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Keywords:

  • alcohol;
  • Alzheimer's;
  • cardiovascular;
  • diabetes;
  • risk factors

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Alzheimer's disease (AD) has become one of the most common chronic diseases in developed countries. Estimates indicate that, by 2050, over 13 million people in the United States alone will have AD [1]. One in eight men, and almost one in four women, will develop AD during their lifetime. Better understanding of the aetiology and prevention of AD has become critical to the public health. Growing literature indicates that cardiovascular disease (CVD) and CVD risk factors are associated with increased risk of AD, and its precursor, cognitive decline. Thus, lifestyle modifications or pharmacological interventions which decrease vascular disease might also hold promise for reducing the burden of AD and cognitive decline. This review discusses the evidence relating CVD and several key CVD risk factors to cognitive decline and AD, and possible mechanisms explaining observed associations (Table 1).

Table 1.   Major risk factors for CVD, and their association with AD
CVD/risk factorEvidence for relation with cognitive decline or AD
  1. CVD, cardiovascular disease; AD, Alzheimer's disease. ***strong evidence; **moderate evidence; *weak evidence.

CVD***
Hypertension**
Lipids**
Type 2 diabetes***
Apolipoprotein E genotype***
Inflammation*
Moderate alcohol intake***
Antioxidant vitamins*

Cardiovascular disease

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Studies of both clinical CVD and subclinical CVD have consistently reported associations with impaired cognitive function. For example, in the Rotterdam study of 4971 older subjects, mean score on the Mini Mental State Examination was significantly lower amongst those with a history of stroke (P < 0.0001), electrocardiographic evidence of myocardial infarction (P = 0.003), peripheral arterial disease (P = 0.0001) or plaques in the internal carotid arteries (P = 0.002) [2]. The odds of cognitive impairment were also significantly greater for subjects with those conditions, with odds ratios ranging from 1.4 to 1.9. However, in that cross-sectional analysis, it was not possible to determine whether vascular disease preceded cognitive impairment. Yet results were similar in the prospective Cardiovascular Health Study [3]. Even after excluding stroke cases, subclinical CVD (including carotid wall thickness >80th percentile, carotid stenosis >25%, EKG abnormalities) was related to a 30% greater risk of substantial cognitive decline over 5 years of follow-up (RR = 1.29, 95% CI 1.03–1.62), and clinical CVD or infarct on magnetic resonance imaging (MRI) was associated with nonsignificant increases in risk (RR = 1.19 and 1.18 respectively). Furthermore, in a subsequent prospective investigation from the Rotterdam study [4], silent brain infarcts on MRI were significantly related to declining cognition; mean decline in cognitive function was almost fivefold greater for those with multiple compared to single infarcts – in particular, this ‘dose–response’ relation provides strong support for the validity of the findings.

Alzheimer's disease

Studying the relation between CVD and AD is complicated; diagnostic criteria for AD exclude anyone with clinical CVD (hence, the combination of dementia and stroke would result in the diagnosis of multi-infarct dementia rather than AD). Nonetheless, there is convincing evidence that CVD contributes to AD. For example, in autopsy studies of AD cases [5], the number of microvascular ischaemic lesions was as closely associated with dementia as the number of Alzheimer lesions (OR =4.59 and 4.27 respectively). Similarly, in the Nun Study [6], the prevalence of AD was 11-fold higher (95% CI 1.8–70.3) in women with brain infarct on autopsy than in those without infarcts.

In MRI studies of older persons [7], periventricular white matter lesions (which are associated with dementia) were increased in those with aortic atherosclerosis at middle age (RR = 2.4, 95% CI 1.2–5.0); this relation was increasingly stronger with increasing severity of atherosclerosis (P =0.002). Epidemiological studies of subclinical CVD and incident AD further support the potential importance of vascular pathology to development of dementia. In the prospective Cardiovascular Health Study [8], carotid artery wall thickness and ankle-arm index (an indicator of extent of peripheral arterial disease) were all associated with an increased risk of AD (RR = 1.5, 95% CI 1.0–2.2 for top versus bottom quartiles of common carotid artery wall thickness; RR = 1.7, 95% CI 1.1–2.5 for internal carotid artery thickness; RR = 1.7, 95% CI 1.1–2.6 for ankle-arm index). Similarly, a prospective investigation in the Rotterdam study [4] indicated that silent brain infarcts on MRI more than doubled the risk of dementia (RR = 2.26, 95% CI 1.09–4.70) over an average 3.6 years of follow-up.

