Observational Study of Brain Atrophy and Cognitive Decline Comparing a Sample of Community-Dwelling People Taking Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Over Time

INTRODUCTION

High blood pressure is an established risk factor for the development of dementia [1]. Results from human observational studies and secondary observations in clinical trials of populations with high cardiovascular morbidity generally favor a beneficial effect of antihypertensive medications (AHM) on reducing dementia risk [2] but are not conclusive [3]. These studies report a wide variation in the magnitude of treatment effect [2, 4]. One possible explanation for this may be that various classes of AHM have differential effects on brain health independent of their blood pressure lowering effect [2, 5].

The Renin Angiotensin System (RAS) has been implicated in the development of cognitive decline [4, 7]. Postmortem studies reported an association between angiotensin converting enzyme and Alzheimer’s disease almost 40 years ago [8, 9] and were further supported by angiotensin I-converting enzyme gene association studies at the end of the last century [10]. A recent literature review reported that six out of seven identified human cohort studies described a trend for Angiotensin Converting Enzyme Inhibitor (ACEi) agents to be associated with a reduced risk of cognitive decline or dementia [2]. In the same review [2], four out of eight studies reported that Angiotensin II Receptor Blockers (ARB) were associated with a reduced risk of cognitive decline or dementia. The results from animal studies suggest that the location of interruption of the RAS may be important in modifying dementia risk but this is yet to demonstrated in human studies [6]. Amyloid-β protein, important in dementia development, is degraded by ACE [11, 12]. It may be that ARBs, which block RAS but do not inhibit the potentially beneficial action of ACE, may be particularly advantageous [13]. Although results from basic science research seemed to support this theory, those from human studies remain inconclusive [2, 4] with recent observational studies reporting a larger beneficial effect of ARB use on the risk of dementia than ACEi [14–16]. A potential limitation of human studies to date is that many were designed to examine neurocognitive measures as only secondary outcomes within the context of large-scale trials of cardiovascular disease, and therefore lacked sensitive and detailed neuropsychological testing or volumetric imaging measures of brain structure. To address these limitations, a number of clinical trials, mainly recruiting people with established Alzheimer’s disease or mild cognitive impairment have commenced to better understand the role of AHM [6].

The aim of this study was to compare differences in brain atrophy and cognitive decline between people taking ACEi and ARB using data from a community-dwelling sample of older people enriched with type 2 diabetes (T2D), as RAS agents are more commonly used in T2D.

MATERIALS AND METHODS

RESULTS

Of a baseline total sample of 711 participants, a further 4 participants with dementia and 2 participants with Parkinson’s disease were excluded leaving a total of 705 participants at baseline. Cognitive data were available for 700 people (>98% of European decent) at baseline, 504 at phase 2, and 431 at phase 3. Brain imaging data were available for 616 people at baseline, 388 at phase 2, and 298 at phase 3. Table 1 describes the characteristics of those who had at least 1 brain MRI available for analysis. Of these, 565 (80%) had at least one follow-up visit and contributed to further analyses. Within each of the drug use categories of no AHM, ACEi use, and ARB use, the characteristics of people with or without brain imaging at each time point was broadly similar (Table 2).

Comparison of ACEi and ARB use

A total of 163 people were taking an ACEi and 125 were taking an ARB on study entry. A total of 11 people were taking both ACEi and ARB and were excluded from analysis. The baseline characteristics of those taking either an ACEi or ARB were similar with regards to age, sex, blood pressure control, and vascular risk factors and are described in detail in Table 1 and across time points in Table 2. Although those taking an ARB had lower baseline volume of WMH, and lower prevalence of brain infarct or microbleeds, these differences were not statistically significant (all p > 0.19). The baseline association of ACEi and ARB use with total brain volume was similar in both groups (p for difference = 0.99). However, adjusting for age, sex, T2D, education, blood pressure, waist-hip ratio, and ApoE4 status there was an interaction between type of RAS inhibitor and brain atrophy over time, whereby those taking an ARB had a slower brain atrophy than those taking an ACEi (interaction β= 2.06, df = 152, p = 0.031). The association of time (years) with brain volume was –6.7 (df = 167, p < 0.001). Figure 1 displays the interaction between RAS agent and total brain volume change over time in the above model. The addition of baseline WMH volume, presence of brain infarcts and microbleeds to the above model resulted in minimal change (interaction β= 2.03, p = 0.033). Neither ACEi nor ARB use were associated with baseline cognitive function or cognitive decline (Table 3). When stratified by diabetes status (i.e., repeating the analysis in the subgroup of people with T2D and then the subgroup of people without T2D), the above associations were no longer statistically significant (data not shown).

