Introduction
In 2006, cardiovascular diseases (CVD) accounted for 34.3% of all deaths in the United States [
1] (approximately the deaths of 831,000 people). In that year, there were an estimated 74 million people with high blood pressure, nearly 18 million with coronary heart disease (CHD), and 6.4 million with strokes. The vast majority of these events and diagnoses occur among people aged ≥65 years, such that the prevalence of heart disease and stroke in people over 65 years of age is nearly four times higher compared with people aged 18 to 64 years [
2]. Personal health care expenditures in 2005 for Medicare recipients for heart disease, stroke, and hypertension totaled nearly $50,000 per person [
3]. According to statistics published by the National Center for Health Statistics, the prevalence of these conditions in the United States in people aged ≥65 years declined by about 20% between1999 and 2006. However, it is likely that death from CVD in people with these conditions is simply being postponed, and that the decline in the death rates will lead to a potential future increase in CVD morbidity in people over the age of 80 years [
1] because those who would have died instead survive with their condition and contribute to the overall population burden of CVD-related chronic conditions [
1]. Treatments for CVD and prevention of risk factors for CVD have become more effective and more widely used. Statin drugs were used by 24 million Americans in 2003 and 2004 and their use is higher among people with higher levels of low-density lipoprotein cholesterol (LDL-C) who are aged ≥75 years than among those aged 20 to 39 years [
4]. Cigarette smoking is a prime example of this kind of change, as prevalence of smoking has declined and in 2006 to 2008, 23% of those over age 18 years were current smokers compared with nearly 40% of those over 65 years of age.
Studies of coronary heart disease, lipids, and coronary atherosclerosis from 2000 to 2010
| 2004 | 185/6852 | 55+ | Europeans | Cohort | e3/e4 or e4/e4 | MI | 1.0 (0.7–1.4) 1.7 (0.8–3.6) |
| 2009 | 2712/22,169 | 40–79 | Europeans | Cohort | Any e4a
| CHD | 1.09 (1.0–1.19) |
| 2001 | 104/730 | 21–96 | US white men | Cohort | Any e4a
| Coronary events | 2.01 (1.4–3.1) |
| 2006 | 447/12,491 | 45–64 | US whites and blacks | Cohort | Any e4a
| CHD | Whites: 1.07 (0.94–1.21) Blacks: 1.13 (0.91–1.40) |
| 2001 | 242/1668 | 11–65 | US white men | Cohort | Any e4a
| CVD | 1.46 (0.99–2.15) |
| 2001 | 121/1739 | 9–62 | US white women | Cohort | Any e4a
| CHD | 1.36 (0.78–2.38) |
| 2007 | 37,850/82,727c
| NA | Mixed studies | Meta-analysis of 121 case-control studies with 500+ | Any e4a
| CHD | 1.06 (0.99–1.13) |
| 2004 | 15,492/32,965 | NA | Mixed studies | Meta-analysis of 48 case-control studies | Any e4a
| CHD | 1.42 (1.26–1.61) |
| 2009 | 25,348/51,484 | 30–64 | Asian, European, Arab, Nepalese | Case control | e4a
| MI | 1.07 (1.01–1.28) |
| 2004 | 4685/3420 | 30–64 | UK whites | Case control | Per e4 allele vs e2/e3 | Nonfatal MI | 1.16 (1.06–1.27) |
| 2009 | 410 | 40–87 | Greek | Patient group | Any e4a
| Myocardial perfusion SSS > 2b
| 35.8 (13.1–98.1) |
Frikke-Schmidt et al. [ 43] | 2000 | 940/9241 | 20–80 | Danish men | Case-referent | e4/e3a
| IHD | 1.16 (0.96–1.41) |
| 2003 | 385/373 | 40–84 | US men | Nested case control | Any e4a
| MI | 0.93 (0.63–1.37) |
| 2006 | 546 | 85 | Dutch | Cohort | e4/e3 modified by plasma APOE | Cardiovascular death | Intermediate plasma APOE: 2.81c (1.02–7.74) High plasma APOE: 4.25c (1.38–13.0) |
Studies of stroke, hypertension, and carotid atherosclerosis from 2000 to 2010
| 1999 | 9 studies | NA | Japanese, Canadian, European | Meta-analysis of 9 case-control studies | Any e4+
| Ischemic CVD | 1.68 (1.36–2.09) |
| 2004 | 149/6852 | 55 + | Dutch | Cohort | e3/e4 e4/e4 | Ischemic stroke | 0.9 (0.6–1.3) 0.6 (0.1–2.5) |
| 2007 | 99/561 | 85+ | Dutch | Cohort | e3/e4+