Mechanisms

There are many hypotheses to explain the mechanism by which vascular disease could influence risk of AD [9], although little firm evidence to clearly support any single hypothesis. Three possibilities are most commonly suggested to explain this relation. First, it is possible that CVD and AD simply share the same risk factors – i.e. that similar risk factors independently increase rates of CVD and of AD. Secondly, there may be an indirect influence of vascular disease; vascular damage in the brain could create conditions which predispose to neurodegeneration. Or, finally, vascular factors could directly affect development of AD by causing neuronal death, and accumulation of plaques and tangles (the hallmark pathology of AD).

Summary

Consistent evidence from a large number of epidemiological studies has established a relation between CVD and cognitive decline or AD. It is not clear however, whether this relation may be due to shared risk factors, or due to direct or indirect influences of CVD on the pathological processes which cause AD.

Hypertension

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Large, prospective studies generally indicate that higher blood pressure at mid-life is associated with worse cognitive function at older ages [10]. For example, in the Honolulu-Asia Aging Study [11], of 3735 men, increasing systolic blood pressure (SBP) at mid-life was associated with decreasing cognitive performance over 20 years later (P < 0.03). Each 10 mmHg increase in SBP was related to a significant 9% increased risk of impaired cognition; even after adjustment for clinical and subclinical CVD, there was a 5% increased risk of impaired cognitive function (95% CI 0–12%) with each 10 mm increase in SBP. It is highly plausible that mid-life blood pressure may be particularly important. Cognitive impairment probably takes many years to develop; risk factors earlier in life could thus have substantially more influence on the course of disease than factors later in life, after the disease process has already been initiated.

In contrast, studies of blood pressure at later life have reported somewhat more mixed results, with the possibility of either a linear or a U-shaped relation (i.e. both low and high blood pressure predicting reduced cognition) emerging in various studies. In particular, in the elderly, low pressure can partly reflect low cardiac output. For example, in one of the largest prospective studies [12], of 5999 subjects in the Cardiovascular Health Study, each 1 SD increase in SBP was related to a decline of 0.96 points on the modified Mini Mental State Examination (MMSE). However, in the East Boston study of 2068 older subjects [13], SBP <130 and >160 mmHg were associated with a similar increase in the percentage of errors on the Short Portable Mental Status Questionnaire (9% and 7% increase respectively).

Alzheimer's disease

Studies of AD are generally consistent with those of cognitive function. Several large studies generally report that higher mid-life blood pressure is associated with an increased risk of AD in later life. Amongst 8845 members of Kaiser Permanente of Northern California [14], those with hypertension at mid-life had a 24% greater risk of dementia at older ages (RR = 1.24, 95% CI 1.04–1.48). In the Honolulu-Asia Aging study [15], with 3703 men, those with borderline high blood pressure at mid-life which was untreated had greater than a threefold increased risk of AD (RR = 3.49, 95% CI 1.28–9.52) and those with untreated high blood pressure had greater than a fourfold increase (RR = 4.47, 95% CI 1.53–13.09). For later life blood pressure, many studies of AD have reported null results. For example, in the Cardiovascular Health Study [16], a prospective study of over 3000 subjects, hypertension had no relation to AD risk (RR = 0.9, 95% CI 0.71–1.19). The few studies with significant findings most consistently report adverse effects of low blood pressure; again, especially with a clinical outcome that has a long latency period, it is most likely that low blood pressure is a sign of impending illness rather than a cause of it.

Hypertension treatment

Several randomized clinical trials have examined the relation of treatment for high blood pressure to cognitive function and dementia. However, findings have been mixed. The Medical Research Council's trial of hypertension [17] measured performance on two cognitive tests (paired associate learning test and trail making test part A) amongst 2584 participants aged 65 years and older; there was no difference in the rates of decline on either test for those assigned to antihypertensive treatment versus placebo. In the Syst-Eur trial [18], of 2418 subjects aged 60 years and older with elevated SBP, antihypertensive treatment for 2 years resulted in a 50% reduction in dementia (mostly AD cases) compared with placebo, although there were few cases in either group (n = 11 in the treated group versus 21 in the placebo group, P = 0.05). In contrast, primary analyses of the SCOPE trial conducted amongst 2093 older subjects reported no differences in cognition or dementia between those treated with antihypertensives and those assigned to placebo, after almost 4 years of follow-up [19]. Finally, amongst 4736 subjects aged 60 years and older in the SHEP trial [20], followed for almost 5 years, no relation was found between treatment and either cognitive performance or risk of dementia (1.6% in treated group versus 1.9% in placebo group). However, later analyses of the data [21] revealed significantly greater loss-to-follow-up amongst the placebo than the treated group; as subjects lost to follow-up are more likely to have cognitive impairment or dementia than those retained in the study, this could have biased results towards the null, and may have masked a benefit.

