By Holly Lam, Human Development, ’16

Author’s Note:  

“I wrote this literature review as an assignment for UWP104F (Writing in the Professions: Health). We were able to choose any health problem of our interest and review current research pertaining to that topic. I chose to write about dementia particularly because it affects my grandmother. To this day, my family and I do not know how she went from being a fairly healthy 40 year old woman to being a person with Alzheimer’s disease. During my research, I came across an abundance of literature pertaining to the relationship between dementia and the blood supply to the brain. The notion of hypertension being a potential indicator of later dementia captured most of my interest given that it is relatively common in the US compared to other countries. What we can learn about the link between blood supply and the brain may give us a better understanding of dementia as well as insight for prevention.”

Abstract

The global prevalence of dementia is expected to double by 2050. Because there is no curative treatment to date, numerous studies have focused on prevention and early detection of cognitive impairment. Several longitudinal studies have demonstrated the efficacy of antihypertensive drug (AHD) treatment in preventing cognitive decline in hypertensive individuals. However, subsequent studies found an association between AHD treatment and greater cognitive decline in individuals 85+ years with baseline cognitive impairment. Overtreatment of AHD, cardiovascular disease as well as high mid-life blood pressure can lead to the development of late-life hypotension, which in turn, can lead to dementia. Thus, further research on different populations is needed to confirm the efficacy, if any, of AHD treatment and blood pressure monitoring in preventing late-life dementia in middle-aged individuals with hypertension.

Introduction

Today, approximately 24 million people in the world suffer from dementia and this number is expected to double every 20 years approaching 81 million by 20401. Because there is no known cure to date, identifying modifiable risk factors are critical for prevention. Chronic hypertension has been associated with an increased risk for cognitive decline, vascular dementia, and Alzheimer’s disease due to vascular mechanisms that ultimately reduce cerebral perfusion (2). Several longitudinal studies have demonstrated the potential of antihypertensive (AHD) treatment in preventing cognitive impairment in hypertensive patients. However, the extent to which studies imply that AHD treatment would be effective in preventing cognitive impairment for all hypertensive patients remains uncertain. For older individuals with hypertension along with baseline cognitive decline, lowering blood pressure increased cognitive decline (6). On the contrary, individuals who received AHD treatment for midlife hypertension had better episodic memory and lower rates of cognitive impairment in later-life than those without midlife hypertension (9). Therefore, AHD treatment seems to be effective in preventing the onset and reducing the progression of dementia, but only for middle-aged hypertensive individuals with no baseline cognitive impairment. Here we review several longitudinal studies on the efficacy of AHD treatment in preventing cognitive decline in hypertensive patients. We then evaluate treatment outcomes in older individuals with baseline dementia compared to middle-aged individuals without baseline dementia. Furthermore, we provide evidence for the importance of blood pressure monitoring in relation to treatment success.

Efficacy of AHD Treatment in Preventing Cognitive Decline

Several longitudinal studies have demonstrated the efficacy of AHD treatment, including ACE-inhibitors, diuretics, and beta-blockers, in preventing or reducing the progression of cognitive impairment in older individuals. In the Honolulu-Asia Aging Study (HAAS), researchers found that men who were treated with beta-blockers had a significantly lower risk of developing cognitive impairment compared to those without treatment especially for men who had higher blood pressure at baseline (3). Similarly, the Gingko Evaluation of Memory Study (GEMS) found an association between the use of diuretics, angiotensin II receptor blockers (ARB), and angiotensin-converting enzyme inhibitors (ACE-Is) and a reduced risk of Alzheimer’s disease in participants with normal cognition at baseline (4). While HAAS and GEMS included participants without cognitive impairment at baseline, Kan et al. (2013) observed the effect of ACE-I use on 70-85 year old hypertensive patients with mild to moderate Alzheimer’s disease and found that individuals with treatment had slower progressions of cognitive decline compared to those without treatment. Findings from these studies highlight the potential of AHD treatment in preventing cognitive impairment in hypertensive patients as well as in reducing the progression of cognitive decline in patients with baseline dementia.

AHD Treatment in Oldest Old

Though the use of AHD treatment for cognitive impairment seems promising based on previous research, one major limitation of HAAS, GEMS, and the study by Kan et al. is the lack of information regarding participant blood pressure before, during and after treatment. The studies focused on the type and duration of AHD treatment and participants’ cognitive scores assessed with the Mini Mental State Examination (MMSE), but changes in individual blood pressure pre and post AHD treatment as well as variations in blood pressure trajectories between subjects were not examined (3, 4, 5). Because blood pressure trajectories vary across age, gender and in the presence of illnesses (6), failure in collecting this data possibly led researchers to overgeneralize or misinterpret the effects of AHD treatment for all hypertensive patients.

In fact, recent studies show that AHD treatments can actually harm a subgroup of the elderly. In this context, Mossello et al. (2015) investigated the effects of AHD therapy on hypertensive patients 85 years and older with baseline dementia or mild cognitive impairment. In contrast with Kan et al. (2013), researchers found low daytime systolic blood pressure associated with a greater progression of cognitive decline among those treated with AHDs (6). Additionally, individuals with higher systolic blood pressure had milder cognitive decline compared to those with lower systolic blood pressure and that this effect was greater for individuals with severe disabilities at baseline (6). These findings are consistent with those of the Leiden 85-Plus Study (2012) which found that higher systolic blood pressure and pulse pressure in the oldest old (85+ years) positively correlated with greater resilience to physical and cognitive decline, especially in individuals with pre-existing physical disabilities (8). Researchers postulate that, contrary to traditional medical belief, high blood pressure in later life serves as a compensatory mechanism to maintain organ perfusion (8) whereas low blood pressure leads to cerebral hypoperfusion that can damage neural tissue and increase the risk of dementia (7). The primary causes of low blood pressure are attributed to heart failure and/or drug treatment (7), but the spontaneous lowering of blood pressure is a pattern typically observed in older `individuals before the onset of dementia (6). Thus, for older patients with baseline cognitive impairment or physical disabilities, excessive blood pressuring lowering via AHD treatment may not only be ineffective in preventing dementia but also harmful to their cognitive health (6).