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Fig.1

Associations between antihypertensive medication use and total brain volume over time. Adjusted for baseline age, sex, education, systolic blood pressure, diastolic blood pressure, history of hypertension, waist hip ratio, ApoE4 status, and total intracranial volume.

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Table 3

Associations between blood pressure agent use and cognitive function

Cognitive z- scores	ACE versus ARB				Any AHM versus no AHM
	β	Degrees of freedom	95% CI	p	β	Degrees of freedom	95% CI	p
Global cognitive z-score
Agent	0.13	245	–0.05 to 0.31	0.17	–0.19	498	–0.37 to –0.02	0.027
Agent×Time	0.01	171	–0.06 to 0.09	0.70	–0.02	329	–0.07 to 0.03	0.53
Verbal fluency
Agent	0.18	259	–0.04 to 0.39	0.10	–0.04	532	–0.25 to 0.16	0.68
Agent×Time	–0.004	150	–0.05 to 0.04	0.88	–0.05	292	–0.08 to 0.01	0.007
Verbal memory
Agent	0.10	252	–0.09 to 0.28	0.31	–0.10	522	–0.28 to 0.08	0.28
Agent×Time	–0.02	162	–0.08 to 0.33	0.49	–0.03	303	–0.07 to 0.01	0.20
Processing speed
Agent	0.05	259	–0.14 to 0.25	0.61	–0.26	527	–0.45 to –0.07	0.008
Agent×Time	–0.003	158	–0.04 to 0.04	0.89	–0.01	296	–0.03 to 0.016	0.49
Executive function
Agent	0.09	220	–0.09 to 0.27	0.32	–0.10	440	–0.27 to 0.06	0.21
Agent×Time	0.04	196	–0.06 to 0.14	0.42	–0.01	368	–0.08 to 0.05	0.73
Working memory
Agent	–0.001	259	–0.22 to 0.22	1.00	–0.20	533	–0.41 to 0.01	0.07
Agent×Time	0.01	148	–0.04 to –0.05	0.81	–0.01	285	–0.05 to 0.02	0.43
Visuospatial function
Agent	0.05	254	–0.17 to 0.26	0.66	–0.26	533	–0.45 to –0.08	0.006
Agent×Time	–0.004	157	–0.08 to 0.07	0.90	0.03	301	–0.03 to 0.08	0.34
Visual memory
Agent	–0.02	255	–0.22 to 0.17	0.82	–0.12	502	–0.26 to 0.03	0.12
Agent×Time	–0.05	157	–0.10 to 0.005	0.08	–0.02	305	–0.05 to 0.27	0.41

Adjusted for baseline age, sex, education, systolic blood pressure, diastolic blood pressure, history of hypertension, waist hip ratio, ApoE4 status. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; AHM, antihypertensive medication.

DISCUSSION

In this sample, enriched with people with T2D, we found those taking an agent targeting the RAS had slower rates of atrophy than those on neither/no AHM. We also found that the use of ARB agents was associated with slower rates of brain atrophy than those taking ACEi, independent of blood pressure control. The size of this association was small, and the clinical significance of this association remains unclear. These results suggest that ARBs may have a beneficial effect on brain atrophy by mechanisms other than their blood pressure lowering effect.

Similar to other studies [2], we report a possible beneficial effect of RAS inhibitors on brain ageing. Although there was a suggestion of beneficial effect of other AHMs, such as CCBs, we lacked the statistical power to have a high degree of confidence in these findings. Isolating the effects of other AHM is challenging in observational studies as many people require at least two agents to successfully control blood pressure, and recent guidelines recommend two first-line agents for the management of stage 2 hypertension [28]. As such, the ability to analyze people using monotherapy is limited. Similarly, we lack the statistical power to sub-analyze the specific ACEi or ARB agent used. Making these distinctions is important as there are variations in the ACE catalytic domains of specific ACEi that affect amyloid-β degradation [6] and potentially dementia risk. There are also within-class differences in blood-brain barrier permeability in ACEi [29] and, to some degree, ARB [30] that require more understanding and may have important implications for dementia risk [6]. Supporting this, one observational study of 414 people (mean age 75 years) taking ACEi noted centrally acting ACEi use was associated with less cognitive decline and a lower rate of progression to dementia than peripherally acting ACEi [31]. Another study, using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, reported the use of centrally acting ACEi and ARBs was associated with better memory performance than all other groups [32].

