Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer’s Disease? A Systematic Review and Meta-Analysis

Abstract

Background:

Epidemiological evidence has associated Alzheimer’s disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain.

Objective:

To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence.

Methods:

Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included.

Results:

Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a non-significant reduced risk of dementia in RCTs (n = 5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69–1.02) and prospective studies (n = 3; RR, 0.77; 95% CI, 0.58–1.01) and with reduced AD risk in prospective studies (n = 5; RR = 0.78; 95% CI, 0.66–0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n = 17; RR, 0.77; 95% CI, 0.63–0.95) and AD (n = 13; RR, 0.86; 95% CI, 0.80–0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk.

Conclusion:

Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed.

Keywords

Alzheimer’s disease dementia meta-analysis prevention prospective studies randomized controlled trials risk factors systematic review

INTRODUCTION

Dementia is a growing public health concern because of the globally aging population and the lack of effective treatments. By 2050, the number of people with dementia worldwide may nearly triple, from 46.8 million to a projected 131.5 million [1]. The major form of dementia is Alzheimer’s disease (AD), accounting for about 60% or more of all cases [2].

Chief pathological hallmarks of the AD brain are neurofibrillary tangles and abnormal accumulation of amyloid-β (Aβ) peptides in amyloid plaques [3]. Recent clinical trials in AD, many based on the amyloid hypothesis, have been disappointing [4] and this has increased interest in other potential therapeutic avenues. Considerable evidence indicates that vascular risk factors (VRFs) [2 , 5] are linked to AD. Observational studies have found that modifiable VRFs, including hypertension, hypercholesterolemia, and obesity in midlife, type 2 diabetes mellitus, physical inactivity, and smoking are associated with an increased risk of AD [2 , 5–7]. It was recently estimated that a third of all AD cases worldwide might be attributable to potentially modifiable risk factors [6]. This suggests that treatment of VRFs might reduce the incidence of AD, but whether treating VRF does indeed reduce the risk of AD is unclear.

Previous reviews have summarized the evidence from randomized controlled trials (RCTs) or observational studies assessing the effect of hypertension [8 –10] or hyperlipidemia [11 –14] treatment on dementia risk. However, to the best of our knowledge, there are no systematic reviews summarizing all available evidence from both RCTs and prospective studies on all major VRFs in relation to incidence of AD and all-cause dementia. We therefore performed a contemporary systematic review and meta-analyses to summarize available data from RCTs and prospective observational studies investigating the influence of treatment of established VRFs (hypertension, hyperlipidemia, and type 2 diabetes mellitus) or smoking cessation, exercise, or weight loss intervention on the incidence of AD and all-cause dementia.

METHODS

Search strategy

This systematic review and meta-analysis followed the PRISMA guidelines [15]. PubMed was searched, without restrictions, from inception until 1 January 2018. The predefined key words used for the database search are described in Supplementary Table 1. The reference lists of relevant publications were scrutinized to identify further studies.

Table 1

Number of randomized controlled trials and prospective studies included in the review

Vascular risk factor and drug treatment or intervention	No. of randomized controlled trials	No. of prospective studies
Hypertension
Antihypertensive drug use versus nonuse/placebo	5	13
Comparison of antihypertensive drug classes	0	7
Hyperlipidemia
Statin	1	25 *
Nonstatin lipid-lowering drug	0	8 *
Any lipid-lowering drug (statin or nonstatin)	0	3 *
Type 2 diabetes mellitus
Oral antidiabetic drug	1	6 †
Insulin therapy	0	5 †
Vascular risk factor intervention
Smoking cessation	0	0
Exercise	0	0
Weight loss	0	0
Multifactorial intervention	1	0

^* Some studies provided results on both statins and nonstatins or a combination of these.

^† Most studies provided results on both oral antidiabetic drugs and insulin therapy.

Selection criteria

Articles were included if they met the following inclusion criteria: 1) randomized controlled trial (RCT) or prospective study (including register-based cohorts); 2) assessed treatment of an established VRF with available drug treatment (i.e., hypertension, hyperlipidemia, or type 2 diabetes mellitus) or smoking cessation, exercise, or weight loss intervention; 3) the outcome was all-cause dementia or AD; and 4) a relative risk (RR) estimate with corresponding 95% confidence interval (CI) or sufficient data to calculate these were provided. Exclusion criteria were cross-sectional study; case-control study; nonrandomized trial; and animal study. Where duplicate publications were available, the study with the longest follow-up or largest number of participants was included.

