European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
New cardiovascular targets to prevent late onset Alzheimer disease Jurgen A.H.R. Claassen Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center and Department of Geriatric Medicine, 925 Geriatric Medicine, PO Box 9101, 6500 HB Nijmegen, The Netherlands
art ic l e i nf o
a b s t r a c t
Article history: Received 6 April 2015 Received in revised form 21 April 2015 Accepted 1 May 2015
The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective diseasemodifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care. & 2015 Published by Elsevier B.V.
Keywords: Cognitive impairment Dementia Cerebral blood flow Cardiovascular disease
1. Introduction An estimated 5% of the general population aged 65 to 70 years has dementia. This number increases to 20% above the age of 80 and reaches a plateau over age 90. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review will discuss recent relevant human studies that have investigated the link between cardiovascular disease and Alzheimer. The wide range of animal studies on this topic will not be included here, because translational evidence is not yet available for most of the investigated mechanisms and translational failure is unfortunately very common in the field of Alzheimer disease. E-mail address: [email protected]
It is important to note that cardiovascular disease may cause cognitive impairment in the absence of Alzheimer disease, through direct vascular neuronal injury, for example in cortical stroke, lacunar infarction, small vessel disease, microbleeds and intracranial hemorrhage (Wiesmann et al., 2013). These causes of dementia are classified as vascular dementia, that represents up to 20% of all dementia. Cardiovascular disease may also cause cerebrovascular disease that contributes to the cognitive disorder in a patient with Alzheimer disease (or any other neurodegenerative disease); these cases are covered in the classification of vascular cognitive impairment (VCI), a term that encompasses all patients in whom cerebrovascular lesions significantly contribute to their cognitive decline (Wiesmann et al., 2013). It is obvious that prevention of cardiovascular disease will impact the prevalence of vascular cognitive impairment and vascular dementia, and these topics will therefore not be covered in this review. In addition, diabetes may also directly, or through cerebrovascular disease, lead to cognitive decline and dementia other than Alzheimer disease (Rawlings et al., 2014). This is also beyond the scope of this review, which will focus on the most common cause of dementia: late onset Alzheimer disease. When reading this review, it must be kept in mind that control of cardiovascular disease and diabetes will have a broader beneficial effect on the prevalence of dementia
http://dx.doi.org/10.1016/j.ejphar.2015.05.022 0014-2999/& 2015 Published by Elsevier B.V.
Please cite this article as: Claassen, J.A.H.R., New cardiovascular targets to prevent late onset Alzheimer disease. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.05.022i
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that reaches beyond its impact on Alzheimer disease.
2. Alzheimer disease A clear definition of Alzheimer disease is an essential starting point for this review of potential cardiovascular targets to prevent this condition. 2.1. Late onset Alzheimer disease versus familial (genetic) early-onset Alzheimer disease 2.1.1. Alzheimer disease and Alzheimer dementia Alzheimer disease is a progressive neurodegenerative disease that starts with an asymptomatic phase (preclinical Alzheimer disease), where neuronal loss does not lead to symptoms because of compensation. This phase may last 5–15 years based on recent studies, but gradually advances to a phase with mild cognitive and behavioral impairments but maintained ability to function independently. With further loss of cognitive function due to progression of Alzheimer disease, independent functioning becomes impaired, and this phase is defined as dementia. Presently, dementia is divided into three stages (mild, moderate and severe). In mild dementia, patients can live outside institutional care with support from professional and family caregivers. Some patients for example maintain the ability to cook, shop, and even to drive a car. In severe dementia, 24 h care is needed as patients require assistance in almost all basic functions (getting dressed, eating, washing) and there is loss of urinary and often fecal continence. 2.1.2. Prevention of Alzheimer disease versus prevention of Alzheimer dementia The distinction between Alzheimer disease and dementia due to Alzheimer disease (where dementia essentially describes a stage of advanced Alzheimer disease) clarifies that efforts towards prevention can have two goals. The first goal is prevention of the disease, i.e. prevention of the neurodegenerative disorder, which is the most idealistic but also least feasible goal, as we will see later. The second goal is prevention of progression of the disease from asymptomatic or mild symptomatic to dementia. With this second goal, the neurodegenerative disease per se is not prevented, but progression is slowed down or the impact of neurodegeneration on cognitive function is reduced, for example due to prevention of (cerebrovascular) co-morbidity. Although the second goal may seem less powerful, on a societal level, postponing the age of onset of dementia leads to substantial reductions in disease burden (Sloane et al., 2002). This review will address both goals for prevention. 2.1.3. Late onset Alzheimer disease When we consider efforts to prevent Alzheimer disease or dementia due to Alzheimer disease it is important to distinguish late onset Alzheimer disease from the familial (genetic) early onset form of this disease. Both are characterized by progressive accumulation of the protein amyloid-beta42 in oligomers and in large aggregates known as plaques, with early involvement of brain areas involved in memory. Genetic Alzheimer disease is a rare (o5% of all cases), autosomal dominant disease caused by mutations in a single gene in each family. Several genes have been identified thus far. These mutations occur in genes that are involved in the processing of amyloid-beta42 and lead to overproduction of this protein (Tanzi, 2013; Tanzi et al., 1996). The age of onset of dementia is o60 years, and mutations lead to development of disease in nearly 100% of those affected. Much of Alzheimer research is based on models based on familial disease, with animal models based on the known mutations.
