Low blood pressure in the elderly is related to dementia

Chengxuan Qiu and Laura Fratiglioni

Aging Research Center, Division of Geriatric Epidemiology, Department of Neurotec, Karolinska Institutet and Stockholm Gerontology Research Center, Stockholm, Sweden

Abstract

Long-term cohort studies have shown that elevated blood pressure beginning at midlife is associated with an increased risk of developing cognitive impairment and dementia in late life. Atherosclerotic pathology is assumed to be a major mediator in the association between long-standing hypertension and dementia and Alzheimer’s disease. Although findings from cohort studies examining blood pressure in relation to dementia and Alzheimer’s disease among the elderly are inconsistent, recent evidence has emerged that low blood pressure in old people may be associated with subsequent development of clinical Alzheimer’s disease and dementia. It is biologically plausible that low blood pressure can be linked to Alzheimer’s disease and dementia through the mediation of severe atherosclerosis as well as impaired cerebral perfusion. Moreover, the finding of low blood pressure in association with elevated risk of dementia draws attention to aggressive blood pressure controls in the elderly, especially in very old people.

Introduction

The relation of blood pressure to cognitive functioning and dementia has received considerable attention over the last decade. A few long-term cohort studies have reported that elevated blood pressure in midlife is associated with an increased risk of cognitive impairment and dementia in late life.1-5 However, findings from cohort studies addressing blood pressure in association with dementia and Alzheimer’s disease (AD) among the elderly are inconsistent: some studies have found that high blood pressure is associated with vascular dementia, but not with AD;6-9  others have shown that low blood pressure is associated with subsequent development of AD and dementia.10-12 Researchers in Sweden have put considerable effort into clarifying the relation of blood pressure to dementia. In this brief report, we summarize key sources of evidence that support the notion that, beyond long-standing high blood pressure, low blood pressure in the elderly may precipitate clinical AD and dementia.

Elevated blood pressure in midlife is related to cognitive impairment in late life

In 1993, the Framingham study showed evidence of an association between high midlife systolic pressure and cognitive decline in late life, especially in untreated individuals.1 Later, the Honolulu-Asia Aging Study in Japanese-American men further confirmed that elevated midlife systolic pressure significantly predicted impaired cognitive functioning in old age independent of major vascular disorders such as stroke and subclinical atherosclerosis.13 A cohort study of 999 men in Sweden showed that high diastolic pressure at age 50 was related to impaired cognitive performance, as measured by the Mini-Mental State Examination, at age 70, particularly among men who were not treated with antihypertensive drugs.2 The US National Heart, Lung, and Blood Institute Twin Study found that individuals with a higher midlife systolic pressure experienced a greater decline in cognitive function and had larger brain atrophy in late life.14 Elevated midlife diastolic pressure and high white matter hyperintensities increased the risk of late life mild cognitive impairment, even among subjects without a history of symptomatic cerebrovascular disease.15 In a Finnish population, midlife high systolic pressure had a marginally significant effect on mild cognitive impairment in old age.4 There was also a dose-response relation between elevated systolic pressure in midlife and severity of cognitive decline in old age.

The findings of these studies imply that elevated blood pressure in midlife is a risk factor for cognitive impairment in late life.

Elevated blood pressure in midlife increases the risk of dementia in late life

The relationship between midlife blood pressure and AD and dementia in late life has been examined in a few studies (Table 1). The Honolulu-Asia Aging Study revealed that increased midlife systolic and diastolic pressure were associated with a higher risk of vascular dementia, AD, and all dementias late in life, particularly among men never treated with antihypertensive medications.3 This study also showed a tendency toward increased dementia risk for individuals with middle-aged low blood pressure. Autopsy evidence from the same cohort supported a link between high blood pressure and increased neuritic plaques.16 In addition, midlife high blood pressure, especially if untreated, was also associated with an increased risk for hippocampal atrophy, a condition that significantly contributes to senile plaques and neurofibrillary tangles in the brain.17 In a Finnish cohort, raised systolic pressure, especially in combination with high cholesterol level, significantly increased the risk of AD in late life.5 Hypertension or high systolic pressure in midlife was also found to be associated with a higher risk of prevalent AD in late life in a rural Chinese population.18 Finally, the Hiroshima cohort study in Japan showed that increased systolic pressure in middle age was associated with later life vascular dementia, but not with AD.19

In summary, the extant studies have consistently reported an association between high midlife systolic pressure and elevated risk of dementia in late life. The cumulated evidence is quite persuasive, as the findings are derived from methodologically sound studies and supported by neuroimaging and neuropathological studies.

Table 1         Summary of major studies investigating midlife blood pressure in relation to Alzheimer’s disease and dementia in late life

AD=Alzheimer’s disease; BMI=body mass index; BP=blood pressure (mm Hg); DBP=diastolic BP; SBP=systolic BP; VaD=vascular dementia.

* Age, sex, and education were included as covariates in all studies.

Low blood pressure in the elderly predicts dementia

Several population-based cohort studies have reported that low blood pressure in the elderly may predict the development of clinical AD and dementia (Table 2).

First, the 15-year observation of the Gothenburg H-70 study found that high blood pressure at age 70 was predictive of clinical onset of AD and dementia between 79 to 85 years of age.20 In the entire cohort, blood pressure showed a general decline over time, with demented subjects showing the greatest decline. The more aggressive decline of blood pressure among demented individuals was not due to the use of antihypertensive drugs. However, the integrative analysis of the 3-year follow-up data from the H-70 study and the Rotterdam study did find an inverse association between blood pressure level and dementia risk. Such an association was primarily confined to persons who were treated with antihypertensive medications.10 An explanation for the apparent discrepancy is that blood pressure starts to decrease in the years preceding the clinical onset of dementia.