Mechanisms

High blood pressure can result in severe atherosclerosis, which greatly increases the risk of cognitive impairment and dementia (see above). Similarly, the clear decreased risk of CVD with antihypertensive treatment could lower the rate of cognitive decline and AD. Direct mechanisms of action are less clear, although it has been suggested that specific pharmaceuticals could provide direct benefits; for example, the intracellular build-up of calcium in neurones can be neurotoxic, and thus calcium channel blockers might result in neuroprotection (calcium channel blockers were the treatment agent in the Syst-Eur trial described above).

Summary

The relation of blood pressure to cognitive function and dementia appears complex, with the possibility of opposite associations at different stages of life and disease. Some studies indicate that high blood pressure at mid-life may increase the risk of impairment whilst low blood pressure at older ages may be related to an elevation in dementia risk; however, the latter relation may be a result of disease rather than a cause. Still, the literature remains unclear, with randomized trials of older men and women given antihypertensive treatment finding mixed results; only one modest-sized trial has found cognitive benefits with antihypertensive agents. Unfortunately, trials of participants at mid-life are difficult to conduct due to the long follow-up needed before neurodegenerative disease becomes fairly common.

High cholesterol

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Several large-scale studies have examined the relation of plasma lipid levels to cognitive function. These studies have been conducted in a wide variety of populations, from women with CVD to largely healthy Hispanic men and women, and are mostly cross sectional. However, the results generally support an association between total and LDL cholesterol levels and lower cognition. In a cross-sectional study amongst 1037 women with CVD [22] participating in a randomized trial of hormone therapy, there were significant trends of increasing cognitive performance with decreasing quartile of total cholesterol and LDL cholesterol (P = 0.01 and 0.02 respectively), after adjusting for numerous potential confounding factors. In addition, when examining changes in plasma cholesterol levels over the previous 4 years, there were significant trends of better scores on the modified MMSE with decreasing levels of total or LDL cholesterol (P = 0.02 for both). However, no associations were found for HDL. In the Women's Health Study, including 4081 healthy women in a randomized trial of low-dose aspirin and vitamin E, LDL levels at baseline were modestly associated with decreased cognitive performance approximately 5 years later [23], but HDL was strongly related to higher average scores across four cognitive tests. Specifically, there was a strong trend of decreasing risk of cognitive impairment with increasing HDL level (OR = 0.50, 95% CI 0.33–0.75 for top versus bottom quintile, P = 0.006), and a modest association for LDL (OR = 1.3, 95% CI 0.9–1.8; P = 0.08). In contrast, in a large, prospective study of 1147 older persons in a multiethnic urban population (the Washington Heights-Inwood Cognitive Aging Project, WHICAP), there was no relation between total cholesterol, LDL or HDL, and decline in memory performance, visuospatial performance or language [24].

Alzheimer's disease

There are also a paucity of large-scale studies of cholesterol levels and dementia. In a cross-sectional analysis in the French Three-City Study of 9294 older subjects [25], high total cholesterol levels were related to increased risk of dementia after adjustment for numerous potential confounding factors (OR = 1.76, 95% CI 1.05–2.96), and findings were similar after exclusion of subjects with vascular disease (OR = 1.88). In an analysis of cases with dementia caused by AD (n = 112), this risk was attenuated (OR = 1.18, 95% CI 0.62–2.23); however, those results are difficult to interpret due to the wide confidence interval.

In a small prospective study, amongst 1026 participants in the Framingham Study (n = 77 AD cases) [26], there was no association between total or HDL cholesterol levels and AD risk (RR = 0.95, 95% CI 0.87–1.04, per each 10 mg dL−1 increase in total cholesterol; RR = 1.10, 95% CI 0.93–1.31, for increasing HDL). In a larger study of 3933 Japanese-American men (n = 215 dementia cases, n = 82 AD cases) [27], each 1 SD increase in total cholesterol was associated with a nonsignificant 10% increase in risk of dementia (95% CI 0.95–1.26); results were not provided separately for AD, although the investigators reported that there were no associations – again, however, the number of AD cases was small. In the WHICAP study of Caucasian, Hispanic and African-American subjects [24], both cross sectional and prospective analyses of AD were conducted. In the cross-sectional analyses, including 244 AD cases, HDL levels were associated with a reduced risk of AD (OR = 0.52, 95% CI 0.34–0.80; OR = 0.61, 95% CI 0.39–0.94; OR = 0.74, 95% CI 0.49–1.13, for second, third and fourth quartiles compared with the bottom quartile respectively). There was no association with total cholesterol or non-HDL cholesterol. In prospective analyses, including less than half the number of AD cases (n =119), there was no relation between HDL or non-HDL cholesterol and AD risk, but there was a significant trend of increasing risk of AD with increasing level of total cholesterol (RR = 0.48, 95% CI 0.26–0.86 for top versus bottom quartile, P = 0.04). Overall, these studies are inconsistent and do not conclusively support or refute a relation between cholesterol levels and AD risk; however, the studies are limited, and the existing data are generally based on investigations with relatively few AD cases, and thus fairly low statistical power to detect effects.