In contrast, the common (495%) late onset Alzheimer disease, also described as sporadic Alzheimer disease, is not linked with single dominant genetic changes, but is thought to result from several factors (genetic and environmental) that lead to an imbalance in production and clearance of amyloid-beta42. Although several genetic variants have been associated with late onset Alzheimer disease, these explain less than 50% of this disease. Compared with the familial form, late onset Alzheimer disease has a much larger variation in age of onset and rate of disease progression.
3. Cardiovascular factors and late onset Alzheimer disease 3.1. Epidemiological evidence Even though Alois Alzheimer reported atherosclerosis in cerebral blood vessels in the post-mortem examination of his 55 year old index patient with Alzheimer disease (Alzheimer et al., 1995), Alzheimer disease and vascular disease have historically been considered separate entities. This distinction was enforced by clinical criteria for the diagnosis of dementia due to Alzheimer disease. For familial Alzheimer disease, this separation seemed valid, because its dominant genetic cause and young age of onset left little room for contributions of vascular disease. However, epidemiological studies of late onset Alzheimer disease identified hypertension, diabetes mellitus, atherosclerosis, atrial fibrillation, coronary artery disease, smoking, obesity, and the metabolic syndrome as risk factors for dementia due to Alzheimer disease (Biessels et al., 2006; Kalaria et al., 2012; Kalaria and Ihara, 2013). Many studies have shown the association between increased blood pressure in mid-life and cognitive decline or Alzheimer dementia in later life (Kivipelto et al., 2001; Skoog et al., 1996). Among all vascular risk factors, hypertension seems to be the most powerful risk factor for Alzheimer dementia (Kennelly et al., 2009). Although these associations do not prove causality between cardiovascular disease and Alzheimer disease, these studies have challenged the historical distinction between these two conditions. The epidemiological studies have in most cases relied on clinical diagnoses of dementia due to Alzheimer disease. They therefore risk misclassification (e.g. misclassification of vascular dementia as Alzheimer dementia in studies where neuroimaging was not available) and, in addition, they provide no information on the relationship between vascular disease and earlier stages of Alzheimer disease, i.e. the preclinical or mild cognitive impairment stage. Recent advances however have made it possible to study these early stages of disease. 3.2. Vascular disease and amyloid-beta42 accumulation Whereas earlier studies had to rely on post-mortem examination of the brain to demonstrate amyloid plaques to confirm Alzheimer disease, it is now possible to reveal accumulation of amyloid-beta42 in vivo. Using nuclear imaging with a radioactively labeled ligand that binds to amyloid-beta42, uptake of tracer, reflecting deposits of amyloid-beta42, can be quantified, a technique described as amyloid imaging. In asymptomatic elderly, amyloid imaging indicates abnormally high levels of amyloid-beta42 in an estimated 30% in age 65–69, increasing to 55% at age4 80–84 (Jack et al., 2014). The current hypothesis is that these so-called amyloid-positive but asymptomatic elderly represent preclinical Alzheimer disease. Longitudinal studies are underway to test this hypothesis, but preliminary data suggest that these amyloid-positive elderly show a decline in cognitive function on follow-up compared to amyloid-negative controls (Wirth et al., 2013). The
Please cite this article as: Claassen, J.A.H.R., New cardiovascular targets to prevent late onset Alzheimer disease. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.05.022i
