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The link between cardiovascular disease and dementia

Key learning points

 - The prevalence and types of dementia - those influenced by cardiovascular disease (CVD) risk factors

- An explanation of CVD causes and risk factors 

- How the risk factors for CVD influence the pathophysiology of dementia 

Dementia is an increasing concern as the ageing population grows worldwide. An estimated 45 million or more elderly people suffer from dementia of some type. Alzheimer's disease (AD) and vascular dementia (VaD) are the most common causes of dementia. Older age is the strongest risk factor for the development of dementia, whether it results from vascular or neurodegenerative disease, or mixed vascular and neurodegenerative changes. Over the last decade, however, several epidemiological and clinicopathological studies have established that cardiovascular disorders are associated with higher risk of dementia. These include hypertension, diabetes mellitus, atherosclerosis, hypercholesterolemia, obesity and metabolic syndrome, smoking and certain forms of coronary disease (see Table 1). 
In addition, any vascular disease that promotes transient ischemic attacks and stroke episodes, as indicators of large or small vessel disease, will increase incidence of dementia, particularly VaD but there is even evidence for AD.1 In fact, silent brain infarcts detected on magnetic resonance (MR) imaging where there is no obvious neurological deficit doubles the risk of dementia and AD. Several gene variants or polymorphisms may modify vascular pathophysiology and as result be a factor in increasing risk. The product of the apolipoprotein E (ApoE; 
APOE) gene involved in the regulation of cholesterol transport is strongly implicated as a vascular risk factor in influencing the progression of AD. 
The foremost vascular disease factor consistently linked to dementia is hypertension. Most studies demonstrate that hypertension (systolic blood pressure >140 mm Hg) in mid-life predisposes to cognitive decline and AD type of dementia in late life.2 While some studies have found no clear correlation, a recent positron emission tomography (PET) scanning study showed that hypertension is associated with a greater burden of amyloid β accumulation, a marker for AD, and is potentiated in the presence of the apolipoprotein E ε4 allele.3 Long-standing increases in blood pressure may also increase risk of dementia by inducing small vessel disease, white matter changes and cerebral hypoperfusion through the disruption of vasoregulatory functions or atherosclerotic disease.1 On the other hand, antihypertensive therapies have shown to have protective effect to decrease the incidence of cognitive decline and dementia and reduce AD pathology.4 
The majority of cross-sectional and longitudinal epidemiological studies suggest cognitive impairment and dementia are increased in patients with diabetes, particularly in non-insulin dependent or type 2 diabetes. The risk of diabetes increases with age, with the prevalence of treated type 2 diabetes peaking at about 15% in 60-80 year olds. Moreover, impaired glucose tolerance and hyperglycaemia (>125 mg/dL) are likely at higher prevalence in the ageing population prior to frank diagnosis of diabetes. Hyperinsulinaemia may be manifested as the pre-clinical syndrome for many years and is a causal factor in most adult onset type II DM.
The risk for Alzheimer type of dementia and particularly VaD is reported to be 2-2.5 fold greater among type 2 diabetics, irrespective of age at which diabetes occurs. The increased risk of dementia in diabetes is largely attributed to cerebrovascular disease5 and the association of AD with DM is less clear and only evident in milder cases. Current understanding shows that DM causes ischaemic cerebrovascular disease, primarily lacunar infarcts, microinfarcts and is positively associated with AD pathology through hyperinsulinemia (causing increased secretion but reduced extracellular degradation of amyloid β), impaired insulin signalling, oxidative stress, inflammatory mechanisms and increased coupling of neuronal components by advanced glycation end products.6 
Remarkably, diabetic subjects with dementia have nearly the double the number of small stroke lesions and increased markers of inflammation such as interleukin 6 indicating a role for a proinflammatory response. Neuroimaging evidence suggests that there is also an association between diabetes and cerebral atrophy and lacunar infarcts.7 It is not unlikely that interactions between vascular and neurodegenerative changes lower the burdens of combined pathologies to accelerate the threshold for clinical dementia. Interestingly, those who were treated with anti-diabetic medication displayed greater microvascular injury yet tended to have less neuritic plaque burden (another marker of AD) compared to untreated diabetic patients.8 