Data extraction and quality assessment

The following information was extracted from each study: first author’s last name, year of publication, name of the study or database used, country in which the study was performed, outcome(s) assessed and diagnostic criteria, total number of participants and cases, age of participants, mean follow-up time, type of treatment, variables adjusted for in full model, and the most fully adjusted RR with corresponding 95% CI. Assessment of study quality (ranging from 0 to 9) was performed using the Newcastle-Ottawa Scale [16]. Details of how the criteria were applied are shown in Supplementary Figure 1.

Fig.1

Relative risks of dementia for antihypertensive treatment versus placebo in individual randomized controlled trials and all trials combined. Trials are ordered by year of publication. Squares represent trial-specific relative risk (RR) (size of the square reflects the trial-specific statistical weight); the horizontal lines represent 95% confidence intervals (CIs); diamond represents combined RR with its 95% CI. HYVET-COG, Hypertension in the Very Elderly Trial-Cognition; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; SCOPE, Study on Cognition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; SYST-EUR, Systolic Hypertension in Europe Study.

Statistical analysis

Where results for a treatment-outcome association were reported by two or more studies, results were combined in a meta-analysis, using a random-effects model [17]. Between-study heterogeneity was assessed with the I² statistic [18]. The following interpretation for the I² values were used: <30% = no or low heterogeneity; 30% –75% = moderate heterogeneity; and >75% = notable heterogeneity. Meta-regression and subgroup analyses were carried out if feasible (≥2 studies per stratum) to assess potential sources of heterogeneity by study quality (quality score 0–7 [low quality] versus 8–9 [high quality]), duration of follow-up (<5 versus ≥5 years), and number of cases (<200 versus ≥200). Publication bias was evaluated with Egger’s test [19]. All statistical analyses were carried out using Stata, version 14.2 (StataCorp, College Station, TX). We considered p-values <0.05 to be statistically significant.

RESULTS

Literature search

A total of 7136 articles of which 60 met the inclusion criteria were identified (Supplementary Figure 2). The eligible studies comprised 8 RCTs and 52 articles based on prospective studies (Table 1).

Fig.2

Combined relative risks of dementia and Alzheimer’s disease for use of any antihypertensive drug and classes of antihypertensive drugs versus nonuse in prospective studies. Results for antihypertensive drug classes are for dementia or Alzheimer’s disease. *Number of studies in each subgroup. ACE-I, angiotensin-converter enzyme inhibitor; AH, anti-hypertensive; CI, confidence interval; RR, relative risk.

Randomized controlled trials

A striking feature was the paucity of data from RCTs with only 8 studies in total, including five on antihypertensive treatment, one each on hyperlipidemia and type 2 diabetes mellitus treatment, and one that assessed the effectiveness of a multifactorial VRF intervention.

Hypertension treatment

Four of the five RCTs [20 –24] found a reduction in dementia incidence in patients randomized to antihypertensive treatment [20 , 24] but results reached statistical significance in only one trial [21] (Supplementary Table 2). In a meta-analysis of these RCTs (total of 22,016 patients and 936 cases) the combined RR of dementia for active treatment versus placebo was 0.84 (95% CI, 0.69–1.02), with moderate heterogeneity between trials (Fig. 1). In a sensitivity analysis in which one trial at the time was omitted and the rest analyzed to assess the influence of single trials on the overall results, the RRs ranged from 0.79 (95% CI, 0.64–0.98) when the Study on Cognition and Prognosis in the Elderly trial [22] was excluded to 0.90 (95% CI, 0.78–1.03) when the Systolic Hypertension in Europe Study [21] was excluded. There was no evidence of significant publication bias.

Hyperlipidemia treatment

The single RCT assessing the influence of hyperlipidemia treatment on dementia incidence was the Heart Protection Study [25]. In this trial, 20 536 UK adults, 40–80 years of age, with non-fasting total cholesterol concentrations of at least 3.5 mmol/L (135 mg/dL) and a history of coronary heart disease, other occlusive arterial disease, or diabetes mellitus were randomly allocated to receive simvastatin or matching placebo. The average difference in low-density lipoprotein cholesterol concentration during a mean follow-up of 5 years was 1.2 mmol/L. Patients assigned to simvastatin had statistically significantly reduced all-cause and coronary mortality but the number of incident dementia cases during follow-up was similar in both groups (0.3%; n = 31 cases).