Two studies which reported a consistent relation between cholesterol and AD examined mid-life cholesterol levels. In one of these, the sample also was small with only 48 cases of AD [28]. High levels of total cholesterol at mid-life were significantly related to an increased risk of AD an average 21 years later (RR = 2.8, 95% CI 1.2–6.7). The second study was much larger, with 721 cases of dementia diagnosed amongst 8845 subjects enrolled in the Kaiser Permanente healthcare system of Northern California [14]. Those with high total cholesterol at mid-life had a 42% increased risk of dementia an average of 27 years later (95% CI 1.22–1.66); however, analyses of AD cases were not presented separately. As with hypertension (see above), it is possible that cholesterol levels earlier in life may have the largest impact on dementia development.

Mechanisms

Growing biological evidence suggests that cholesterol may play a role in the pathogenesis of dementia. One mechanism by which cholesterol may influence dementia is via its effect on CVD risk. There are possible additional, direct mechanisms as well. Cholesterol appears to modulate production of amyloid beta. In cell culture, the addition of cholesterol increased amyloid beta 1-40 by up to twofold, and cholesterol was necessary for any secretion of amyloid beta 1-42 (which appears to be the most toxic form of amyloid beta); similarly, reduction of cholesterol levels in cell cultures decreased amyloid beta by 40% [29]. In a mouse model, diet-induced hypercholesterolaemia led to elevated amyloid beta levels in the central nervous system, as well as increased size and number of amyloid deposits in the brain [30].

Summary

Epidemiological studies of cholesterol suggest that high LDL or low HDL may increase the risk of cognitive decline and dementia; however, data are sparse and are not entirely consistent. Nonetheless, cholesterol levels are important determinants of CVD risk, and in vitro and in vivo evidence demonstrates that cholesterol levels are directly related to amyloid beta production and deposition in the brain. Thus modulation of cholesterol levels continues to be a strong candidate for dementia prevention.

Type 2 diabetes

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Type 2 diabetes is amongst the best-established risk factors for cognitive impairment. In several reviews of the epidemiological literature [31, 32], across over 30 studies, type 2 diabetes is consistently associated with diminished cognition and increased risk of cognitive impairment. Cukierman et al. [31] quantified these relations amongst prospective studies, and reported that rates of cognitive decline on the MMSE were 20–60% worse for those with versus without diabetes. A modest increase in risk of substantial decline on the MMSE was also detected; the summary relative risk was 1.2 (95% CI 1.05–1.4). At least part of the relation between diabetes and cognition is probably caused by direct effects of insulin. Limited data indicate that higher levels of insulin, even in those without diabetes, are related to higher risk for impaired cognition. For example, in an investigation of 719 women without clinical diabetes [33], the risk of cognitive impairment increased with increasing levels of insulin secretion (RR = 3.2, 95% CI 1.3–7.8 for top versus bottom quartile; P = 0.001).

Alzheimer's disease

Epidemiological evidence strongly supports an association between type 2 diabetes and AD. In a recent review of prospective studies [31], a summary relative risk of dementia of 1.6 (95% CI 1.4–1.8) was estimated, comparing those with and without type 2 diabetes. Although a summary relative risk was not provided specifically for AD, all investigations which separately examined AD also found increased risks (range of RRs from 1.2 to 2.3). In addition, although few studies have examined the effects of insulin, these have generally reported that increasing levels of fasting insulin are associated with increasing risk of dementia. For example, Luchsinger et al. [34] found that those in the highest quartile of insulin level (with or without clinical diabetes) had a 70% higher risk of developing AD compared with the bottom quartile (95% CI 1.0–2.7).

Mechanism

Diabetes may increase cognitive impairment and dementia via the micro and macrovascular damage that often accompany it. In addition, there may be direct effects of insulin. There are insulin receptors throughout the brain, especially in the hippocampus [35], the brain region where learning and memory occur. In rats, insulin appears to affect neurone firing, as well as the neurotransmitters which influence learning and memory [36, 37]. In addition, the insulin degrading enzyme (IDE) was the first protease demonstrated to degrade Aβ [38]. In mice, IDE deficiency was associated with greater than 50% reduction in Aβ degradation, and cerebral accumulation of endogenous Aβ was increased by 64% [39]. A recent investigation of 16 healthy older adults [40] found that, upon acute infusion of insulin, levels of Aβ in cerebrospinal fluid were increased by 15% (P = 0.02).