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following vascular factors have been investigated regarding their potential relationship with amyloid accumulation. 3.2.1. Hypertension and amyloid accumulation A recent study investigated factors related to abnormally high amyloid uptake (indicating amyloid accumulation) in asymptomatic (no dementia) elderly. Elderly subjects with unmedicated hypertension had significantly higher amyloid accumulation than those with normal blood pressure (normotensive or medicated hypertension), however, this association was only seen in subjects with a genetic risk factor for late onset Alzheimer disease: ApoEε4 (Rodrigue et al., 2013) Homozygous carriers of the ApoE-ε4 gene (14% of the population) have a 15 fold increased risk to develop Alzheimer disease by age 75 (compared to ApoE-ε3 carriers, 78% of the population). ApoE-ε4 is involved in cholesterol metabolism and, in the brain, for cholesterol transportation to astroglial cells. How ApoE-ε4 leads to increased Alzheimer risk remains unknown. This study suggests an important interaction between hypertension, ApoEε4, and amyloid-beta42. Untreated hypertension increases amyloid-beta42 levels in the brains of ApoE-ε4 carriers, whereas this effect was not observed in controlled hypertension. It is important to note that approximately 30% of ApoE-ε4 carriers will never develop Alzheimer dementia. Whether this is explained by for example absence or adequate control of hypertension remains speculative but highly plausible. 3.2.2. Vascular stiffness and amyloid accumulation Independent of hypertension or ApoE status, cognitively healthy elderly with greater vascular stiffness had a higher rate of amyloid accumulation (Hughes et al., 2014) on follow-up. Vascular stiffness is associated with aging and atherosclerosis, and leads to elevated pulse pressure and end-organ damage, for example in kidney and brain. How vascular stiffness may promote amyloid accumulation remains unknown. However, cardiovascular interventions that may slow down or prevent the development of vascular stiffness are available (treatment of atherosclerosis, hypertension, exercise) and could reduce amyloid accumulation in later life. 3.2.3. Diabetes and amyloid accumulation Two longitudinal studies found no relationship between diabetes and brain amyloid accumulation. The first study combined post-mortem pathology in one cohort with in vivo amyloid imaging in another. Both cohorts had longitudinal (4 20 years) assessments of glucose homeostasis using repeated oral glucose tolerance tests. There was no relationship between glucose levels, insulin levels, or insulin resistance, and amyloid pathology or amyloid imaging (Thambisetty et al., 2013). The second study compared amyloid imaging in a cognitively normal population with and without diabetes. Amyloid accumulation was similar in diabetic versus non-diabetic participants (Roberts et al., 2014). These studies suggest that the negative effect of diabetes on cognitive function may not be mediated by Alzheimer disease. As indicated in the introduction however, this does not implicate that treatment of diabetes will have no effect on late-life cognitive decline, as diabetes may have a direct effect on the brain (Rawlings et al., 2014). 3.3. Cerebral perfusion and Alzheimer disease Normal brain function critically depends on adequate cerebral perfusion (Claassen and Zhang, 2011; van Beek et al., 2008). The brain (2% of body weight) receives 15–20% of cardiac output under resting conditions, and a strong regional flow increase during cognitive activation (neurovascular coupling). Adequate control of
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cerebral blood flow (cerebral autoregulation) is therefore a prerequisite for normal cognitive function. In patients with sporadic Alzheimer dementia without significant cerebrovascular disease (no or limited white matter disease and absence of lacunar or cortical infarction), there was evidence of reduced cerebrovascular reactivity to carbon dioxide (den Abeelen et al., 2014), and mildly impaired cerebral autoregulation (Claassen et al., 2009a, 2009b; den Abeelen et al., 2014). Patients in these studies had cardiovascular risk factors (hypertension, hyperlipidemia), and we speculate that these factors are associated with the impairment in cerebrovascular function and could thus contribute to the development of Alzheimer disease.