A previous pathological study had demonstrated that demented diabetics, who had a combination of insulin and oral hypoglycaemic agents, exhibited significantly lower neuritic plaque pathology compared to diabetics who were not on any treatment or the non-diabetics.7 From these studies, it is reasonable to conclude that antidiabetic medication reduces Alzheimer pathology but unmasks brain microvascular changes. Lower plaque burden in the treated group could be accounted for by an increased clearance facilitated by diminished integrity of the microvasculature. 
Dietary and lifestyle factors
Individuals with high body mass index (>25) have a significantly greater risk of dementia whereas those who were obese at mid-life have a three-fold increased risk of dementia (AD or VaD) in old age.9 Hypercholesterolemia in mid-life also tends to show positive association with dementia including AD and VaD10 although cholesterol levels assessed in late life reveal less significant association with AD. Statins have a broad range of properties including antioxidant activity, immunomodulation and regulation of inflammatory processes, all of which could prevent neuronal death and generally exhibit beneficial effects. 
Simvastatin has been found to reduce the levels of amyloid β peptides (Aβ42 and Aβ40), but the results of clinical studies do not consistently show robust protective effects of statins in preventing AD.11 
Smoking predisposes to oxidative stress, atherosclerosis, plaque formation and silent brain infarctions. The association between mid-life smoking and late-life dementia, following adjustment for age, education and APOE genotype, showed the risk of AD in smokers increases with pack-years of smoking. Neuropathological findings in a sub-sample showed increased number of neuritic plaques with higher smoking levels. Furthermore, heavy smoking in mid-life is associated with >100% increased risk of AD and VaD after over twenty years.12 In this context, antioxidants are considered to have protective value in general but large-scale studies are lacking. However, based on 15 longitudinal studies of two to eight years with more than 14,000 participants it noteworthy moderate alcohol users have reduced risk of 26-28% compared to “non-drinkers.” At least two studies focused on red wine, but most examined general alcohol intake and thresholds of modest drinking varied between the individual studies.13
Atherosclerosis predisposes to small and large infarcts and cerebral hypoperfusion leading to vascular and degenerative changes associated with cognitive decline and both AD and VaD.14 Other complications relating to atherosclerosis include coronary heart disease and congestive heart failure. The Rotterdam study revealed that atherosclerosis, predominantly of the carotid arteries, was associated with an increased risk of dementia, both AD and VaD.15 It reasons that then that the association between coronary disease and dementia, and AD is through the causation of multiple cerebral emboli and reduced cerebral perfusion.1 Homocysteine is an established risk factor for cardiovascular disease but its role in the aetiology of dementia is not clear. However, high homocysteine concentrations in mid-life is an independent risk factor for the development of late-life AD in women.16 
Irrespective, it is widely accepted that folate substitution in the diet of the elderly may not necessarily be harmful. Although these epidemiological studies do not explain how pre-existing or co-morbid vascular disease precisely impacts on processes that lead to neurodegeneration characteristic of AD, they collectively demonstrate that there is a clear link between vascular disease and an increased burden of AD. Thus a number of vascular disease risk factors indicate greater or cumulative risk of AD primarily via a vascular effect rather than distinctive neuronal degeneration. On the other hand, physical activity can reduce potential risk by 18-45% based on several prospective studies focusing on AD and dementia with >150,000 subjects. 
Irrespective of the type of dementia, it is also clear that interventions, which reduce risk of or control cardiovascular disease would be beneficial to reduce the risk of developing dementia. Careful monitoring and treatment of modifiable vascular risk factors is of benefit in preventing dementia. Lifestyle measures that maintain or improve vascular health including consumption of healthy diets with fibre and antioxidants, moderate use of alcohol and implementing regular physical exercise in general appear effective for reducing dementia risk. These measures will improve vascular function to sustain brain perfusion in the long-term. 
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