Summary

Consistent data from epidemiological studies have found a strong relation between type 2 diabetes and cognitive impairment or dementia. This association may caused by the vascular damage which often accompanies diabetes, or may be caused by direct effects of insulin on the brain.

Apolipoprotein E genotype

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Apolipoprotein E (apoE) modulates lipid transport, and the e4 allele of this gene raises levels of total and LDL cholesterol and increases risk of CVD. Data on apoE genotype and cognitive function generally suggest an increased risk of cognitive impairment for those with the e4 allele, and a possible decrease in risk for those with an e2 allele. In a meta-analysis [41], significantly worse performance on global cognition, episodic memory and executive function were found for those with an e4 allele. In addition, in an investigation of 4227 women, clear gene–dose relations were found [42]. For example, mean cognitive decline was almost twice as great for those homozygous versus heterozygous for the e4 allele (P = 0.0003). Overall, the relative risk of substantial cognitive decline was 1.48 (95% CI 1.12–1.95) comparing subjects with any e4 allele to those homozygous for e3. Finally, although there are few data on the e2 allele, a meta-analysis [41] reported significantly better cognition for those with an e2 allele.

Alzheimer's disease

The epidemiological data on apoE genotype and dementia are very consistent in identifying apoE e4 as an important risk factor. In 1993, a study in families with AD first implicated the e4 allele in late-onset AD [43]. In these families, the risk of AD increased steadily with increasing gene dose (up to a 4.5-fold higher risk in those homozygous for e4) and age at onset decreased steadily from a mean of 84 to 68 years with increasing gene dose. Since then, a large number of population-based epidemiological studies have confirmed this association, and apoE e4 is one of the best-established risk factors for AD. In a meta-analysis amongst Caucasians [44], the risk of AD was approximately three times higher for those with a single e4 allele (RR = 2.6, 95% CI 1.6–4.0 for e2/e4 and RR = 3.2, 95% CI 2.8–3.8 for e3/e4) compared to e3/e3; this relative risk rose to 14.9 (95% CI 10.8–20.6) in those homozygous for e4. In contrast, the e2 allele is associated with lower levels of cholesterol, and may decrease risk of AD. Although there are limited data (largely because the e2 allele is the least common and few studies have sufficient statistical power to provide informative data), a meta-analysis [44] reported that those with any e2 allele had a 40% lower risk of AD (RR = 0.6, 95% CI 0.5–0.8 for e2/e3 and RR =0.6, 95% CI 0.2–2.0 for e2/e3) relative to those with e3/e3.

Mechanism

The mechanism by which the apoE genotype affects risk of cognitive impairment and dementia is not clear. Certainly, the influence of the apoE genotype on cholesterol levels and the risk of CVD suggests one possible mechanism by which apoE may affect the development of cognitive impairment and dementia (see discussions of atherosclerosis and of cholesterol above). Additional mechanisms are also likely, as the impact of the apoE genotype seems much stronger than one would predict based on its effects on CVD and lipid levels. Indeed, direct mechanisms have also been proposed. For example, there is evidence that apoE may be involved in amyloid beta deposition; in mice which overexpress amyloid precursor protein, substantial amybid beta deposition is induced when apoE is present, but no deposition is noted when apoE is deficient. In addition, the apoE e4 allele appears to have less antioxidant properties than the e3 allele, and the e2 allele has the greatest antioxidant effects in cell culture [45].

Summary

The apoE genotype is one of the best-established risk factors for cognitive impairment and AD. The mechanism by which the apoE genotype influences risk is unclear, but understanding this action could be important to AD prevention and treatment.

Inflammation

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Extensive evidence has established that C-reactive protein (CRP), an inflammatory marker, is a strong predictor of cardiovascular risk. However, in epidemiological studies of cognitive function, such a relation has not been clear. In the largest study, amongst over 4000 women, there was no relation between levels of high sensitivity CRP and cognitive function measured an average of 5 years later [46]. On a global composite score averaging performance across five cognitive tests, measuring general cognition, verbal memory and verbal fluency, mean scores amongst women in the highest quintile of high sensitivity (hs)-CRP did not differ from those in the lowest quintile (multivariable-adjusted mean difference = 0.04, 95% CI −0.02 to 0.11, P across quintiles = 0.4). In a cross-sectional study of 599 subjects in the Leiden 85+ Study [47], there was no difference in MMSE score according to levels of two cytokines that reflect inflammation [tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10)] amongst subjects who had no CVD; however, amongst subjects with CVD, the mean MMSE score was significantly lower amongst those with a higher inflammatory state (mean difference = −1.3, 95% CI −1.7 to −1.0). Thus it is possible that inflammation may be important in certain subgroups.