4. Conclusion Two markers of cardiovascular disease, hypertension and vascular stiffness, have been linked to a core feature of Alzheimer disease, i.e. accumulation of amyloid-beta42. Based on these observations, the hypothesis has been put forward that cardiovascular treatment, trough reduction of atherosclerosis, hypertension and vascular stiffness, may prevent, reduce, or postpone amyloid accumulation. Amyloid accumulation precedes the clinical development of Alzheimer disease and Alzheimer dementia. The percentage of the elderly population with abnormally high levels of brain amyloid is strikingly similar to the proportion of elderly that develop Alzheimer dementia one to two decades later (Jack et al., 2014). Thus, the speculative next step is to pose that targeting cardiovascular disease may reduce or postpone the incidence of Alzheimer dementia. Recent studies indicate that this is a plausible speculation. First, epidemiological studies have noted a reduction in the prevalence of dementia (Doblhammer et al., 2015; Jones, 2013; Norton et al., 2014). Even though absolute numbers of patients with dementia continue to rise, due to the rapidly growing population aged 80 and older, relative prevalence has fallen. This has been related to improved cardiovascular care, in addition to better education. Second, a recent landmark study evaluated a two-year intervention to improve diet, exercise and cardiovascular control in a population at elevated risk of cardiovascular disease. This intervention was successful in improving cognitive function in the intervention group, compared to controls (Ngandu et al., 2015). Followup analyses need to determine if this is linked to an effect on Alzheimer disease. Nonetheless, the incidence rates of cognitive decline in this study suggest that not only vascular dementia was postponed in this study. Taken together, at present the evidence that targeting cardiovascular disease may be effective in delaying the onset of sporadic Alzheimer dementia is stronger than the evidence for anti-amyloid drugs. Enhancing collaboration between the scientific and clinical fields of cardiovascular and Alzheimer disease, fields that historically have long been separated, is arguably at present the best bet in the battle against Alzheimer disease (Claassen, 2015).
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Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
New cardiovascular targets to prevent late onset Alzheimer disease Jurgen A.H.R. Claassen Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center and Department of Geriatric Medicine, 925 Geriatric Medicine, PO Box 9101, 6500 HB Nijmegen, The Netherlands
art ic l e i nf o
a b s t r a c t
Article history: Received 6 April 2015 Received in revised form 21 April 2015 Accepted 1 May 2015
The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective diseasemodifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care. & 2015 Published by Elsevier B.V.
Keywords: Cognitive impairment Dementia Cerebral blood flow Cardiovascular disease
1. Introduction An estimated 5% of the general population aged 65 to 70 years has dementia. This number increases to 20% above the age of 80 and reaches a plateau over age 90. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review will discuss recent relevant human studies that have investigated the link between cardiovascular disease and Alzheimer. The wide range of animal studies on this topic will not be included here, because translational evidence is not yet available for most of the investigated mechanisms and translational failure is unfortunately very common in the field of Alzheimer disease. E-mail address: [email protected]
It is important to note that cardiovascular disease may cause cognitive impairment in the absence of Alzheimer disease, through direct vascular neuronal injury, for example in cortical stroke, lacunar infarction, small vessel disease, microbleeds and intracranial hemorrhage (Wiesmann et al., 2013). These causes of dementia are classified as vascular dementia, that represents up to 20% of all dementia. Cardiovascular disease may also cause cerebrovascular disease that contributes to the cognitive disorder in a patient with Alzheimer disease (or any other neurodegenerative disease); these cases are covered in the classification of vascular cognitive impairment (VCI), a term that encompasses all patients in whom cerebrovascular lesions significantly contribute to their cognitive decline (Wiesmann et al., 2013). It is obvious that prevention of cardiovascular disease will impact the prevalence of vascular cognitive impairment and vascular dementia, and these topics will therefore not be covered in this review. In addition, diabetes may also directly, or through cerebrovascular disease, lead to cognitive decline and dementia other than Alzheimer disease (Rawlings et al., 2014). This is also beyond the scope of this review, which will focus on the most common cause of dementia: late onset Alzheimer disease. When reading this review, it must be kept in mind that control of cardiovascular disease and diabetes will have a broader beneficial effect on the prevalence of dementia
http://dx.doi.org/10.1016/j.ejphar.2015.05.022 0014-2999/& 2015 Published by Elsevier B.V.