Second, the East Boston cohort study of people aged ≥65 years found no association between high blood pressure measured 13 years before diagnosis and risk of AD.21 Instead, the finding suggested an inverse association of blood pressure measured 4 years before the diagnosis and risk of AD. In this cohort, each 10-mm Hg increment in systolic or diastolic pressure was related to an approximate 20% decrease in AD risk independent of major potential confounders such as vascular disorders and APOE ε4 allele. Low diastolic pressure (<70 vs. 80–89 mm Hg) was related to an increased risk of AD (hazards ratio=1.6; 95% CI 0.6–4.1), whereas high systolic pressure (≥140 vs. 130–139 mm Hg) was related to an over 70% decreased risk for AD. There was no obvious variation in blood pressure level by AD status over 15 years period.

Third, the relation of blood pressure to dementia and AD has been extensively examined in the Kungsholmen project of Stockholm, a longitudinal study on aging and dementia among community residents aged ≥75 years.22 Cross-sectional data showed that both systolic and diastolic pressure were inversely related to prevalence of AD and dementia.23 The relatively low blood pressure among demented subjects may be a correlate of the dementing process, but we could not rule out the possibility that low blood pressure may predispose a subpopulation to developing dementia. The 6-year follow-up data from the same project indicated that both very high systolic pressure (>180 mm Hg) and low diastolic pressure (<70 mm Hg) were associated with an increased risk of AD and dementia.11 The association between low diastolic pressure and increased risk of dementia was particularly evident among individuals who took antihypertensive drugs, and such an association could be confirmed even when blood pressure was measured at least 6 years before dementia diagnosis. In addition, clinically significant decline in systolic pressure over 6 to 3 years before diagnosis was predictive of AD and dementia mainly among older adults who initially had systolic pressure <160 mm Hg or had been affected by vascular disorders such as stroke and diabetes mellitus.24 The dementia-related decline in blood pressure was evident only 3 years before dementia diagnosis, and continued to decline thereafter. In a collateral study from the Kungsholmen project, we also found that both high and low pulse pressure were associated with an elevated risk of AD and dementia, especially among women.25

Finally, the Bronx Aging Study on community-dwelling volunteers aged 75 to 85 years showed that, for an observation period of up to 21 years (median 7.6 years), low diastolic pressure (≤70 vs. 71–89 mm Hg) was associated with a 2-fold increased risk of dementia.12 The dementia risk was even higher for individuals with persistently low blood pressure. By contrast, mild-to-moderate high systolic pressure (149–179 vs. 111–139 mm Hg) was linked to a 45% decreased risk of dementia. The significant association between low diastolic pressure and high dementia risk remained even after subjects who received a dementia diagnosis in the first 2 years were excluded from the analysis.

Evidence from these studies supports the notion that low blood pressure in the elderly is related to AD and dementia, and that aggressive hypotensive treatment in very old people may be harmful in terms of dementia prevention.

Table 2         Summary of major population cohort studies indicating an association of low blood pressure in old age to Alzheimer’s disease and dementia

AD=Alzheimer’s disease; BMI=body mass index; BP=blood pressure (mm Hg); DBP=diastolic BP; MMSE=Mini-Mental State Examination; SBP=systolic BP.

* Age, sex, and education were included as covariates in all studies.

Possible biological mechanisms of both high and low blood pressure as risk factors of dementia

Long-standing hypertension may cause severe atherosclerosis.26 Neuropathological studies have linked chronic hypertension and atherosclerotic burden in the brain to Alzheimer pathological changes.16,27 In addition, high blood pressure is a powerful risk factor for cerebrovascular disorders such as white matter lesions and clinical or silent stroke, which in turn could cause dementia and promote clinical expressions of AD.28 Thus, it is biologically plausible that long-term high blood pressure beginning from middle age may have a causal link to the development of dementia and AD late in life.

Similarly, low blood pressure in the elderly can be linked to dementia and AD through at least 2 pathways.22,27 First, low diastolic pressure is an indicator of severe atherosclerosis, a condition that has been associated with Alzheimer pathology. Thus, atherosclerosis may mediate the link between low blood pressure and dementing disorders. Second, episodic or persistent hypotension may impair cerebral perfusion and lead to brain ischemia, which accelerates the neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy.

Conclusions

Evidence from our studies as well as others in the literature supports the following major points: (1) High blood pressure in middle age is a risk factor for cognitive decline and dementia, including AD, in late life; (2) Very high systolic pressure (e.g., >180 mm Hg) in the elderly may be a risk factor for dementia, whereas it remains unclear whether old people with systolic pressure levels between 140 and 180 mm Hg are at increased risk; (3)  Low diastolic pressure (e.g., <70 mm Hg) is related to an increased risk of AD and dementia; (4) Clinically significant decreases in systolic pressure (e.g., ≥15 mm Hg) in the elderly are related to an increased risk of dementia and AD, but more studies are imperative before a causal link between blood pressure decline and dementia risk can be established.

We conclude that treatment of high blood pressure in middle age is a powerful preventive strategy against dementia, as is proper control of blood pressure in the elderly. Although the optimal level of blood pressure in the elderly remains unclear, our findings highlight the potential harmful effects of aggressive blood pressure control in the elderly, and the relevance of monitoring diastolic pressure when high systolic pressure is under treatment.

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Acknowledgments:

Research grants were received from the Alzheimer’s Association (USA), the Swedish Research Council, and the private foundations.