These studies (6, 7, 8) provide evidence of the limitations of AHD treatment for preventing dementia and emphasize the importance of measuring blood pressure and screening for pre-existing cognitive impairment before issuing AHD treatment. Additionally, the close monitoring of blood pressure during treatment is also equally as important. A daytime systolic blood pressure between 130 to 145 mmHg has been classified as the most appropriate therapeutic target of AHD treatment (6) where excessive blood pressure lowering (below 130 mmHg) may lead to negative outcomes (7).

AHD Treatment in Middle-Aged

Though AHD treatment has been shown to be ineffective and potentially harmful for older patients with cognitive impairment, several studies suggest its effectiveness for middle-aged hypertensive individuals. Gottesman et al. (2014) recruited hypertensive 50 year-old females and observed the effect of AHD treatment on their blood pressure trajectories biannually for 20 years. After two decades, researchers found that women with elevated blood pressure in midlife who received AHD treatment had better episodic memory than those who did not (9). Similarly, study by Joas et al. (2012), which assessed AHD treatment in Swedish women at a 37-year follow up, found that among hypertensive women without AHD treatment at midlife, higher baseline systolic blood pressure was linked to late-life dementia, especially AD (10).

Additionally, women with higher baseline systolic blood pressure who were treated with AHDs had the least cognitive decline, supporting claims of higher blood pressure in old age as a neuroprotective factor, which may have buffered the effects of excessive blood pressure lowering from over treatment (8). Furthermore, and consistent with the study by Mossello et al. which emphasizes the importance of baseline blood pressure in determining the efficacy of treatment, Joas et al. found that among those who were treated with AHD, women who developed dementia had lower baseline systolic blood pressure compared to those with higher baseline systolic pressure. Because blood pressure decreases spontaneously before the onset of dementia and is lower in individuals who manifest dementia compared with those who do not (6), AHD treatment may only be effective for those with extremely high blood pressure (9). Individuals at risk for hypertension may not benefit from AHD treatment as much those with extreme hypertension and may be better off reducing their risk of dementia with lifestyle modifications (10).

These findings emphasize the importance of detecting increased blood pressure in midlife and controlling blood pressure in those treated in efforts to maximize treatment benefits and prevent dementia in later life. Antihypertensive treatments have been shown to be successful in mediating the effects of midlife hypertension in individuals with higher systolic blood pressure, but less so in individuals with lower baseline systolic blood pressure, who may benefit more with lifestyle modifications.

Future Directions

Implications for Future Research

Because most studies of AHD treatment are observational, further randomized clinical trials are needed to determine causality (3), especially in populations at high risk for cognitive decline. In addition, increasing the duration of follow-up in longitudinal studies and frequency of blood pressure monitoring may provide us with a more holistic understanding of the relationship between blood pressure trajectories and cognition as they change with age (2). Also, variations in blood pressure trajectories across age, gender and the presence of illness emphasize the importance of homogenizing participant pools to differentiate the effects of AHD treatment on the basis of these factors (5). Furthermore, future studies investigating the biochemical mechanisms behind low blood pressure and cognitive impairment may guide pharmaceutical scientists and developers to make appropriate modifications to AHDs in hopes of increasing their efficacy (1).

Implications for Clinical Practice

Due to the negative relationship between low blood pressure and cognition, physicians should carefully consider blood pressure fluctuations and screen for signs of cognitive impairment before issuing AHD treatment to older patients (3). In addition, close blood pressure monitoring may be necessary to avoid high blood pressure overtreatment, if at all, in this population6. Lastly, given that individuals at risk for hypertension are currently not candidates for pharmacological interventions, doctors should encourage these patients to adopt lifestyle changes in an effort to reduce their risk of developing hypertension and of cognitive impairment (10).
Conclusions

AHD treatment seems to be effective in preventing the onset and reducing the progression of dementia, but only for middle-aged hypertensive individuals with no baseline cognitive impairment. Several longitudinal studies such as HAAS and GEMS demonstrate the potential of AHDs in reducing dementia in the elderly but their lack of blood pressure records make their findings hard to generalize across different populations (3,4) because blood pressure trajectories vary across age, gender, and in the presence of disease (8). Additionally, the importance of monitoring blood pressure was evident in a study that isolated the oldest old (85+) from other hypertensive individuals in the assessment of AHD efficacy, in which low blood pressure, baseline dementia and physical disability were associated with greater cognitive decline in conjunction with AHD treatment (6). Furthermore, an increase in blood pressure in middle age was classified as the biggest predictor of late-life dementia (10), whereas higher blood pressure exhibited a neuroprotective effect in older individuals (7,8). Though further research on specific populations is needed, targeting midlife hypertension while closely monitoring blood pressure seems promising in the prevention of dementia.

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References

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