|Alzheimer's Disease and Stroke|
|Image source: Ians. (2012). Tiny stroke could bring on
Alzheimer’s [Photograph]. Retrieved March 28, 2013, from
Dementia, stroke, or both is diagnosed in 1 out of every 3 people. Given this statistic and the fact that Alzheimer's disease (AD) and stroke regularly co-occur, it is evident that AD needs to be studied in conjunction with stroke. Past research has found that the risk of dementia is increased after the occurrence of stroke. A number of different mechanisms, such as axonal changes, have been studied to identify their role in the development of AD after the experience of a stroke. Although the association between AD and stroke has been studied in the past, limited research is available regarding the topic of AD as a risk factor for stroke. Nevertheless, some studies, such as cohort studies and studies on animal models, are available to gain knowledge of the occurrence and effects of stroke in AD patients. In addition, AD and stroke have many common risk factors, such as hypertension; therefore, treating these risk factors will be efficient in the prevention of both AD and stroke. Furthermore, endogenous neuroprotectants have been studied for their use in the prevention of stroke and neurodegenerative disorders, such as AD.
Table of Contents
Alzheimer's after stroke
|Figure 1. Types of stroke|
|Figure 1. Ischemic and hemorrhagic strokes are two different types of stroke described in this figure.
Adapted from: Heart and Stroke Foundation. (2008). Ischemic stroke [Photograph]. Retrieved March 30, 2013, from
Heart and Stroke Foundation. (2008). Hemorrhagic stroke [Photograph]. Retrieved March 30,2013, from
Incidence of Alzheimer's in stroke survivors
In comparison to control patients, the risk of dementia is nine times higher in stroke patients who do not develop dementia within three months of experiencing a stroke. Stroke patients over 75 years old have an additional risk of developing dementia compared to younger patients by three times. In addition, one year after the occurrence of a stroke, the risk of developing AD is 50% higher in stroke survivors compared to controls.
Previous studies propose that after ischemic stroke, there is a major loss of hippocampal CA1 neurons. Interestingly, hippocampal neurodegeneration, especially in the region of the CA1 neurons, is believed to be involved in AD development. Research shows that compared to control patients, the density of CA1 neurons in post-stroke and AD patients are altered. There is a 10% to 20% reduction in the volume of CA1 and CA2 neurons of post-stroke patients with dementia and AD patients compared to control patients. Post-stroke patients without dementia and control patients have comparable neuronal volumes.
|Figure 2. Axonal swelling after cerebral ischemia|
|Figure 2. After cerebral ischemia, axonal swelling can be seen in the sensory
cortex, motor cortex, hippocampus, and striatum. The arrows point to swollen axons.
A: Primary sensory cortex; B: Primary motor cortex; C: Hippocampus; D: Striatum.
Image adapted from .
Axonopathy, which includes axonal swelling and the damage of axonal transport, is involved in the development of AD after the occurrence of a stroke. In rats, transient focal cerebral ischemia/reperfusion leads to axonal changes, such as axonal swelling, in the sensory cortex, motor cortex, striatum, and hippocampus of the ischemic hemisphere (Fig. 2). Axonal changes can last for at least six hours and continue to change until four weeks after transient cerebral focal ischemia/reperfusion; for this reason, changes to axons are believed to occur early on and is considered to be chronic . Since axonal changes are identified after cerebral ischemia, it is thought that axonopathy may link ischemia to AD. Furthermore, it has been suggested that axonopathy leads to β-amyloid plaque formation and hyperphosphorylated tau protein.
After cerebral ischemia, there is an increase in the expression of β-amyloid precursor protein (APP) in the brain. In addition, it is believed that APP cleavage is increased by ischemia. As a result, the amount of toxic β-amyloid is increased; this increase in toxicity can cause an increase in the expression of APP and apolipoprotein E (ApoE).