| Stroke | 3.01 (1.34–6.74) |
| 2009 | 396/396 | 57 (mean) | Han Chinese | Case control | Any e4+
| Stroke | 1.50 (1.13–1.91) |
| 2007 | 180/5054 | 45–64 | US white men | Cohort | Any e4+
| Ischemic stroke | 0.98 (0.70–1.38) |
| 2007 | 97/1499 | 45–64 | US black men | Cohort | Any e4+
| Ischemic stroke | 0.77 (0.49–1.24) |
| 2007 | 6107 | 50–70 | Asian | Meta-analysis | Any e4+
| Stroke | 1.47 (1.00, 2.15) |
| 2001 | 242/1668 | 11–65 | US white men | Cohort | Any e4+
| CVD | 1.46 (0.99–2.15) |
| 2009 | 1812/1762 | 40+ | Asian | Meta-analysis of 6 case-control studies | Any e4+
| Hypertension | 1.97 (1.11–3.52) |
| 2006 | 15,792 | 45–64 | US white and black | Cohort | Any e4+
| Carotid IMT (mean [SE])a
| e4: 0.74 (0.003) |
| 2006 | 5856 | 65+ | European | Cohort | e4/e4 vs. e33 | Carotid plaque | 2.12 (1.27–3.53) |
| 2003 | 1109 | 27–77 | Australian white men | Cross-sectional | e4/e4 e3/e4 | Carotid plaque | 2.85 (0.49–16.6) 1.79 (1.01–3.17) |
The apolipoprotein E (APOE) genotype is a genetic risk factor for dementia, Alzheimer’s disease, and CVD. It is among the more common genotypes. It includes 3 alleles (e2, e3, e4) and 6 genotypes (e22, e23, e24, e33, e34, e44) that occur on chromosome 19q3.2. The e3 allele is the most common of the three and may be considered an ancestral allele. The e4 allele is more common in people of Northern European ancestry and lower in those of Asian ancestry [
5]. Those with at least one e4 allele are at increased risk for CVD outcomes, and homozygosity for e4 (ie, e4/e4) increases risk further. It is well established that the presence of an e4 allele is linked to higher LDL-C levels; this is found even at younger ages, and LDL-C increases more rapidly with age in those with the e4 allele [
6].
Apolipoprotein E is often found to interact with environmental risk factors, such as smoking or diet, to increase risk. Compared with e2 or e3, the e4 allele may contribute to earlier and higher mortality, which in turn contributes to a lower occurrence of the e4 allele in older compared with younger people [
7‐
9]. Apolipoprotein E is often reported to modify the effects of environmental risk factors such as diet, smoking, or physical activity on cardiovascular outcomes.
Multiple individual studies, reviews, and meta-analyses have previously examined and summarized the influence of the APOE genotype on the risk of CVD. Most studies have focused on CHD, atherosclerosis, hypertension, and ischemic stroke, and some mechanistic studies have evaluated the role of lipids and inflammation in the links between apolipoprotein e4 and vascular outcomes. This review includes only studies published after 1998 that were sufficiently large to have statistically significant effects. In addition, only studies for which the referent or target population was identifiable were selected. This review is divided into studies examining 1) cerebrovascular diseases, including ischemic stroke, hypertension, or carotid atherosclerosis; and 2) studies examining CHD, lipids, and coronary atherosclerosis. Only studies in which there were older adults were included, with the exception of a longitudinal study of young adults modeling change over time in LDL-C in relation to apolipoprotein E [
6]. Only a few studies that are restricted to older populations (age ≥65 years) have been done of the effects of apolipoprotein E on these outcomes. Most studies include middle-aged individuals with smaller numbers of older individuals, and they do not report apolipoprotein E effects by age strata or test interactions between apolipoprotein E and age. Therefore, information about the differences between younger and older people in the effects of apolipoprotein E on vascular outcomes is limited. The effects of population heterogeneity by nationality, race, or ethnicity on apolipoprotein E and vascular outcomes is addressed in a number of recent studies.
