In a large, well characterized cohort of treated, hypertensive older adults followed for a median of six years, duration of exposure to ACE inhibitors as a class versus other antihypertensive classes was not associated with a reduction in risk of dementia. However, when examined by central activity, exposure to ACE inhibitors that do not cross the blood brain barrier was associated with a 73% greater risk of incident dementia and a 56% greater risk of incident IADL disability over three years of exposure compared to other antihypertensive agents. In contrast, exposure to ACE inhibitors that do cross the blood brain barrier was associated with a 65% reduction in cognitive decline per year of exposure as measured by the 3MSE. And, qualitatively, the direction of results for all outcomes was in favor of ACE inhibitors that cross the blood brain barrier.
The finding that the association of ACE inhibitors with cognition depends on whether the drug crosses the blood brain barrier has also been reported by Ohrui et al34
who found no difference in the incidence of Alzheimer’s disease (n= 90 cases) in Japanese patients on various types of antihypertensive drugs, but did find a significantly lower risk of AD in a subgroup analysis of ACE inhibitors that cross the blood brain barrier (captopril and perindopril) vs. those that do not (enalapril, imidapril). There were no data on cognitive scores or functional status reported. Improvement in cognitive function, independent of blood pressure control, has also been shown with the angiotensin II receptor blocker (ARB), losartan, which crosses the blood brain barrier.35
However, in the SCOPE trial, participants receiving candesartan-based antihypertensive therapy were no less likely to develop dementia than participants receiving other classes of antihypertensives.12
In secondary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), there was not a significant reduction in the incidence of all cause dementia among patients assigned to perindopril (centrally active ACE inhibitor), but there was a reduced risk of cognitive decline (defined by decline in MMSE score).11
The CHS population in this study differs from that of PROGRESS in that all participants in PROGRESS had a cerebrovascular accident prior to entry into the study.
There is biologic plausibility for why centrally active ACE inhibitors may benefit cognition. For example, in addition to the anti-inflammatory actions of ACE inhibitors as a mechanism for reduced cognitive decline discussed in the introduction, several other mechanisms are also plausible. First, there are increased concentrations of ACE, angiotensin II, and AT1 receptors in the cerebral cortex of AD patients36,37
and angiotensin II has been shown to inhibit acetylcholine release in rats and humans.38,39
Thus, blocking ACE activity with a centrally active ACE inhibitor could decrease angiotensin II levels, potentially reducing the inhibitory action on acetylcholine release and thereby increase acetylcholine concentration. This mechanism may relate more to acute effects of central ACE inhibition on cognitive testing (such as 3MSE) than to long term dementia risk. There is also microvascular pathology and decreased cerebral blood flow in AD.40
Angiotensin II is a vasoconstrictor and an increase in perivascular staining for ACE and angiotensin II has been shown in AD patients.36
Thus, centrally active ACE inhibitors may improve cerebral blood flow. On the other hand, a recent study showed that ACE may be important in converting amyloid--β 1–42 into Aβ1–40 and that ACE inhibitors block this process and increase Aβ1–42 deposition in the brain of mice.41
These results suggest that ACE inhibitors that cross the blood brain barrier might increase AD risk. The net effects of these potentially opposing mechanisms should be determined in a randomized trial.
In this study, exposure to ACE inhibitors that do not cross the blood brain barrier was associated with greater risk of incident dementia and IADL disability (which are primarily cognitive tasks) when compared to other classes of antihypertensive drugs. While there is biologic plausibility for the reduction in cognitive decline seen among patients taking centrally active ACE inhibitors, why would non-centrally active ACE inhibitors be associated with a greater risk of dementia and IADL disability? While it is possible that non-centrally active ACE inhibitors are harmful, it is more likely that they are simply less helpful in prevention of dementia and IADL disability than other antihypertensive drug classes combined. ACE inhibitors may be less effective in reducing the risk of selected blood pressure related complications than other blood pressure lowering drugs, and, perhaps most pertinently to cognition, the risk of stroke remains higher than when other classes of antihypertensive agents are used.42,43
These previous studies support the possibility that the effects of different agents on cognition might differ. Similarly, our results support the hypothesis that the centrally active ACE inhibitors are associated with lower risk of cognitive decline via mechanisms other than blood pressure control. A difference in the brain mechanisms of centrally and non-centrally active ACE inhibitors may account for some of the variable trial results with respect to ACE inhibitors and cognition. The results of the sensitivity analyses using time dependent, current exposure to ACE inhibitor subclasses were consistent with the directions of associations in our primary analyses, but were not statistically significant, and may be interpreted as providing insight more relevant to the association of acute exposures than to those of chronic or cumulative exposures. When interpreted in the context of our primary results, these additional analyses provide support for the contention that cumulative (or chronic) exposure to ACE inhibitor subclasses may be more strongly associated with risk of dementia and cognitive decline than is acute exposure.