β-amyloid peptides, such as β-amyloid 1-40 and β-amyloid 1-42, can induce toxic effects on neurons. A study of 43 focal cerebral infarction patients found that β-amyloid 1-40 expression is significantly increased in hippocampal CA1 and CA3 neurons around two to five hours after cerebral ischemia; this increase continues and reaches its maximum at four days (Fig. 3). The same increase is identified for β-amyloid 1-42 around two to five hours after cerebral ischemia; however, maximum expression is seen at two days (Fig. 3). This study, as well as other studies, demonstrates that cerebral ischemia leads to the upregulation of β-amyloid, which may contribute to the development of AD.
|Figure 3. β-amyloid 1-40 and 1-42 immunoreactivity after cerebral ischemia|
|Figure 3. β-amyloid 1-40 and 1-42 expression is increased in hippocampal CA1 and CA3 neurons after cerebral
ischemia. The top row shows the increase of β-amyloid 1-40 expression in hippocampal CA1 neurons. The second
row shows the increase of β-amyloid 1-42 expression in hippocampal CA1 neurons. The last row shows the increase
of β-amyloid 1-42 expression in hippocampal CA3 neurons.
A: Control; B: After 23 hours of experiencing cerebral ischemia; C: After 72 hours of experiencing ischemia.
Image adapted from .
Tau protein phosphorylation and cell apoptosis
After focal cerebral ischemia/reperfusion in rats, there is abnormal hyperphosphorylation of tau proteins in the cortex. Undissolved phosphorylated tau proteins, which lead to the formation of AD neurofibrillary tangles, are also identified in the cortex after focal cerebral ischemia/reperfusion, . Tau hyperphosphorylation has been found to be associated with cell apoptosis, which influences the onset of AD. Bcl-2 and bax are genes that control cell apoptosis; a decrease in bcl-2/bax ratio results in the promotion of cell apoptosis. After focal cerebral ischemia/reperfusion, there is an increase in the expression of both bcl-2 and bax. However, there is a decrease in bcl-2/bax ratio, which means that cerebral ischemia promotes cell apoptosis. Therefore, through tau protein hyperphosphorylation and cell apoptosis, cerebral ischemia promotes pathological changes that are characteristic of AD.
Stroke after Alzheimer's
Incidence of stroke in Alzheimer's patients
A nationwide cohort study of AD patients and non-AD control patients matched for age, sex and residence examined the risk of stroke in AD patients; the study consisted of 56,186 participants and was conducted in Finland. The study found that the risk of ischemic stroke is the same in AD patients and non-AD patients when all age groups are considered. The risk of hemorrhagic stroke is increased in AD patients when compared to non-AD patients. If different age groups are studied for association, the risk of any stroke is increased for AD patients 79 years old and younger, but not for those 80 years old and over. The age at which AD was diagnosed also has an effect on the incidence of stroke. The risk of any stroke is higher for AD patients diagnosed at a young age (38.9-73.9 years old) compared to non-AD patients. However, AD patients diagnosed at an older age have a lower risk of hemorrhagic stroke compared to non-AD patients. Therefore, research suggests that the risk of hemorrhagic stroke is increased for younger AD patients.
A population-based cohort study of AD patients and non-AD control patient matched for vascular risk factors was conducted in Taiwan; the study consisted of 980 participants. The study identified results that are inconsistent with the results found in the nationwide study conducted in Finland, . The study found that the risk of ischemic stroke and intracerebral hemorrhage is higher in AD patients compared to non-AD patients.
|Click below for an interactive learning experience|
|To learn more about hemorrhagic stroke, go to select a topic. Retrieved from: http://watchlearnlive.heart.org/CVML_Player.php?moduleSelect=iscstr#.UVdKYuLBg5Q|
In 2011, Garcia-Alloza et al were the first to propose a direct causal relationship between cerebrovascular disease and the deposition of β-amyloid. Their study was the first to show, in live animals, that β-amyloid is deposited in the form of plaques and cerebral amyloid angiopathy after stroke. They identified that stroke causes the transient acceleration of β-amyloid deposition. Human tissue samples were examined and photosensitive dye was used in mouse models in order to visualize the formation of plaques in real time. Seeing as their paper examines a key mechanism of AD development, β-amyloid deposition, and the contribution of stroke to this mechanism, it is an important paper for the study of AD and stroke.
|Figure 4. Cortical layer distribution after middle cerebral
|Figure 4. A week after middle cerebral artery occlusion in AD mouse models,
cortical layer distribution is lost in the ipsilateral hemisphere compared
to the contralateral hemisphere.
A: Ipsilateral hemisphere; B: Contralateral hemisphere.
Image adapted from .