Several large prospective studies of cognitive decline have found mixed results. For example, amongst 1284 participants of the Longitudinal Aging Study Amsterdam [48] there was no relation between CRP or IL-6 and decline on four cognitive tests. One inflammatory marker, alpha(1)-antichymotrypsin (ACT), was associated with borderline significant decline on the MMSE (RR = 1.60, 95% CI 1.05–2.43, comparing top versus bottom tertiles). Similarly, in the Health, Aging and Body Composition Study, IL-6, TNF-α and CRP were measured amongst 3031 older subjects [49]. There was little association between any of the inflammatory markers and decline on the modified MMSE (IL-6: RR =1.23, 95% CI 0.96–1.59; CRP: RR = 1.24, 95% CI 0.96–1.63; TNF-α: RR = 1.23, 95% CI 0.95–1.59, comparing top versus bottom tertiles). Only in one study was there a strong association between inflammation and cognitive decline; in the MacArthur Study of Successful Aging [50], those in the highest tertile of IL-6 had a twofold higher risk of cognitive decline than those in the lowest tertile (RR = 1.90, 95% CI 1.14–3.18). Overall, however, there is little consistent support for a strong relation between inflammatory markers and cognition.

Alzheimer's disease

Few studies have examined the relation of inflammatory markers to dementia. In the Rotterdam study, there was little to no relation between several inflammatory proteins and risk of AD [51]. For each standard deviation increase in ACT, CRP, IL-6, serum intracellular adhesion molecule-1 (sICAM-1) or serum vascular cell adhesion molecule-1 (sVCAM-1), the risk of AD ranged from a 13% decrease to a 35% increase (ACR: RR = 1.35, 95% CI 1.09–1.67; CRP: RR = 1.10, 95% CI 0.96–1.26; IL-6: RR = 1.30, 95% CI 1.06–1.61; sICAM-1: RR = 0.87, 95% CI 0.63–1.21; sVCAM-1: RR =1.02, 95% CI 0.75–1.38). In the only other prospective study, the Honolulu-Asia Aging Study measured hs-CRP at mid-life and followed subjects over 25 years [52]. Mid-life levels of CRP were associated with approximately a twofold increased risk of AD (RR = 2.3, 95% CI 1.0–5.4 for top versus bottom quartile; P across quartiles <0.01). Similar to the Leiden 85+ Study of cognition, the strongest results appeared to be for those with AD and CVD (RR = 4.2, 95% CI 1.1–16.4; P < 0.07), although confidence intervals were wide in these subgroup analyses.

Mechanisms

Inflammation may contribute to the development of dementia in many ways. Inflammation strongly affects risk of CVD. Additionally, microglial activation and acute phase reactants have been noted at typical sites of AD pathology [53], although this could be an effect rather than a cause of neurodegeneration. Inflammation appears to directly contribute to neuronal dysfunction and death, and mice which overexpress COX-2 (an enzyme which regulates inflammation) demonstrate increased neuronal susceptibility to toxic insult [54]. Moreover, in transgenic mice, inflammatory proteins induce amyloid beta accumulation and deposition [54]. Finally, in direct studies of memory, mice that overexpress IL-6 exhibit deficits in learning and memory tasks [54].

Summary

Inflammatory markers have been established as important predictors of CVD, and there is extensive biological evidence that inflammation may play a role in the development of AD pathology. Nonetheless, the epidemiological literature on inflammation and cognitive impairment or dementia is not very convincing.

Diet

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Although substantial evidence indicates that diet is a major risk factor for CVD, relatively little research has been conducted on diet and cognitive function or dementia. This review focuses on two dietary risk factors for CVD which have been best examined in neuroepidemiological studies: moderate alcohol intake and antioxidant vitamins.