Our finding that the use of any AHM and RAS inhibitors was associated with lower brain volume on study entry is likely related to the indication for AHM use. Such indications could include, but not be limited to, hypertension, T2D, and chronic kidney disease. Our sample was enriched with people with T2D who, as described in previous work in this sample were more likely to be prescribed an ACEi or ARB and have better blood pressure control [18]. A sample enriched with people with T2D has the advantage of likely including more people taking RAS inhibitors but may come with heightened risk factor identification and management in a person with known high risk of vascular complications, limiting generalizability. If the indication for AHM explains the differences in brain volume seen on study entry then it is likely that this indication bias is removed by the mixed longitudinal modelling, allowing the isolation of the beneficial effect of both ACEi and ARB. This would explain our finding of between-group differences at baseline but the absence of a subsequent association with greater rates of cognitive or structural brain decline.

To our knowledge, only one other study has examined the associations of RAS inhibition and longitudinal changes in brain volume [32]. This study used the ADNI dataset to compare 183 people with hypertension taking an ARB to people with hypertension taking any other AHM (n = 621) and those with normal blood pressure (n = 782). The authors found no between-group differences in brain volume change over three years but reported an association between centrally acting ACEi and ARB use and reduced WMH development in post hoc exploratory analysis. The between-agent differences we report may be the result of our sample having a larger burden of cerebrovascular disease and T2D than ADNI [32, 33] and a longer period of follow up with measurements at three time points providing additional statistical sensitivity to detect subtle changes. The benefits of including brain volume measures as an early marker of brain health are becoming increasingly recognized and are now beginning to be included as study outcome measures in AHM clinical trials [6, 34].

Although we report brain structural differences between groups, we did not find consistent cognitive differences. This lack of correlation between cognitive and brain structural measures may reflect the small effect size (∼30% of the size of the effect of time) that may not be large enough to result in detectable cognitive changes. Future studies, over longer time periods are required to understand the clinical significance of the associations we report.

Both vascular and neurodegenerative pathways have been implicated in explaining how ARB may have a beneficial effect on brain health. The specific targeting of ARB to Angiotensin II receptors (AT1 and possibly AT2) may result in greater vasodilation and improved cerebral blood flow than ACEi [35, 36]. Head-to-head studies comparing ACEi and ARB are lacking but results from animal models of stroke suggest that ARB may also have an anti-inflammatory action and neuroprotective role in humans [37, 38]. The results for a small number of studies suggest that ARB use is associated with lower AD pathology on autopsy [39] possibly via a beneficial effect on brain tau concentrations [40]. Supporting these observations, the ACE-sparing effect of ARBs may help preserve the proteolytic action of ACE on amyloid-β [11]. Future studies are required to confirm our findings taking advantage of advances in dementia biomarker development such as in vivo neuroimaging of amyloid and tau as well as serum and cerebrospinal fluid analysis to better understand the mechanisms through which ARB may be beneficial.

This study has a number of limitations. We followed people for a relatively short period of time and it may be that larger signals would be identified in cognition and brain structure over a longer period of time. We examined AHM use on study entry only and not for changes in medication use over time. Data regarding duration of exposure to AHM was unavailable in this study. As such we are unable to improve confidence in our results by exploring whether the duration of AHM use was associated with the size of the cognitive and structural associations we describe. Furthermore, the absence of this data prevents modelling of changes in AHM classes that commonly occur during an individual’s clinical management of hypertension. Clinical drug trials described in the review by Kehoe et al. [6] are actively recruiting participants that will collect this data. Similar to other longitudinal studies, a proportion were lost to follow-up. Our analytical techniques allowed us to reduce the impact of different follow up periods for participants but does not completely eliminate this potential source of bias. Due to an unavoidable change in MRI scanner during our study period, we were unable to measure whether changes in WMH volume play a mediating or modifying role. Future studies, in cohorts with a larger burden of cerebrovascular disease may be able to further examine whether ARB have beneficial effects and explore if this is via more traditional cerebrovascular pathways. A further limitation associated with MRI scanner change was the loss of an ability to examine the regional distribution of brain volume loss. It would be of interest if the regions of volume loss were consistent with the greater ACE activity seen in the medial hippocampal, parahippocampal, and temporal region in postmortem studies of people with Alzheimer’s disease [8, 9]. Strengths of our study include the careful collection and classification of AHM use based on direct interview and use of a broad battery of neurocognitive tests and detailed serial brain MRIs allowing great sensitivity to detect subtle changes.

In summary, those taking agents targeting RAS appear to have reduced volume loss compared to those not taking an AHM. ARB use may be associated with slower rates of brain atrophy than ACEi. There was no association between individual RAS inhibitor use and cognitive decline. The effect sizes we report are small, of uncertain clinical significance and may only manifest over long time periods.