the diagnosis of these conditions overlapped by 20% to 30%, whereas greater overlap was suggested by autopsy findings of mixed pathological features, including cerebrovascular lesions and neurodegeneration resulting from amyloid and tau accumulation up to Braak stage V AD. Magnetic resonance images (two horizontal slices) in a patient with dementia (Fig. 1) show both ischemic lesions and atrophy. Mixed-type dementia, as in this patient, is common, particularly in the oldest age group (i.e., more than 85 years of age).
Brain damage from hypertension and/or blood pressure fluctuation. Magnetic resonance images (fluid-attenuated inversion recovery images) of a patient (an 80-year-old woman) with dementia, whose Mini-Mental State Examination score was 19/30.
Although dementia in elderly patients is often associated with AD, most cases of early-onset dementia are VaD, which occurs after stroke (infarction or hemorrhage). HTN in early and middle adulthood probably accelerates atherosclerosis and cerebral vascular damage, leading to dementia, as shown in Fig. 25). White matter lesions have been extensively found in neuroimaging of patients with dementia. These lesions have mixed pathological features; this finding is hypothesized to be attributable to HTN-related mechanisms, including oxidative stress or systemic inflammation6). However, the actual mechanism remains unclear.
Possible pathophysiological mechanisms of brain damage occurring after hypertension, which led to cognitive decline or dementia. This flowchart was modified from the review article5) by Zlokovic et al.
On the other hand, AD is caused by different pathophysiological mechanisms involving amyloid and tau accumulation. Amyloid beta deposition is manifested by senile plaque and cerebral amyloid angiopathy, which causes microcirculation insufficiency or cerebral hemorrhage (Fig. 2)5). Hypoperfusion can cause the accumulation of not only amyloid beta but also hyperphosphorylated tau5). Furthermore, some reports have suggested that the glymphatic system or intramural periarterial drainage, which are systems of clearance of amyloid, may be also affected in AD7,8). Damage of these pathways may be associated with small vessel disease caused by arteriosclerosis. Therefore, as shown in Fig. 2, factors that damage the cardiovascular system, including HTN, are probably associated with the progression of AD5). Thus, AD and VaD may be closely linked and indistinguishable pathologically (Fig. 1).
Dementia and mild cognitive impairment are common in patients with HTN. Epidemiological evidence that HTN is a risk factor for cognitive impairment has been reported. The results of initial studies from the Framingham Study and the Honolulu-Asia Aging Study, for example, indicated that cognitive impairment was associated with higher blood pressure that had manifested several decades earlier9,10). Since then, results of several epidemiological studies of HTN have suggested that HTN in middle age is more likely to be a risk factor for cognitive decline than that in old age. In the Honolulu- Asia Aging Study, the risk ratio of VaD in patients with untreated HTN in midlife was 11.8 (95% confidence interval [CI]: 3.52–39.5), whereas that of AD is 1.2 (95% CI: 0.37–4.04), in comparison with patients without midlife HTN10). Kuopio and Joensuu demonstrated that the odds ratio of AD in Finnish patients with midlife HTN was 2.8 (95% CI: 1.1–7.2)11), which was similar to that in Linxian county in China (1.97; 95% CI: 1.10–3.54)12). A systematic review and meta-analysis of 209 prospective studies revealed extensive evidence of this association,13) although some investigations yielded inconsistent findings, which suggest that HTN-related risk for cognitive decline cannot be attributable to chronic elevation in blood pressure alone8).
The association between blood pressure variability (BPV) and the risk of cognitive impairment has also been investigated. Blood pressure fluctuation is characterized by changes in blood pressure from office visit to visit or from day to day and, independently of absolute blood pressure values, is increasingly recognized as playing a clinically important role in the progression of target-organ damage and cardiovascular events14). In one meta-analysis, the findings suggested that high BPV was associated with an increased risk of dementia and cognitive decline15). BPV has a potential role in the pathogenesis or progression of not only cardiovascular disease but also dementia, including AD16). Ambulatory blood pressure monitoring and home blood pressure measurement may be important for assessing both HTN and future risk of dementia. Furthermore, for BPV measurement, continuous beat-to-beat blood pressure monitoring is preferable to intermittent monitoring. Wearable devices for continuous blood pressure monitoring would enable more accurate detection of BPV17).
Hypotension or shock can also accelerate cerebral ischemic damage through the same mechanism as that of BPV. Evidence that hypotension is a risk factor for cognitive decline and dementia has been reported in cross-sectional studies, in which authors have speculated about whether blood pressure levels decrease during the course of the dementia process or whether low blood pressure induces or accelerates cognitive decline through reduced cerebral blood flow. Some studies have demonstrated that low blood pressure or orthostatic hypotension is associated with cognitive impairment in elderly people18). Of interest is that in some epidemiological studies of patients with dementia, results indicated that blood pressure begins to decrease approximately 3 years before the diagnosis of dementia and continues to decline in patients with AD19). Although hypotension may protect healthy elderly people from cardiovascular disease, low blood pressure levels in elderly patients who are frail and have associated diseases may cause cerebral hypoperfusion and accelerate cognitive decline18).
If HTN or BPV is a key factor in the development of dementia, the effects of intervention and treatment for controlling blood pressure must be considered because HTN is a treatable risk factor. In previous studies of whether antihypertensive drugs would prevent cognitive decline, the findings have been inconsistent. Clinical evidence that antihypertensive drugs delay the onset of or ameliorate cognitive decline has not been established, as shown in the Cochrane Database of Systematic Reviews20). The Systolic Blood Pressure Intervention Trial showed that more intensive blood pressure control with antihypertensive drugs did not result in significant cognitive benefits21). However, the Cochrane Reviews does not contain studies indicating whether treating HTN in midlife delays or prevents dementia in later life20). Further longitudinal cohort studies of patients with HTN who take antihypertensive drugs are required.
In conclusion, studies have shown that HTN may adversely affect cognitive function, which is impaired not only by cerebral vascular disease but also by neurodegenerative disease in some pathological pathways. Although no consistent epidemiological evidence has been obtained so far, HTN is probably to some extent a risk factor for dementia, especially in later life. Conversely, hypotension and BPV may also be associated with cerebral damage and cognitive decline. Thus, blood pressure control may play an important role in the clinical approach for dementia prevention.
Disclosures: Authors have no potential conflicts of interest to declare.