Type 2 diabetes mellitus treatment

One RCT evaluated the efficacy of intensive glucose control on vascular outcomes in 11 140 type 2 diabetes mellitus patients [26]. The mean glycated hemoglobin concentration was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%) after a median 5 years of follow-up. Intensive glucose control reduced the incidence of combined major macrovascular and microvascular events but not dementia (n = 109 cases) [26].

Multifactorial VRF intervention

One RCT has examined whether more intensive treatment of VRFs in patients with first ever stroke or transient ischemic attack influences poststroke cognitive functioning or risk of dementia (secondary outcome) [27]. Pharmacological intervention included antiplatelet agents or warfarin, antihypertensives, statins, antidiabetic drugs, and vitamin B complex including folic acid. Patients were also offered smoking cessation courses and were encouraged to perform regular moderate physical activity, to consume a diet rich in fruit, vegetables, fish, and low-fat dairy products, and less sugar, and not to use alcohol excessively. Patients were randomized either to the intervention group (n = 98) or the control group (n = 97) that received care as usual. One-year poststroke, 11 (13%) patients in the intervention group and 17 (19%) in the control group had developed dementia (p = 0.30) [27].

Prospective observational studies

Among the prospective studies, results on hypertension, hyperlipidemia, and type 2 diabetes mellitus treatment were reported in respectively 20, 27, and seven studies (two studies reported results on two treatments).

Hypertension treatment

Thirteen prospective studies [28 –40] were included in the meta-analysis of hypertension treatment and dementia or AD risk (Supplementary Table 3). The combined RRs for any antihypertensive medication use versus nonuse were 0.77 (95% CI, 0.58–1.02) for dementia, with moderate heterogeneity among studies, and 0.78 (95% CI, 0.66–0.91) for AD, with low heterogeneity (Fig. 2). In two studies that reported results on duration of use of antihypertensive drugs in relation to risk of dementia or AD, the inverse association was more pronounced with longer use [32, 36]. Of the different classes of antihypertensive drugs, angiotensin receptor blockers, calcium channel blockers, and diuretics were statistically significantly inversely associated with risk of dementia and AD (Fig. 2). There was no evidence of publication bias.

Seven studies compared different classes of antihypertensive drugs and risk of dementia or AD [41 –47] (Supplementary Table 4). Among three studies that compared angiotensin-converting enzyme inhibitors with other antihypertensive drugs, one study observed a stronger inverse association with angiotensin-converting enzyme inhibitors [44], whereas the other two studies found no clear difference [41, 42]. Angiotensin receptor blockers seemed to be more strongly inversely related to risk of dementia or AD than angiotensin-converting enzyme inhibitors or other antihypertensive drugs in three [43 , 46] out of four studies [43 –46]. One study found that use of calcium-channel blockers was associated with reduced risk of dementia and AD [47].

Hyperlipidemia treatment

A total of 27 studies were included in the meta-analysis of hyperlipidemia treatment and risk of dementia or AD (Supplementary Table 5). Among these, 25 studies reported results on statin therapy [46 , 48–71], eight on nonstatin lipid-lowering agents [48 , 66], and three on any lipid-lowering agent (statins or nonstatins) [58 , 73]. The combined RRs for statin use versus nonuse were 0.77 (95% CI, 0.63–0.95) for dementia, with notable heterogeneity among studies, and 0.86 (95% CI, 0.80–0.92) for AD, with moderate heterogeneity (Fig. 3). The associations of statin therapy with dementia and AD risk did not differ significantly by study quality, follow-up time, or number of cases (all p > 0.10; Supplementary Table 6). High potency statins (i.e., atorvastatin, rosuvastatin, and simvastatin) appeared to be more strongly associated with reduced risk of dementia and AD than low potency statins (i.e., fluvastatin, lovastatin, and pravastatin) [55 , 71] (Supplementary Table 6). In seven studies that reported results on duration of statin use [49 , 74], the combined RRs of dementia or AD were 0.83 (95% CI, 0.68–1.01) for short-term use and 0.57 (95% CI, 0.40–0.82) for long-term use.