Please cite this article as: Claassen, J.A.H.R., New cardiovascular targets to prevent late onset Alzheimer disease. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.05.022i
67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97
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that reaches beyond its impact on Alzheimer disease.
2. Alzheimer disease A clear definition of Alzheimer disease is an essential starting point for this review of potential cardiovascular targets to prevent this condition. 2.1. Late onset Alzheimer disease versus familial (genetic) early-onset Alzheimer disease 2.1.1. Alzheimer disease and Alzheimer dementia Alzheimer disease is a progressive neurodegenerative disease that starts with an asymptomatic phase (preclinical Alzheimer disease), where neuronal loss does not lead to symptoms because of compensation. This phase may last 5–15 years based on recent studies, but gradually advances to a phase with mild cognitive and behavioral impairments but maintained ability to function independently. With further loss of cognitive function due to progression of Alzheimer disease, independent functioning becomes impaired, and this phase is defined as dementia. Presently, dementia is divided into three stages (mild, moderate and severe). In mild dementia, patients can live outside institutional care with support from professional and family caregivers. Some patients for example maintain the ability to cook, shop, and even to drive a car. In severe dementia, 24 h care is needed as patients require assistance in almost all basic functions (getting dressed, eating, washing) and there is loss of urinary and often fecal continence. 2.1.2. Prevention of Alzheimer disease versus prevention of Alzheimer dementia The distinction between Alzheimer disease and dementia due to Alzheimer disease (where dementia essentially describes a stage of advanced Alzheimer disease) clarifies that efforts towards prevention can have two goals. The first goal is prevention of the disease, i.e. prevention of the neurodegenerative disorder, which is the most idealistic but also least feasible goal, as we will see later. The second goal is prevention of progression of the disease from asymptomatic or mild symptomatic to dementia. With this second goal, the neurodegenerative disease per se is not prevented, but progression is slowed down or the impact of neurodegeneration on cognitive function is reduced, for example due to prevention of (cerebrovascular) co-morbidity. Although the second goal may seem less powerful, on a societal level, postponing the age of onset of dementia leads to substantial reductions in disease burden (Sloane et al., 2002). This review will address both goals for prevention. 2.1.3. Late onset Alzheimer disease When we consider efforts to prevent Alzheimer disease or dementia due to Alzheimer disease it is important to distinguish late onset Alzheimer disease from the familial (genetic) early onset form of this disease. Both are characterized by progressive accumulation of the protein amyloid-beta42 in oligomers and in large aggregates known as plaques, with early involvement of brain areas involved in memory. Genetic Alzheimer disease is a rare (o5% of all cases), autosomal dominant disease caused by mutations in a single gene in each family. Several genes have been identified thus far. These mutations occur in genes that are involved in the processing of amyloid-beta42 and lead to overproduction of this protein (Tanzi, 2013; Tanzi et al., 1996). The age of onset of dementia is o60 years, and mutations lead to development of disease in nearly 100% of those affected. Much of Alzheimer research is based on models based on familial disease, with animal models based on the known mutations.
In contrast, the common (495%) late onset Alzheimer disease, also described as sporadic Alzheimer disease, is not linked with single dominant genetic changes, but is thought to result from several factors (genetic and environmental) that lead to an imbalance in production and clearance of amyloid-beta42. Although several genetic variants have been associated with late onset Alzheimer disease, these explain less than 50% of this disease. Compared with the familial form, late onset Alzheimer disease has a much larger variation in age of onset and rate of disease progression.
