Cardiovascular disease and dementia risk: an ever growing problem in an aging population

KEYWORDS:

• Vascular disease
• dementia
• hypertension
• aging
• diabetes
• pulse wave velocity

The very high incidence of dementia, especially in very old age groups is well documented [1]. Most dementia in older individuals age 80+ is due to a combination of Alzheimer’s disease (AD), neurodegeneration, and vascular pathology [2]. In 2005, we reported that 44% of the incident dementia cases in older individuals age 65+ had vascular disease, either as the sole cause of dementia or as a contributory factor, usually also with AD [3]. Pathology studies demonstrated a linear increase in small vessel disease in the brain with increasing age [4].

In December 2013, the Alzheimer’s Association and the National Institutes of Health evaluated the scientific evidence for the relationship of brain vascular disease to AD and dementia [5]. The conference concluded (1) that there was less AD pathology in demented individuals who also had cerebral vascular disease, (2) that decreased cerebral blood flow (CBF) may be a determinant of amyloid deposition and may contribute to the development of amyloid plaques, and (3) that there may be unique genetic markers for vascular and mixed types of dementia.

High blood pressure (BP) is the most important risk factor for microvascular disease in the brain, including endothelial dysfunction, microhemorrhages, and small brain infarcts [6], as well as diabetes and cigarette smoking. Vascular markers of atherosclerosis increase the risk of dementia, including greater carotid intimal medial thickness, lower ankle-brachial index, coronary artery disease, and calcifications in the internal carotid arteries and Circle of Willis [7]. Subclinical markers of vascular disease are associated with AD pathology. Vascular stiffness is a risk factor for both the extent of amyloid deposition and progression of amyloid deposition in the brain based on PET imaging, at least over the short term [8]. The extent of vascular disease in the brain is positively linked to neurodegeneration and amyloid deposition [9]. Ischemic injury in the brain may result in an inflammatory response and increased synthesis of amyloid precursor protein and beta amyloid (Aβ). Amyloid deposition and inflammation may result in increased intracellular hyperphosphorylated tau and neurodegeneration [10].

The brain has a very high energy requirement, 20% of the cardiac output and oxygen consumption and 25% of glucose utilization [11]. CBF is reduced in AD patients. Congestive heart failure (CHF) is very prevalent among older individuals, especially after myocardial infarction (MI) and with extent of coronary artery disease [12]. CHF risk factors include age, hypertension, vascular stiffness, and diabetes. CHF patients have decreased CBF and increased risk of dementia. Recent studies have noted abnormalities of protein folding in the heart and brain [13]. There is an increased prevalence of amyloid deposition in the heart (transthyretin protein) in patients with CHF and preserved ejection fraction [14].

Vascular disease in the brain may also alter the blood brain barrier (BBB) function allowing transport of substances, such as drugs and environmental toxins, into the brain. Vascular disease may also adversely affect the perivascular clearance of amyloid from the brain to periphery.

The BBB separates the brain from peripheral lipoprotein metabolism. The association of apolipoprotein E (ApoE) and several other genetic variants of apolipoproteins is risk factors for dementia and suggests an important role of cholesterol metabolism in AD pathology. The brain is the most cholesterol rich organ in the body, about 25% of the total body cholesterol, 70% of which is in myelin. Brain cholesterol is synthesized de novo in the brain. Oxysterols metabolized in the CNS, especially 24-hydroxycholesterol, can cross the BBB and transport of cholesterol out of brain and is a marker for brain cholesterol metabolism. ApoE4 plays a major role in the transport of both cholesterol and amyloid in the brain. Other apolipoproteins, especially ApoJ, are also important in both amyloid and cholesterol metabolism and transport in the brain. Animal and some human studies have suggested that increased brain cholesterol synthesis or levels are associated with greater amyloid deposition [15].

Prevention of vascular disease in the brain may be an effective approach to prevent AD pathology and dementia. However, there have been few clinical trials that have demonstrated efficacy of lowering BP, cholesterol, or treating diabetes to reduce the risk of dementia. Multifactorial community behavioral and drug interventions, especially exercise, have shown a modest effect on improving cognitive function [16].

Anti-amyloid drugs may have a beneficial effect on reducing the risk of dementia. These drugs are currently being evaluated. However, they may be more effective in younger individuals, especially with specific genetic disorders associated with increased production of amyloid, rather than in older ages where decreasing clearance of amyloid may be the primarily problem [17]. There is increasing emphasis on evaluating these drugs in younger and asymptomatic individuals. The hope is that these drugs will be similar to lipid lowering drugs, such as statins, in reducing the amount of amyloid in the brain and subsequently the amount of neurodegeneration and risk of dementia. Potentially better anti-inflammatory drugs and antioxidants that are currently being tested, for example, cocoa flavonoids, omega-3 fatty acids, could also modulate the ischemic brain injury and reduce incidence of dementia. To date, however, such drugs have had limited success, at least for prevention of CVD.

1. The basis of the vascular hypothesis

We hypothesize that among older individuals 80+ who account for most of the prevalent dementia in the population that the extent of vascular disease and subsequent interrelated physiopathological mechanisms in the brain are the primary determinant of amyloid deposition, tau, and neurodegeneration leading to dementia.