Fig.3

Relative risks of dementia and Alzheimer’s disease for statin use versus nonuse in individual prospective studies and all studies combined. *First author’s last name and year of publication. Studies are ordered by year of publication. NS, not specified; M, men; W, women. Squares represent study-specific relative risks (RR) (size of the square reflects the study-specific statistical weight); the horizontal lines represent 95% confidence intervals (CIs); diamonds represent the combined RR with its 95% CI.

Nonstatin lipid-lowering agents were not associated with dementia or AD risk in the overall analysis (Fig. 4) or in stratified analysis by study quality, follow-up time, and number of cases (data not shown). Use of any lipid-lowering agent (statins or nonstatins) was associated with a lower risk of dementia/AD (RR, 0.47; 95% CI, 0.35–0.62; I²= 48%). No evidence of publication bias was noted.

Fig.4

Forest plot of prospective studies of nonstatin lipid-lowering agent use versus nonuse in relation to incidence of dementia and Alzheimer’s disease. *First author’s last name and year of publication. LLA, lipid-lowering agent; M, men; W, women. Squares represent study-specific relative risks (RR) (size of the square reflects the study-specific statistical weight); the horizontal lines represent 95% confidence intervals (CIs); diamonds represent the combined RR with its 95% CI.

Type 2 diabetes mellitus treatment

Seven prospective studies of antidiabetic treatment in relation to risk of dementia or AD [56 , 75–80] were identified (Supplementary Table 7). In two cohorts of type 2 diabetes mellitus patients [77, 79], the combined RRs of dementia or AD were 0.94 (95% CI, 0.91–0.97; I²= 0%) for oral antidiabetic drug use and 1.17 (95% CI, 0.80–1.71; I²= 68.2%) for insulin therapy. In four studies that included both diabetics and nondiabetics, the combined RRs of dementia or AD were 1.51 (95% CI, 0.83–2.77; I²= 86.7%) for oral antidiabetic drug use [75 –77] and 2.10 (95% CI, 1.14–3.85; I²= 55.0%) for insulin therapy [56 , 77], relative to nondiabetics.

One study investigated whether metformin is associated with a lower incidence of dementia compared with sulfonylureas [80]. After accounting for confounding by indication, metformin versus sulfonylurea use was associated with a lower risk of dementia in those <75 years of age but not in those ≥75 years of age [80] (Supplementary Table 7).

DISCUSSION

This systematic review found evidence that antihypertensive use may lower the incidence of dementia and AD. Statin use was related to a lower risk of dementia in prospective studies but not in the single RCT. There was no support for a beneficial effect of treatment with nonstatin lipid-lowering agents or antidiabetic drugs. Studies on smoking cessation, exercise, and weight loss interventions in relation to dementia or AD incidence were lacking, except for a small (<200 participants) multifactorial VRF intervention study showing no beneficial effect. This finding is consistent with a small lifestyle-based intervention showing no benefit of 24-month multidomain intervention with focus on improvement in lifestyle and vascular risk factors on the incidence of poststroke cognitive decline in comparison with standard stroke care [81].

Four of the five RCTs of antihypertensive therapy observed a 12% to 55% reduction in dementia incidence in the active treatment group. However, the number of dementia cases in each RCT was limited and the results were statistically significant only in the Systolic Hypertension in Europe Study [21]. The inconsistent results may partly be related to different antihypertensive therapies, and to differences in the reduction in blood pressure in the active treatment and placebo groups. In the Study on Cognition and Prognosis in the Elderly trial, which did not show a lower dementia risk with treatment, patients were allocated to receive an angiotensin receptor blocker or placebo, with open-label active antihypertensive therapy added as needed [22]. This resulted in 84% of the placebo group taking additional antihypertensive medication. As a consequence, systolic and diastolic blood pressure at the end of follow-up was only marginally lower in the treatment group than in the placebo group. Other trials showed larger differences in the reduction in blood pressure between treatment arms. Different participant characteristics and diagnostic criteria for dementia may also have contributed to the inconsistent findings. The RCTs did not have dementia as the primary endpoint [20 –23] or the main trial was stopped early [24] and therefore was not powered to detect a statistically significant effect of blood pressure-lowering on dementia incidence. The prospective studies of any antihypertensive therapy and risk of dementia or AD were also generally based on a limited number of cases, ranging from 65 to 333 AD cases and 108 to 440 dementia cases, but an overall statistically significant inverse association between any antihypertensive medication use and risk of AD was observed in the meta-analysis.