3. Cardiovascular factors and late onset Alzheimer disease 3.1. Epidemiological evidence Even though Alois Alzheimer reported atherosclerosis in cerebral blood vessels in the post-mortem examination of his 55 year old index patient with Alzheimer disease (Alzheimer et al., 1995), Alzheimer disease and vascular disease have historically been considered separate entities. This distinction was enforced by clinical criteria for the diagnosis of dementia due to Alzheimer disease. For familial Alzheimer disease, this separation seemed valid, because its dominant genetic cause and young age of onset left little room for contributions of vascular disease. However, epidemiological studies of late onset Alzheimer disease identified hypertension, diabetes mellitus, atherosclerosis, atrial fibrillation, coronary artery disease, smoking, obesity, and the metabolic syndrome as risk factors for dementia due to Alzheimer disease (Biessels et al., 2006; Kalaria et al., 2012; Kalaria and Ihara, 2013). Many studies have shown the association between increased blood pressure in mid-life and cognitive decline or Alzheimer dementia in later life (Kivipelto et al., 2001; Skoog et al., 1996). Among all vascular risk factors, hypertension seems to be the most powerful risk factor for Alzheimer dementia (Kennelly et al., 2009). Although these associations do not prove causality between cardiovascular disease and Alzheimer disease, these studies have challenged the historical distinction between these two conditions. The epidemiological studies have in most cases relied on clinical diagnoses of dementia due to Alzheimer disease. They therefore risk misclassification (e.g. misclassification of vascular dementia as Alzheimer dementia in studies where neuroimaging was not available) and, in addition, they provide no information on the relationship between vascular disease and earlier stages of Alzheimer disease, i.e. the preclinical or mild cognitive impairment stage. Recent advances however have made it possible to study these early stages of disease. 3.2. Vascular disease and amyloid-beta42 accumulation Whereas earlier studies had to rely on post-mortem examination of the brain to demonstrate amyloid plaques to confirm Alzheimer disease, it is now possible to reveal accumulation of amyloid-beta42 in vivo. Using nuclear imaging with a radioactively labeled ligand that binds to amyloid-beta42, uptake of tracer, reflecting deposits of amyloid-beta42, can be quantified, a technique described as amyloid imaging. In asymptomatic elderly, amyloid imaging indicates abnormally high levels of amyloid-beta42 in an estimated 30% in age 65–69, increasing to 55% at age4 80–84 (Jack et al., 2014). The current hypothesis is that these so-called amyloid-positive but asymptomatic elderly represent preclinical Alzheimer disease. Longitudinal studies are underway to test this hypothesis, but preliminary data suggest that these amyloid-positive elderly show a decline in cognitive function on follow-up compared to amyloid-negative controls (Wirth et al., 2013). The
Please cite this article as: Claassen, J.A.H.R., New cardiovascular targets to prevent late onset Alzheimer disease. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.05.022i
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following vascular factors have been investigated regarding their potential relationship with amyloid accumulation. 3.2.1. Hypertension and amyloid accumulation A recent study investigated factors related to abnormally high amyloid uptake (indicating amyloid accumulation) in asymptomatic (no dementia) elderly. Elderly subjects with unmedicated hypertension had significantly higher amyloid accumulation than those with normal blood pressure (normotensive or medicated hypertension), however, this association was only seen in subjects with a genetic risk factor for late onset Alzheimer disease: ApoEε4 (Rodrigue et al., 2013) Homozygous carriers of the ApoE-ε4 gene (14% of the population) have a 15 fold increased risk to develop Alzheimer disease by age 75 (compared to ApoE-ε3 carriers, 78% of the population). ApoE-ε4 is involved in cholesterol metabolism and, in the brain, for cholesterol transportation to astroglial cells. How ApoE-ε4 leads to increased Alzheimer risk remains unknown. This study suggests an important interaction between hypertension, ApoEε4, and amyloid-beta42. Untreated hypertension increases amyloid-beta42 levels in the brains of ApoE-ε4 carriers, whereas this effect was not observed in controlled hypertension. It is important to note that approximately 30% of ApoE-ε4 carriers will never develop Alzheimer dementia. Whether this is explained by for example absence or adequate control of hypertension remains speculative but highly plausible. 