Alcohol

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Many studies have consistently reported better cognitive function for those with moderate alcohol intake, compared to no alcohol intake. In the largest prospective study, amongst 12 480 older participants of the Nurses’ Health Study [55], there was a 20% lower risk of cognitive decline for those consuming <15 g of alcohol per day (about one drink) compared with nondrinkers (RR = 0.85, 95% CI 0.74–0.98). Women who had recently changed their alcohol intake (possibly because of changes in their health – i.e. ‘sick quitters’) were excluded in an attempt to minimize confounding by health factors or comorbid conditions. In addition, the decreased risk of cognitive decline appeared to be similar across all types of alcohol, including beer, wine and liquor. In the Women's Health Initiative Memory Study [56], amongst 4461 older women, there was a 31% lower risk of cognitive decline with less than one drink per day (RR = 0.69, 95% CI 0.49–0.97) and a 47% lower risk with one or more drinks per day (RR = 0.53, 95% CI 0.28–0.99), compared with no alcohol intake. Finally, in another large, prospective study [57], moderate alcohol intake at mid-life (up to 60 ounces of alcohol per month) was associated with a statistically significant 22–40% lower risk of poor cognitive function measured approximately 18 years later in 3556 Japanese-American men.

Alzheimer's disease

Few studies have examined the association of moderate alcohol consumption with AD, with just two prospective studies that included more than 100 cases of incident AD. In the largest investigation, a nested case–control study from the Cardiovascular Health Study, with up to 7 years of follow-up, 373 cases of incident dementia were identified [58]. Alcohol intake was averaged across reports at the baseline interview and the last interview prior to diagnosis; the reference group excluded any subjects whose alcohol intake had substantially decreased (to diminish a ‘sick quitter’ bias). Intake of up to 13 drinks per week was associated with a decrease in AD, compared with no alcohol intake (<1 drink: RR = 0.59, 95% CI 0.37–0.94; 1–6 drinks: RR = 0.43, 95% CI 0.25–0.72; 7–13 drinks: RR = 0.65, 95% CI 0.35–1.23). Although there were few cases with alcohol consumption of more than 13 drinks per week, this higher level of intake did not appear to be related to AD risk (RR = 0.95, 95% CI 0.46–1.96). Findings were less clear in the smaller Rotterdam Study, with an average 6 years of follow-up and 146 cases of incident AD [59]. For subjects with less than one drink per day, compared to none, there was no significant relation between alcohol intake and dementia (<1 drink per week: RR = 0.91 and for >1 drink per week but <1 drink per day: RR = 0.91); however, there was a suggestion of a decreased risk for those with 1–3 drinks per day (RR = 0.72, 95% CI 0.43–1.20) and a suggestion of an increased risk with more than three drinks per day (RR = 1.17, 95% CI 0.35–3.55), although the confidence interval was very wide for the latter estimate.

Mechanism

The most plausible mechanism by which moderate alcohol intake probably influences cognitive decline and dementia relates to the consistently lower rates of CVD amongst moderate alcohol drinkers in many studies. This risk reduction has been attributed partly to alcohol-induced elevations in HDL cholesterol and to the impact of alcohol on other biomarkers including reductions in fibrinogen and other thrombotic factors. Thus, perhaps moderate levels of alcohol also aid the preservation of brain vasculature, prevent small, subclinical strokes and could thus result in better cognitive function. In support of this concept, Mukamal et al. [60]. found that moderate alcohol was associated with fewer white matter abnormalities and infarcts on MRI amongst older individuals without prior cerebrovascular disease. More directly, some data suggest that moderate alcohol intake might favourably alter release of acetylcholine in the brain (the acetylcholine neurotransmitter system regulates learning and memory) [59].

Summary

Strong and consistent evidence indicates that moderate alcohol intake might reduce the risk of cognitive impairment and AD, although higher levels have an adverse effect on brain function. The potential neuroprotection of moderate alcohol most probably is the result of numerous vascular benefits associated with alcohol intake.

Antioxidant vitamins

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Cognitive function

Several large randomized clinical trials have tested whether antioxidant vitamin supplementation protects against cognitive impairment. In a trial of 20 536 adults, aged 40–80, randomized to a combination of vitamins E (600 mg), C (250 mg) and beta-carotene (20 mg) or placebo for 5 years [61], no cognitive benefits were observed on a single cognitive test administered at the close of the trial. In a trial amongst older subjects with mild cognitive impairment followed over 3 years, there was no relation between high-dose vitamin E (2000 IU) and cognition [62]. In a third trial of 2166 older adults in a study of eye disease prevention, followed for an average 6.9 years [63], there were no significant differences in cognitive performance between those assigned to a combination of vitamins E (400 mg), C (500 mg) and beta-carotene (15 mg) and those assigned to placebo; nonetheless, scores were higher on all eight cognitive tests for the treatment than the placebo group. Moreover, as participation in the cognitive testing in this trial was low (60%), the ability to detect effects may have been reduced by a limited range of cognitive function amongst participants, who were significantly younger and more educated than nonparticipants. Finally, in the Physicians' Health Study II [64], men assigned to beta-carotene supplementation for an average 18 years had significantly better cognition than those assigned to placebo.