AD begins many years before dementia symptoms emerge and VRF in midlife appear to be better related to dementia than VRF in old age [82]. The RCTs and most prospective studies of antihypertensive treatment and dementia risk were short term (2.2–5 years in the RCTs), or had short follow-up, and generally included older participants (≥60 years of age). The short-term antihypertensive treatment in old age may explain negative findings in RCTs and some of the prospective studies.

Antihypertensive treatment might reduce the risk of dementia and AD by decreasing blood pressure or by specific neuroprotective effects. Hypertension is the major risk factor for cerebral white matter hyperintensities visible on T2-weighted MRI, which are associated with an increased risk of dementia [83]. In the Perindopril Protection Against Recurrent Stroke Study trial, antihypertensive therapy delayed the progression of white matter hyperintensities [84] and reduced the incidence of dementia by 34% in patients with recurrent stroke but had no effect on dementia incidence in the absence of recurrent stroke [23]. Antihypertensive drugs that cross the blood-brain barrier may have specific neuroprotective actions. For example, an experimental study in mice showed that the calcium channel blocker nifedipine, which can cross the blood-brain barrier, attenuated peroxide anion production in the brain and this reduction in oxidative stress was related to better cognitive performance [85]. Two other experimental studies showed that certain calcium channel blockers, including nifedipine and nitrendipine (the antihypertensive drug used in the Systolic Hypertension in Europe Study [21]), decreased brain Aβ peptide concentrations [86, 87] and improved Aβ clearance across the blood-brain barrier [86]. A prospective study found that angiotensin-converting enzyme inhibitors that cross the blood-brain barrier were more strongly inversely associated with AD risk than angiotensin converting enzyme-inhibitors that cannot cross the blood-brain barrier [41].

Results from the present meta-analysis of prospective studies showed that statin therapy was associated with a reduced risk of dementia and AD. However, a large RCT did not support a reduction in dementia incidence with simvastatin therapy [25]. Whether hypercholesterolemia is a risk factor for dementia and AD remains elusive. Observational studies have found that hypercholesterolemia in midlife is associated with AD risk [7], but Mendelian randomization studies, which are less prone to bias, do not support a causal association between cholesterol levels and AD [88, 89]. Statins may have neuroprotective actions through their ability to improve blood-flow, modulate the immune system and lower oxidative damage [90].

A meta-analysis of published studies inherits the limitations of the original studies. Observational studies are susceptible to confounding and reverse causality and we cannot rule out the possibility that these biases may have affected the results. Another potential limitation is the accuracy of dementia diagnosis and differentiation of AD from other causes of dementia. An AD diagnosis based on standard criteria has good sensitivity and specificity for differentiating between AD patients and individuals without dementia but the ability to discern between AD and other causes of dementia is less accurate [3]. Another shortcoming is that the literature search and data extraction were performed by a single investigator, and that only one database was searched. We therefore cannot preclude the possibility that we may have missed relevant studies for inclusion. Finally, as a meta-analysis of published studies, the possibility that publication bias may have affected the results cannot be excluded. We found no evidence of such bias but tests for publication bias have low power, in particular when the number of studies is limited.

In conclusion, available evidence from RCTs and prospective studies indicates that antihypertensive therapy might have a role in preventing dementia and AD. Further studies are required, particularly on whether more intensive lowering of blood pressure to 120 mm Hg systolic or below, which has been shown to reduce cardiovascular outcomes [91], is also associated with a lowering of the incidence of dementia and AD. Prospective studies have indicated an inverse association between statin use and risk of dementia and AD, but there is yet no support from RCTs that statins are beneficial.

A striking feature was the paucity of RCTs investigating the effect of treatment of vascular risks factors on AD. A cost-efficient method of obtaining such data would be to include long-term follow-up for cognitive endpoints in trials of cardiovascular prevention. This is important considering both the huge population burden of dementia, and the lack of other effective treatment approaches.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the CoSTREAM project (), which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667375. Susanna Larsson is supported by the Swedish Brain Foundation (Hjärnfonden). Hugh Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Comprehensive Biomedical Research Centre.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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