Stroke
Ischemic stroke is the most common form of stroke and the most frequent stroke outcome studied in relation to apolipoprotein e4. Three of the publications included here did not distinguish ischemic from hemorrhagic stroke. Overall, the risk of ischemic stroke in those with an e4 compared with an e3 allele ranges from a risk of 0.77 (95% CI, 0.49–1.24) in US middle-aged black men [
46] to 3.01 (95% CI, 1.34–6.74) in Dutch people over the age of 85 years [
34]. Among studies of people of Asian origin, the elevated risk of stroke associated with apolipoprotein e4 is more consistent (around 1.50 for e4 vs e3) than in people of European origin, in whom it ranges from 0.90 to 1.68 in samples of middle-aged individuals [
20,
44].
Hypertension and carotid atherosclerosis are common mechanisms related to stroke risk. Only one recent study has examined the association between apolipoprotein e4 and hypertension [
10], yielding a risk of 1.97 (95% CI, 1.11–3.52) in a meta-analysis of six cohort studies of Asians [
46]. In addition, four studies in various population groups have reported significant increases in carotid atherosclerosis or carotid plaques in those with an e4 compared with an e3 allele [
19,
48,
49]. Of all the studies of apolipoprotein E and cerebrovascular disease that we reviewed, only four were restricted to people over the age of 55 years and none examined age-specific effects or tested interactions between apolipoprotein E and age [
20,
34,
47,
48].
Notable among these studies are the following. 1) The only study to focus on elderly people (age ≥85 years) found that the effects of the e3/e3 and e3/e4 genotypes on stroke were mediated by plasma apolipoprotein E levels [
34]. In e3/e4 carriers, a 1-SD difference in plasma apolipoprotein E was associated with a threefold increase in stroke risk (
P = 0.002). In the e3/e3 genotype, this risk was 1.95 (
P = 0.002). Stroke risk in e2 carriers was not mediated by plasma apolipoprotein E. 2) A meta-analysis of six studies of hypertension risk including only Asian participants that compared the e3 to the e4 allele found that the odds of hypertension were elevated in e4 carriers [
47]. The summary estimate was more consistent than studies of Europeans. It is possible that there is less subpopulation heterogeneity in this group of Asian studies than in European studies.
Coronary Heart Disease
In the current literature, several large cohort studies report that the apolipoprotein e4 allele is associated with an increased risk of CHD, with a risk ranging between 1.1 and 2.0 [
11‐
16]. Six of the 13 found a significantly increased risk of CHD in e4 carriers. Three of the 13 studies found no association between the e4 allele and CHD [
17‐
19]. Mooijaart et al.’s study [
18] was the only population-based study we found that restricted enrollment to elderly participants who were Dutch and ≥85 years of age. Some of these studies may have lacked power to detect differences in CHD risk due to small sample size.
In a Dutch cohort study of 6852 men and women 55 years of age were followed for up to 8 years, the authors reported that the e4 allele was weakly associated with myocardial infarction, with e3/e4 individuals experiencing no increased risk (RR = 1.0; 95% CI, 0.7–1.4) compared with e3/e3 individuals [
20]. In the same study, e4/e4 individuals, who made up a small proportion of the sample (
n = 162), experienced an increased risk that was not statistically significant (relative risk = 1.7; 95% CI, 0.8–3.6) [
20].
In a cohort study of 25,630 English men and women aged 40 to 79 years who were followed for up to 11 years, individuals with the e4 allele experienced a slightly higher risk for CHD (hazard ratio = 1.09; 95% CI, 1.0–1.19) [
21•]. This relation was mediated by the ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL); adding this variable to the regression models changed the hazard ratio to 1.06 (95% CI, 0.95–1.18), but the association remained statistically significant.