Together, these trials suggest that very long-term vitamin supplementation might be required to achieve neuroprotection. Indeed, in two observational investigations, duration of antioxidant vitamin use was specifically examined; results support the hypothesis that long-term supplementation may be necessary. The Nurses’ Health Study [65] reported that 10 or more years of vitamin E supplementation was associated with significantly better cognitive function, whilst short-term use was not related to cognition. Similarly, in the Honolulu-Asia Aging study [66], inverse associations between vitamin E and C supplements and cognitive impairment were evident only amongst long-term users (10+ years).

Alzheimer's disease

Unlike for cognitive function, no randomized trials of primary prevention of AD via antioxidant vitamins have been conducted. In observational studies, data regarding vitamin supplementation are mixed. For example, in the Cache County study, with 104 incident cases of AD [67], there was an apparent decrease in AD risk with use of vitamin E supplementation in combination with vitamin C supplements (RR = 0.36, 95% CI 0.09–0.99); however, this estimate was based on just three exposed cases, and the confidence interval was very wide. In contrast, the WHICAP study included 242 incident cases of AD [68] and found no relation between use of vitamin E supplements and AD (RR = 0.91, 95% CI 0.68–1.22), but the duration of follow-up was short.

Some studies have suggested that dietary vitamin E may be important for neuroprotection. In the Rotterdam Study [69], there was an 18% decrease in AD risk with each standard deviation increase in vitamin E intake (RR = 0.82, 95% CI 0.66–1.00); the results were not changed after supplement users were excluded. In the CHAP study [70], there was an apparent 70% lower AD risk for those in the highest versus lowest quintile of dietary vitamin E (RR = 0.30, 95% CI 0.10–0.92), but little relation when both food and supplement intake were combined (RR = 0.81, 95% CI 0.37–1.81). In further analyses in CHAP [71], with additional follow-up, there was a significant inverse relation between dietary vitamin E intake and AD (RR = 0.74, 95% CI 0.62–0.88 for each 5 mg day−1 increase in vitamin E). In addition, strong relations were found not just for α-tocopherol (the form traditionally found in supplements) but also for γ-tocopherol (which is commonly ingested only in foods), with a 40% lower risk of AD with each 5 mg day−1 increase in intake (95% CI 0.41–0.88). Nonetheless, the WHICAP study reported no relation between dietary vitamin E and AD risk (RR = 0.98, 95% CI 0.67–1.44), although intake was low in this urban population [68]. Finally, no relation was found between mid-life intake of vitamin E and risk of AD at older ages in the Honolulu study (RR = 1.58, 95% CI 0.87–2.85 for top versus bottom quartile of vitamin E), although intake was based on a single 24-h recall of diet, which may be subject to random misclassification and bias to the null [72].

Mechanism

In addition to potential vascular benefits provided by antioxidant vitamins, brain tissue readily undergoes oxidative damage, and long-term oxidative stress is probably a contributing factor to declines in cognition observed with ageing [73]. Neurones are particularly susceptible to cumulative oxidative damage as they are nondividing cells and survive for decades. In animal models, antioxidant supplementation appears to improve memory performance [74, 75]. Thus, it is plausible that antioxidant vitamins could protect against cognitive decline and dementia.

Summary

Epidemiological data regarding the potential impact of antioxidant vitamins on cognitive decline and dementia are mixed. Clear evidence from several randomized clinical trials establishes that short-term use (<10 years) of vitamin supplements does not protect against cognitive impairment, but very long-term use (15+ years) could be neuroprotective. Similarly, there is no consistent evidence that antioxidant supplements decrease the risk of AD, but no studies have specifically addressed long-term use of supplements.

Conclusions

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References

Consistent epidemiological data indicate that CVD increases the risk of cognitive decline and AD. Interestingly, many, but not all, cardiovascular risk factors are also associated with an elevated risk of brain ageing – although insufficient data are available to make firm conclusions regarding several of the major CVD risk factors. Moreover, a mechanism explaining the relation of CVD to cognitive decline and AD has not been established, and many CVD risk factors could plausibly be related to cognition independent of their impact on vascular disease. The effect of CVD and its risk factors on dementia remains an active area of investigation and further research will help establish whether vascular factors have a clear impact. A fuller understanding of any vascular aetiology in cognitive decline and AD could have an important role in developing effective preventive strategies.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Cardiovascular disease
  5. Hypertension
  6. High cholesterol
  7. Type 2 diabetes
  8. Apolipoprotein E genotype
  9. Inflammation
  10. Diet
  11. Alcohol
  12. Antioxidant vitamins
  13. Conclusions
  14. Conflict of interest statement
  15. References
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