3.2.2. Vascular stiffness and amyloid accumulation Independent of hypertension or ApoE status, cognitively healthy elderly with greater vascular stiffness had a higher rate of amyloid accumulation (Hughes et al., 2014) on follow-up. Vascular stiffness is associated with aging and atherosclerosis, and leads to elevated pulse pressure and end-organ damage, for example in kidney and brain. How vascular stiffness may promote amyloid accumulation remains unknown. However, cardiovascular interventions that may slow down or prevent the development of vascular stiffness are available (treatment of atherosclerosis, hypertension, exercise) and could reduce amyloid accumulation in later life. 3.2.3. Diabetes and amyloid accumulation Two longitudinal studies found no relationship between diabetes and brain amyloid accumulation. The first study combined post-mortem pathology in one cohort with in vivo amyloid imaging in another. Both cohorts had longitudinal (4 20 years) assessments of glucose homeostasis using repeated oral glucose tolerance tests. There was no relationship between glucose levels, insulin levels, or insulin resistance, and amyloid pathology or amyloid imaging (Thambisetty et al., 2013). The second study compared amyloid imaging in a cognitively normal population with and without diabetes. Amyloid accumulation was similar in diabetic versus non-diabetic participants (Roberts et al., 2014). These studies suggest that the negative effect of diabetes on cognitive function may not be mediated by Alzheimer disease. As indicated in the introduction however, this does not implicate that treatment of diabetes will have no effect on late-life cognitive decline, as diabetes may have a direct effect on the brain (Rawlings et al., 2014). 3.3. Cerebral perfusion and Alzheimer disease Normal brain function critically depends on adequate cerebral perfusion (Claassen and Zhang, 2011; van Beek et al., 2008). The brain (2% of body weight) receives 15–20% of cardiac output under resting conditions, and a strong regional flow increase during cognitive activation (neurovascular coupling). Adequate control of
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cerebral blood flow (cerebral autoregulation) is therefore a prerequisite for normal cognitive function. In patients with sporadic Alzheimer dementia without significant cerebrovascular disease (no or limited white matter disease and absence of lacunar or cortical infarction), there was evidence of reduced cerebrovascular reactivity to carbon dioxide (den Abeelen et al., 2014), and mildly impaired cerebral autoregulation (Claassen et al., 2009a, 2009b; den Abeelen et al., 2014). Patients in these studies had cardiovascular risk factors (hypertension, hyperlipidemia), and we speculate that these factors are associated with the impairment in cerebrovascular function and could thus contribute to the development of Alzheimer disease.
4. Conclusion Two markers of cardiovascular disease, hypertension and vascular stiffness, have been linked to a core feature of Alzheimer disease, i.e. accumulation of amyloid-beta42. Based on these observations, the hypothesis has been put forward that cardiovascular treatment, trough reduction of atherosclerosis, hypertension and vascular stiffness, may prevent, reduce, or postpone amyloid accumulation. Amyloid accumulation precedes the clinical development of Alzheimer disease and Alzheimer dementia. The percentage of the elderly population with abnormally high levels of brain amyloid is strikingly similar to the proportion of elderly that develop Alzheimer dementia one to two decades later (Jack et al., 2014). Thus, the speculative next step is to pose that targeting cardiovascular disease may reduce or postpone the incidence of Alzheimer dementia. Recent studies indicate that this is a plausible speculation. First, epidemiological studies have noted a reduction in the prevalence of dementia (Doblhammer et al., 2015; Jones, 2013; Norton et al., 2014). Even though absolute numbers of patients with dementia continue to rise, due to the rapidly growing population aged 80 and older, relative prevalence has fallen. This has been related to improved cardiovascular care, in addition to better education. Second, a recent landmark study evaluated a two-year intervention to improve diet, exercise and cardiovascular control in a population at elevated risk of cardiovascular disease. This intervention was successful in improving cognitive function in the intervention group, compared to controls (Ngandu et al., 2015). Followup analyses need to determine if this is linked to an effect on Alzheimer disease. Nonetheless, the incidence rates of cognitive decline in this study suggest that not only vascular dementia was postponed in this study. Taken together, at present the evidence that targeting cardiovascular disease may be effective in delaying the onset of sporadic Alzheimer dementia is stronger than the evidence for anti-amyloid drugs. Enhancing collaboration between the scientific and clinical fields of cardiovascular and Alzheimer disease, fields that historically have long been separated, is arguably at present the best bet in the battle against Alzheimer disease (Claassen, 2015).
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