A cohort study of 1094 Swedish men and women 75 years or older at baseline who were followed for up to 18 years found Individuals with the e4 allele were significantly more likely to die than individuals who were homozygous for the e3 allele over the 18 years of follow-up (RR = 1.22; 95% CI, 1.07–1.41) [
9]. The authors investigated whether this relation was modified by ischemic heart disease or dementia. They found that increased risk of mortality was mediated by dementia but not by ischemic heart disease, but gender was an effect modifier.
A 2007 meta-analysis of 121 large studies found that individuals with the e4 allele had a slightly higher risk of CHD (odds ratio = 1.06; 95% CI, 0.99–1.13) [
16]. There are very few large studies examining the role of apoe4 in relation to coronary atherosclerosis. One study of patients aged 61 years (mean) who underwent exercise-rest myocardial perfusion single positron emission computed tomography (SPECT) reported that individuals who were homozygous for e3 and e4 and individuals who were heterozygous for e4 had significantly higher values of a summed stress score (SSS) compared with those who were heterozygous for the e3 allele (
P < 0.001) [
22]. After adjustment for demographic and clinical risk factors, both APOE genotypes were independent predictors, with a cumulative contribution for the prediction of SSS and summed difference score. All APOE4 genotypes had higher levels of abnormal SSS, indicating they are linked to coronary atherosclerosis.
Statins Use and APOE Genotype
Statin use has increased rapidly over the past 10 to 15 years for the purpose of lowering LDL-C levels and preventing CHD and possibly stroke. Statins are highly effective in lowering LDL-C and may also affect inflammation [
38]. Although apolipoprotein E is linked to LDL-C, relatively few studies have been able to evaluate the effectiveness of statin therapy in those with the e4 allele compared with the e3 or e2 allele. A genome-wide association study was conducted on a sample of 1984 men with a mean age of 62 years [
39]. They were enrolled in a randomized trial to test the effects of low-dose versus high-dose statins on cardiovascular outcomes. This trial evaluated 17 single nucleotide polymorphisms in relation to LDL-C response to treatment over an 8-week period. Of these, only APOE genotypes met study criteria; the least LDL-C change occurred in those with an e4/4 genotype and the largest change occurred in those with an e2/2 genotype. In a series of patients with and without familial hypercholesterolemia, the effects were tested of apolipoprotein E on lipid response to either atorvastatin for those with familial hypercholesteremia or to fenofibrate in those without familial hypercholesteremia [
40]. Among those with familial hypercholesteremia, the largest change occurred in those with the e2 allele (46-mg/dL decline) and the smallest change occurred in carriers of the e4 allele (34.5-mg/dL decline; comparison of baseline to post-treatment in both alleles was
P < 0.0001). Among those without familial hypercholesteremia, a similar pattern of change in LDL-C did not occur and the results were similar for carriers of e2,e3 and e4 alleles.
Conclusions
Our summary of recent research on the effects of the APOE genotypes on CVD in the elderly reveals a complex system of relationships. APOE genotypes clearly influence lipids and potentially inflammation, and may be linked to atherosclerosis and hypertension. However, the association of these biomarkers with CVD outcomes is altered in the elderly, in part by age- and time-dependent changes in exposure. The occurrence of APOE4 genotypes in older populations has been seen to decline as well. From a population perspective, this may mean that the fraction of CVD cases attributable to apolipoprotein e4 may be smaller and that the ability of e4 to influence CVD risk by increasing LDL-C is more limited. There are few studies of these issues in elderly people, and most of the research includes middle-aged individuals. This age inclusion would tend to attenuate the ability to observe age-specific effects. The more recent research has provided some information about subpopulation heterogeneity in the occurrence of e4 alleles and about related differences in effects on CVD. The work by Niu et al. [
10] is of particular value as it is one of the only studies on e4 and hypertension in Asians.
The efficacy of active lipid-lowering interventions such as statin use or diet on CVD may or may not be affected by genetic risk factors such as apolipoprotein E. Most trials are not designed to test whether the apolipoprotein genotypes affect treatment efficacy. Given that in some populations e4 carriers comprise as much as 25% of the population, this is an important omission. Clearly, more research is needed that can help to elucidate the mechanisms by which apolipoprotein E affects CVD in older populations.