Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults With Hypertension

Abstract

Background Hypertension (HTN) is a risk factor for dementia and animal studies suggest that centrally active (cross the blood brain barrier) angiotensin converting enzyme (ACE) inhibitors may protect against dementia beyond HTN control. Methods Participants in the Cardiovascular Health Study cognition substudy (mean age 75 yrs) with treated HTN and no diagnosis of heart failure (n= 1054) were followed for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared to other antihypertensive agents, was associated with lower risk of incident dementia, cognitive decline (by the modified mini mental state exam, 3MSE), or incident disability in instrumental activities of daily living (IADL). Results Among 414 participants exposed to ACE inhibitors and 640 not, there were 158 cases of incident dementia. Compared to other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (HR 1.01, 95% CI 0.88–1.15), difference in 3MSE scores (−0.32 points/yr, p=0.15), or odds of IADL disability (OR (95% CI) 1.06 (0.99–1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (p= 0.01) and non-centrally active ACE inhibitors were associated with greater risk of incident dementia (adjusted HR 1.20 (1.00–1.43) per year of exposure) and greater odds of IADL disability (adjusted OR 1.16 (1.03–1.30) per year of exposure) compared to other anti-HTN drugs. Conclusions While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within class differences in regards to these outcomes. These results should be confirmed with an RCT of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.

Pharmarcogenetic Mechanism of ACE I/D Polymorphism Adversely Responding to ACE Inhibitors in Regulating the ACE Promoter Activity in Neurons

“…The similar pharmacologic effects of the ACE inhibitors on cognitive function were also found in recent clinical trials [9][10][11] and in animal models [12,13]. It is noteworthy that some studies denoted that the direct effects of the ACE inhibitors to lower the risk of developing dementia could be independent from the controlling of cardiovascular disease and blood pressure control [2,4,14]. Nevertheless, these inconsistent results have also been reported in other studies [4,[15][16][17][18].…”

“…They indicated that the introduction of an ACE inhibitor in order to block the ACE activity might not only reduce the benefits to Aβ degradation [42,43], but also decrease the potential harm of Angiotensin II action on either acetylcholine release or hypertension. In addition, the inhibition of an ACE activity in the brain has also been reported to associate with cognitive improvement via increasing substance P, diminishing inflammatory cytokines, suppressing reactive oxygen species generation, or improving cerebral blood flow [2,4,6,12]. In addition to the well-known functions of an ACE enzyme as mentioned above, the physiological implications of ACE continue to expand, in which ACE has been found to exert many other functions than is usual and is localized in different brain tissues.…”

“…It is noteworthy that some studies denoted that the direct effects of the ACE inhibitors to lower the risk of developing dementia could be independent from the controlling of cardiovascular disease and blood pressure control [2,4,14]. Nevertheless, these inconsistent results have also been reported in other studies [4,[15][16][17][18]. Whatever the positive or negative results, no clear mechanisms have been delineated.…”

Association Between Blood Pressure Lowering and Quality of Life by Treatment of Azilsartan

“…46,47) In previous studies regarding HT and dementia, ARBs and ACE inhibitors with a higher degree of BBB penetration could prevent the development of dementia; however, this preventative effect was not confirmed in randomized controlled trails. 48,49) Thus, the precise mechanisms by which ARBs and ACE inhibitors affect psychiatric and cognitive functions are yet unclear.…”

Assessment of risk in longitudinal observational studies with time-varying drug exposures for treatment of a chronic disease

“…Advancing age, comorbid conditions, and cumulative drug exposures contribute to long-term health outcomes among persons with chronic diseases [1][2][3]. Historically, observational studies using administrative pharmacy claims characterize drug exposure as either dichotomized variables or as cumulative CrossMark ← Click for updates doi: 10.7243/2054-9911-3-2 exposure for drug class, combination regimens, or specific drugs [4].…”