Prevention of dementia by ACE inhibitors and angiotensin receptor blockers - potential but not proven

Dementia currently exacts a substantial economic burden on societies, health and social care systems and carers in addition to the devastating personal and emotional cost to patients and families (1,2). This burden is predicted to increase substantially in the coming decades and is the major public health issue of this century (1). Currently available therapies are symptomatic only (3), with little or no prospect of disease-modifying treatments entering routine clinical use in the short to medium term. Strategies to prevent or delay the onset of dementia or retard its’ progression are, therefore, urgently required and will be of extreme importance to individuals and societies. Currently available medications that could achieve these goals would have many advantages – potential for immediate use; established safety profile; familiarity to clinicians; relatively low cost giving favourable cost-effectiveness breakdown. Recent reports have highlighted that a number of common cardiovascular risk factors are associated with both Alzheimer’s disease (AD) and vascular dementia (VaD), the two most prevalent forms of dementia (4,5). Additionally, postmortem studies have demonstrated that the characteristic neuropathological changes of both AD (senile plaques and neurofibrillary tangles) and VaD (subcortical/white matter ischaemia) are highly prevalent in the brains of normal individuals as well as those with AD, VaD and other forms of dementia (6–8). From this and earlier works, the hypothesis has arisen that treatment of these common cardiovascular risk factors, in particular hypertension and hypercholesterolaemia, will result in a reduction in the incidence and/or progression of dementia. Our group has performed systematic reviews and meta-analyses of blood pressure lowering therapies (9) and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) treatment (10) for the prevention of dementia and/or cognitive impairment. At present, there is no evidence from randomised clinical trials (RCTs) that treatment of either hypertension or hypercholesterolaemia reduces the incidence of dementia (9,10). However, we found several limitations in the literature. In the blood pressure lowering systematic review (9), significant bias may have been introduced by the number of participants lost to follow up, with differential loss between active treatment and placebo groups, and the large proportions of placebo allocated participants receiving active treatment in the included RCTs. The primary outcomes in the included studies were cardiovascular and the studies stopped when significant benefits in these primary outcomes were found. Dementia or cognitive impairment was secondary outcomes and the assessments used, the duration of the trials and the number of participants randomised may have been insufficient to have detected true significance for these outcomes. In the statin prevention systematic review (10), only two studies met the inclusion criteria and, again, cognition was a secondary or tertiary outcome. There was a low rate of incident dementia in both placebo and active treatment groups. Two analyses from prospective cohort studies that add further data to the debate on treatment of hypertension for benefits on cognition have been reported recently (11,12). Sink et al. (11) examined data from participants of the Cognition substudy of the Cardiovascular Health Study (13) on the effect of angiotensin converting enzyme inhibitor (ACEI) use on cognitive decline. ACEIs were classified into those that crossed the BBB (centrally active) and those that did not cross the blood-brain barrier (BBB) (non-centrally active) using data mainly from animal studies (11). The majority of the 1054 participants in the study were female (64%) and white (76%), with a mean age of 75 years. ACEIs were not associated with a reduction in the risk of dementia when compared as a class to other anti-hypertensive drug classes (adjusted HR 1.01; 95% CI 0.87–1.18). However, centrally active ACEIs were associated with a 65% reduction in cognitive decline, as measured using the Modified Mini-Mental State Examination (3MSE) (14), per year of drug exposure when compared with other anti-hypertensive medications (p = 0.01). Non-centrally active ACEIs were associated with a 73% increased risk of dementia over 3 years, compared with other anti-hypertensive agents. The brain, as with most organs, has a paracrine renin-angiotensin system (RAS). In brain, RAS has specific local effects, including on memory, independent of the systemic circulatory RAS, unlike other organs such as the heart or kidney (15). Preliminary data suggest possible effects of drugs acting on RAS on cognition beyond blood pressure (BP) control. ACE activity is increased in AD postmortem brain and correlates with amyloid plaque load and with AD severity [reviewed in (16)]. Some, but not all, animal studies show alteration in amyloid pathology and cognitive performance with RAS active medications [reviewed in (16)]. ACE degrades amyloid-β (Aβ) peptide, the precursor of plaques, in the brain and captopril caused an increase in the neurotoxic Aβ42 in one mouse model (17). Therefore, will long-term ACEI therapy have detrimental effects on cognition? Various mouse models treated with angiotensin type 2 receptor blockers (ARBs) have been associated with reduced Alzheimer’s neuropathology and improved performance on tests of learning and memory (16,18,19). However, it may not be appropriate to extrapolate animal models to humans. Other small observational studies have also reported reduced progression of mild cognitive impairment to AD (20) and reduced incidence of AD (21). One small RCT has suggested that centrally active ACEIs slow cognitive decline in AD more than non-centrally active