While this study is based on a large, well characterized cohort with extensive cognitive follow-up and sub-clinical disease markers, there are several methodological limitations to highlight. As with all pharmacoepidemiology studies, it is impossible to entirely rule out confounding by indication. However, we significantly limited the effect of this type of confounding by methods of restriction and adjustment.44
We restricted our analyses to treated hypertensive patients, thus everyone had an indication for an ACE inhibitor. Furthermore, we excluded people with the other main indication for ACE inhibitors, congestive heart failure, and censored people if they developed CHF during the study. While hypertensive patients with diabetes are more likely to receive ACE inhibitors, we did control for diabetes in the analyses. Since diabetes is associated with cognitive decline, an increased proportion of diabetics among ACE inhibitor users would not explain the reduced risk of cognitive decline seen with ACE inhibitors that cross the blood brain barrier. In addition, it is unlikely that physicians consider whether ACE inhibitors cross the blood brain barrier when selecting which ACE inhibitor to prescribe and so it is unlikely that confounding by indication could explain the results. In addition to confounding by indication, there could also be residual confounding from other factors. While CHS has a rich set of clinical measures and biomarkers, many of which we controlled for, there is always the possibility of residual confounding.
Treatment related imbalances in loss to follow-up among patients becoming cognitively impaired has also been cited as a potential source of bias in clinical trials measuring cognition as an outcome.45
There were not significant differences in loss to follow-up among categories of ACE inhibitor use in this study. The classification of centrally and non-centrally active ACE inhibitors was made predominantly based on basic science animal data because human data was generally lacking and due to variable methods of measurement, we were unable to provide units of measure for degrees of centrally activity. And while a compound’s ability to cross the blood brain barrier largely depends on its size, charge, and lipophilicity, the integrity of the blood brain barrier and the dose of the medication could influence its central activity. However, if there was misclassification (i.e., drugs classified as not centrally active did actually cross the blood brain barrier), we would expect this to bias the results towards the null. Another potential source of misclassification bias of the exposure is that we do not know what the exposure to ACE inhibitors was prior to baseline. However, this likely affects few of our participants since ACE inhibitor use didn't gain momentum until the late 1980s (only 10% of antihypertensive users were taking ACE inhibitors in 1988).46
We could not account for timing of ACE inhibitor exposure. For example, our models treated three years of exposure to ACE inhibitors the same, regardless of whether it occurred early or late in the study. We do note, however, that approximately 40% of ACE inhibitor users were continuous users throughout the study period and that the median duration of use did not differ between users of centrally and non-centrally active ACE inhibitors. There were few cases of dementia that were not attributable to Alzheimer’s disease, thus we could not separate our analyses by dementia type. Further studies are needed to determine if the effects of ACE inhibitors on cognition and dementia risk is the same for the most common dementia subtypes.
The potential public health impact of these findings is significant given the burden of cognitive impairment-related disability, the high prevalence of HTN, and the potential impact that the choice of agents to manage HTN may have beyond blood pressure control and cardiovascular disease risk. Based on the results of this study, compared to other antihypertensive drug classes, the use of non-centrally active ACE inhibitors (independent of use of other antihypertensive drugs) is associated with greater risk of IADL disability by approximately 56% and a 73% greater risk of dementia after three years of exposure. Conversely, use of centrally active ACE inhibitors was associated with 65% slower cognitive decline on a global measure of cognition. While these results come from an observational study and should be confirmed with a randomized, controlled trial of the use of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia, it would appear that there may be within the class differences in the association of ACE inhibitors and cognition.