Although we still do not know the sequence of events that lead to AD, we describe a constellation of possible interrelated pathological processes that lead to AD pathology and dementia. First, a possible model for vascular disease and risk of dementia begins with elevated BP and possibly diabetes, advanced glycation end products (AGEs), and cigarette smoking, which cause vascular stiffness leading to cerebrovascular disease [6]. Second, brain inflammation increases in response to the vascular injury. Third, increased cholesterol production in the brain in response to inflammation leads to increased synthesis of Aβ. Fourth, decreased clearance of Aβ from brain to periphery; vascular stiffness may reduce perivascular excretion of Aβ possibly by modifying the cerebral arterial pulsatility. Fifth, there is reduced degradation of Aβ by neprilysin or insulin degradation enzyme, possibly secondary to insulin resistance, hyperglycemia, metabolic syndrome, etc. [18,19]. Sixth, there is increased amount of Aβ return to the brain via the receptor for AGE (RAGE). Increased RAGE will also suppress lipoprotein-related receptor, the major source of removing Aβ from the brain. Seventh, decreased excretion of Aβ among individuals who are ApoE4 positive. ApoJ and other apolipoprotein markers may contribute to the decreased extracellular clearance of Aβ. Eighth, increase in Aβ is toxic to neurons resulting in increased intracellular hyperphosphorylation of tau with loss of neurons and synapses and neurodegeneration. Ninth, the adverse effects of increased BP, diabetes, cigarette smoking, hyperlipidemia leads to large vessel atherosclerosis as well as MI, necrosis, and fibrosis with increasing risk of CHF, atrial fibrillation, and stroke, decreased cardiac output and perfusion in the brain, and decreased CBF which leads to further increase in Aβ production and decreased clearance to the periphery, renal disease, and reduced clearance of Aβ [20].

Better education and higher IQ, physical and cognitive activities, and fitness increase brain cognitive reserve and slow cognitive decline in the presence of the above pathology. The individuals with higher brain reserve remain above the threshold for the diagnosis of mild cognitive impairment or dementia at similar levels of pathology as compared to individuals with less cognitive reserve. Therefore, these individuals will develop dementia associated with more severe brain pathology, for example, amyloid deposition and tau [1]. Decreased levels of brain-derived neurotrophic factor (BDNF) have been associated with both dementia and depression. Higher levels of brain natriuretic peptide may protect against cardiac dysfunction after MI. Higher levels of glucose in the brain may reduce synthesis of BDNF. Blood levels are inversely related to blood glucose levels. Exercise is associated with increased BDNF. Increased exercise or reduction of blood, brain glucose, for example diabetes, might also decrease risk of dementia [21].

The model suggests first that prevention of increasing vascular stiffness and declining fitness beginning at early ages is the first approach, then reducing cardiopulmonary disease in middle to older ages by prevention of insulin resistance, diabetes mellitus, and cigarette smoking, and aggressive treatment of hypertension and hyperlipidemia, especially with statins that can cross the BBB, could result in decrease in brain vascular disease, reduced amyloid deposition and plaques, phosphorylated tau, and neurodegeneration. Third, at older ages, more aggressive risk factor reductions for brain vascular disease as well as identification and treatment of AF, prevention of decreased cardiac output, and CBF secondary to CHF, may slow the progression of vascular disease and associated brain pathology and prevention or delay of onset of dementia. Host susceptibility, that is, genetic attributes, will continue to identify individuals at higher or lower risk of dementia given the above cascade of risk factors and pathology [22].

2. Testing the hypothesis

A key question, therefore, is how to evaluate this hypothesis. One approach is to conduct aggressive prevention trials of cardiovascular risk factors. The goal would be to prevent the increased vascular stiffness with age, loss of fitness, myocardial damage, brain microvascular disease, and brain atherosclerosis, which could lead to decreased dementia in older individuals.

Trials would have to begin at younger age groups perhaps under the age of 65 with the preliminary outcomes being the development of amyloid, vascular changes in the brain, neurodegeneration, and changes in cognition [23]. They need a large sample size, be long (both intermediate and long-term outcomes), and will be very expensive. Smaller, low-cost pragmatic trials are unlikely to provide definitive answers and may result in misinterpretation of the results.

The basic problem is that interventions based on lowering BP, cholesterol, diabetes, stopping smoking, and increasing physical activity have already demonstrated benefits for cardiovascular effects and untreated control groups would be unethical. Thus, such trials would have to compare very aggressive interventions with usual care and therefore will require intensive efforts in the intervention group to maximize the difference between the intervention and usual care.

Another approach is to identify unique populations, ‘natural experiments’ to test vascular hypotheses. For example, the prevalence of homozygous ApoE4 varies dramatically among populations, especially in Africa where the prevalence of ApoE4 is very high. Therefore, there may be opportunities to determine in such populations whether exposure to low levels of cardiovascular risks results in much less amyloid deposition, neurodegeneration, and dementia among older individuals [24]. Similarly, there are populations in which BP remains low throughout life and have less increase in vascular stiffness with aging. Is brain vascular disease in such populations reduced in the elderly as well as amyloid deposition, neurodegeneration, and dementia [25]?

There are also large populations in which extent of atherosclerosis is very low. The amount of amyloid deposition and neurodegeneration may be reduced compared to populations with a high prevalence of atherosclerosis. Populations of older physically active individuals who have less reduction of fitness with age may also be an interesting target for evaluation of brain vascular disease and dementia as well as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a monogenic variant of small vessel disease due to mutations in notch 3 [26].

3. The bottom line

Reduced vascular stiffness, higher fitness, low amounts of arteriosclerosis and atherosclerosis could result in much less dementia in older individuals. The alternative hypothesis is that dementia in the elderly is ‘untreatable cognitive aging’ or that increased amyloid and tau and neurodegeneration in the elderly is not caused by vascular disease.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.