ACEIs or calcium channel blockers (22). Li et al. reported that ARBs were associated with a reduction in the incidence and progression of dementia and AD compared with the ACEI lisinopril and with ‘cardiovascular comparators’ (12). Of note, Li classified lisinopril as non-centrally active, whereas in Sink’s study lisinopril was classified as centrally active. Li et al. based their classification on the hydrophilicity of lisinopril (23). However, this report references an animal study showing prolonged cerebrospinal fluid ACE inhibitory activity by lisinopril (24), suggesting a possible peptide carrier at the BBB. Sink classified central activity or non-activity on the basis of this earlier study (11). The summary of product characteristics for lisinopril states ‘studies in rats indicate lisinopril crosses the BBB poorly’. The cohort was predominantly male (98%) with a mean age of 74 years. Ethnicity was unknown for most subjects. There are several limitations in this study. Firstly, the three groups are not comparable as there are significant differences in morbidity profiles and mean BP and small differences in ethnicity. All of these impacts on the risk or recognition of dementia. The ‘cardiovascular comparator’ group had lower rates of hypertension and diabetes and higher rates of cardiovascular disease and stroke than the ARB and lisinopril groups. Mean BP was 3/2 mmHg lower in the ‘cardiovascular comparator’ group. Low BP in late-life is associated with dementia and AD (4). The level of absolute BP reduction rather than the agent(s) used is considered paramount in reduction of cardiovascular mortality and morbidity. Secondly, the prevalence of the use of other cardiovascular medications, such as anti-platelet or other anti-hypertensive agents, across the three groups was not reported. Statins were specifically excluded from the ‘cardiovascular comparator’ group, with no rationale provided. The corresponding author had previously reported a similar large association between use of statins and decreased prevalence of AD (25). However, subsequent RCTs have not shown a beneficial effect of statins on the prevention of dementia (10). The progression outcome (nursing home admission) was primarily driven by reduction in stroke in the ARB group. Modification of risk factors other than BP by use of other agents may have contributed to this. However, in an RCT of an ACEI and thiazide diuretic regimen, reduction in stroke recurrence was associated with reduced dementia incidence (26). Finally, the clinical plausibility of such large reductions in the incidence and progression of dementia and AD in a late-life population with relatively short follow up was not considered. As noted earlier, AD and vascular neuropathological changes are highly prevalent in this age-group (7) and have been present for many years before incident dementia becomes symptomatic and is diagnosed. There are few interventional studies of vascular risk factor modification, either singly or in combination, in AD. Observational studies suggested that cognition declined less on statin treatment (27) and function declined less on statin and β-blocker treatment (28). However, RCTs have not shown benefit of statins on progression of cognition in AD. An observational study reported that treatment of vascular risk factors was associated with slower cognitive decline in patients with AD and no CVD than no treatment (29). One recent small RCT failed to show a benefit of intensive vascular risk factor modification over usual care in slowing dementia progression in subjects with AD and vascular lesions on neuroimaging (30). It may be that this stage of the disease process with established neuropathology is too late to initiate these treatments. However, although BP was reduced in both intensive and usual care groups, the difference was not significant (30). It is possible that lowering BP and cholesterol in AD may be harmful as blood pressure falls in older people with AD (4) and cholesterol may be lower in AD (5). A trial is ongoing to establish if a similar regimen is of benefit in reducing dementia incidence in elderly people with vascular risk factors (ISRCTN29711771) (31). Given the current lack of reliable RCT evidence and these interesting but limited retrospective, observational studies, several questions remain to be answered: does treatment of hypertension in mid-life result in reduced risk of dementia or cognitive decline in late-life? Does treatment of hypertension in late-life result in reduced incidence and/or progression of dementia? If so, is one anti-hypertensive class, or sub-group that crosses the BBB, associated with these better cognitive outcomes? Are certain anti-hypertensives, such as ACEIs discussed previously (16), associated with worse cognitive outcomes? Does addressing the overall cardiovascular risk with lifestyle interventions, anti-platelet and lipid lowering therapies, in addition to antihypertensives, provide additional benefit in reducing dementia incidence or progression? As has been suggested previously by other commentators (16,32), the recent reports highlight that well-designed RCTs, adequately powered and of sufficient duration to answer these questions, with appropriate primary outcomes which assess dementia (and subtype) incidence and progression are urgently required. The use of effective, inexpensive, currently available therapies to reduce the considerable burden from dementia would be of major benefit to older individuals and their carers, health and social systems and economies not only in the developed world but also the developing world (33). None. ST: drafting article, critical revision of article, approval of article. BMcG: critical revision of article, approval of article. APP: critical revision of article, approval of article. None.

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