Garcia-Alloza et al showed that middle cerebral artery occlusion in AD mouse models results in increased stroke volume compared to wild-type mice; this suggests that neurotoxicity due to β-amyloid in AD may lead to more vulnerability to ischemia, . In comparison to the contralateral hemisphere, more senile plaques were found on the ipsilateral hemisphere after middle cerebral artery occlusion. There was no difference in the average size of plaque in each hemisphere. Stroke regions in the contralateral hemisphere maintained their cortical layer distribution a week after middle cerebral artery occlusion; however, the ipsilateral hemisphere lost its distribution (Fig. 4).
|Figure 5. β-amyloid burden in human tissue|
|Figure 5. β-amyloid burden in human tissue is the same for AD-stroke patients
and AD patients.
A: AD-stroke patient; B: AD-patient.
Image adapted from .
In human tissue of patients diagnosed with AD and stroke, β-amyloid burden around stroke areas were no different from patients who were not diagnosed with stroke (Fig. 5). This is explained by research in AD mouse models indicating that the acceleration of plaque formation in stroke areas is only transient. Increased β-amyloid burden is not associated with existing plaque growth, but involves plaque formation. In addition, deposition of amyloid in targeted vessels, which indicates cerebral amyloid angiopathy, was also found in AD models after the occurrence of stroke.
Garcia-Alloza et al were unable to identify β-amyloid breakdown or production as the source of increased β-amyloid deposition; as a result, future research should focus on studying clearance pathways as the source of the increase.
Prevention of Alzheimer's and stroke
Hypertension is associated with an increased risk of dementia and stroke. Particularly, hypertension is associated with a higher risk of lacunar and cortical strokes, which are known to promote the progression of dementia in AD and non-AD patients, . The risk of dementia and stroke is effectively decreased by antihypertensive treatment when optimal blood pressures are identified for each patient. The brain’s optimal blood pressure is ≤130/80 mm Hg. It has been shown that a systolic blood pressure of <130mm Hg, in comparison to 130-139mm Hg, results in more protection against stroke in those who are at risk of cerebrovascular disease. Antihypertensive treatment is advised for patients whose blood pressure is ≥140/90 mm Hg, although a blood pressure of ≤130/80 mm Hg is ideal for preventing stroke.
The interaction between hypertension and existing AD pathology has been studied in a rat model of both AD and stroke; the clinical results of the Nun Study were mimicked in this model, . In this combined disease model, the presence of β-amyloid burden was found to cause an increased infarct size and an increase in the corresponding neuroinflammatory response. As a result, treatments should not only target hypertension, but should additionally focus on decreasing β-amyloid burden and neuroinflammation as well.
|Hypertension and Stroke|
|This news report discusses hypertension as a risk factor for stroke.|
|Hypertension and Alzheimer's Disease|
|This news report discusses the association between hypertension and AD.|
Neuroglobin as an endogenous neuroprotective molecule
|Figure 6. Neuroglobin|
|Figure 6. Structure of human neuroglobin.
Image source: Proteopedia. (2012). Neuroglobin
[Photograph]. Retrieved March 30, 2013, from
Neuroglobin (Ngb), an intracellular globin protein found in brain neurons, has been identified as an endogenous neuoprotective molecule. Research has shown that Ngb protects against ischemia and neurotoxicity due to β-amyloid. For instance, the deficits resulting from ischemic stroke are less severe when there is an increase in the expression of the Ngb gene, . Furthermore, the overexpression of Ngb has been shown to decrease the size of infarct after cerebral artery occlusion in rats.
Given the fact that Ngb does not usually cross cell membranes, exogenous Ngb is not effective for prevention; therefore, strategies that can successfully increase the expression of endogenous Ngb can be used to protect against stroke and neurodegenerative disorders, such as AD. For example, compounds, such as valproic acid, cinnamic acid and 17β-estradiol, have been shown to upregulate Ngb, .
Pages related to Alzheimer's and stroke
For more on AD and dementia visit:
Alzheimer's Disease Models
Effects of Lifestule on the Prevalence of Alzheimer's Disease
Genetics of Alzheimer's Disease
Immunology of Alzheimer's Disease
miRNA in Alzheimer's Disease
Sex and Gender in Alzheimer's Disease
Tagged for Failure- CREB, CBP and other molecules associated with memory disruption
For more on AD and stroke treatments visit:
Shock Therapy Treatment in Alzheimer's Disease
Musical Treatment for Dementia: Remembering who you are your Music, your Identity
Music & Alzheimer's Disease
The Role of Music Therapy in Stroke Rehabilitation
Music as an alternative