Alzheimer’s disease concerns us as medical scientists as by the middle of this century it could affect as many as 1 in 85 people worldwide. However, it is unfortunate that the mechanism of Alzheimer’s disease is still not well understood. It is very important to understand the mechanism because it may open up new avenues for treatment. For example, Alzheimer’s disease may be strongly associated with cardiac arrhythmias. Thus, on one hand, patients diagnosed with cardiac arrhythmias may benefit from early screening for Alzheimer’s disease. On the other hand, if cardiac arrhythmias contribute to the existing Alzheimer’s disease, worsening its prognosis, then a more aggressive treatment of arrhythmias should be considered. Finally, findings that suggest that arrhythmias and Alzheimer’s disease are associated should raise the important question: What is it about this association that may further advance our understanding of Alzheimer’s disease?
Interestingly, it has been more than a century since the discovery of Alzheimer’s disease and yet, the cause of Alzheimer’s disease as well as its exact mechanism remains unknown. Once we understand the mechanism of the development as well as the cause of Alzheimer’s disease, we will be able to find an effective treatment. There are numerous published materials on clinical, diagnostic and treatment aspects of Alzheimer’s disease. For the purpose of a brief introduction, a few aspects of Alzheimer’s disease not directly related to the scope of the book will be also discussed below.
Alzheimer’s disease is a neurodegenerative disease with a strong vascular component and the most frequent form of dementia. Common symptoms include confusion, irritability and aggressive behavior. Alzheimer’s disease affects language and memory skills as well as other vital functions. The prognosis varies from one person to another but is generally poor with the average lifespan of the Alzheimer’s patient of about seven years[4,5]. Only about one in fifty individuals diagnosed with Alzheimer’s disease will survive longer than 14 years following the diagnosis[4,5].
Alzheimer’s disease is on the rise, perhaps due to improvements in diagnostic methods. The cause of it is probably one of the most fundamental questions when it comes to Alzheimer’s disease. A number of hypotheses have been developed, yet the cause is still unknown. One of the early hypotheses, the cholinergic hypothesis, led to the development of several therapeutic regimens, which turned out to be of low efficacy. Other hypotheses include abnormal tau protein pairing, age-related demyelination and oxidative stress[7-11].
The amyloid hypothesis suggested that the deposit of the β-amyloid peptide can lead to cognitive decline as well as to disrupted cerebral blood flow. This can lead to certain symptoms of Alzheimer’s disease (such as intellectual decline) and can be explained by extraneuronal plaque deposition [12-15]. The β-amyloid peptide deposition and its further accumulation which can result in degeneration of smooth muscle cells in the endothelial wall to the extent of the appearance of defects in the wall itself[16,17]. A controversy as to whether amyloid deposition can actually cause cognitive decline has appeared as a result of studies which showed that the extent of amyloid deposition does not necessarily correlate with synaptic or neuronal lost or with severity of cognitive decline. Interestingly, Davis et al. showed that older individuals can have extensive plaque deposition while having no symptoms of Alzheimer’s disease.
A “vascular” explanation of sporadic Alzheimer’s disease was suggested by de la Torre[20-22]. It is well known that ageing results in certain structural changes of the vascular wall such as thickening of the basement membrane or decrease in vascular elasticity. But ageing does more than that. Whether these are age-related pathologies such as atherosclerosis or normal metabolic changes such as menopause, ageing is likely to compromise hemodynamics. In turn, human brain vessels undergo substantial structural changes during ageing (i.e. atrophy, decrease elasticity of vascular wall, amiloid deposition (“senile plaques”) etc.). Such changes result in a whole cascade of hemodynamic and rheologic responses (such as an increase in blood viscosity or appearances of zone of turbulence) which, in turn, can reduce the delivery of oxygen and other important chemicals to the brain.
De la Torre and colleagues[20-22] have proposed that lowered cerebral perfusion in combination with an energy-dependent intracellular metabolic breakdown can cause sporadic Alzheimer’s disease. A cascade of biochemical reactions can be initiated by decreased cerebral blood flow eventually leading to neurodegeneration. Results from several studies have supported the idea that cerebral hypoperfusion may be associated with Alzheimer’s disease[24-29]. Additionally, population-based research supports the idea that Alzheimer’s disease may be associated with disorders that either have a strong vascular origin or may cause vascular hypoperfusion[30-35]. Thus, cumulated research evidence has suggested that Alzheimer’s disease is linked to vascular pathology[21,22,36-39].
However, the mechanism explaining how lowered cerebral blood flow can result in suboptimal delivery of metabolic substances to the brain tissue is not well understood. As mentioned earlier, the beta amyloid peptide deposition and its further accumulation can result in degeneration of smooth muscle cells in the endothelial wall to the extent of the appearance of defects in the wall itself[16,17]. Other vascular changes include hyalinization and aneurismal dilatation of the vascular wall[16,17]. Animal-based studies showed that long-term hypoperfusion can lead to vascular lumen distortion as well as basement membrane thickening[40,41]. One of the theories is that a degenerated vascular wall can result in the normal laminar blood flow becoming turbulent [20,23]. Amyloid deposits (as well as other changes described above) can disturb the structure of vascular wall by changing its geometry. In turn, there will be conditions for the appearance of turbulent flow, which can decrease the normal delivery of oxygen and other important chemicals to the brain tissue. In addition, wasted metabolic products can not be properly removed from local brain tissues.
Other disease-specific mechanism-related considerations
Ischemic stroke can be caused by inadequate local blood flow resulting from decreased blood flow velocity due to decreased cerebral perfusion pressure. On the other hand, increased prevalence of stroke among patients with polycythemia vera or multiple myeloma suggests another pathophysiological mechanism of ischemic stroke, namely, increased blood viscosity, which, as mentioned earlier, results in increased rouleaux formation and local stasis.
Elderly patients diagnosed with primary hypothyroidism are more likely to have lower TSH concentration as opposed to younger individuals. From a cardiovascular point of view, those with primary hypothyroidism are likely to have lower blood pressure, hypotension, and, therefore, lower shear stress and yield velocity. In turn, such individuals are more likely to have an increase of blood viscosity through increased erythrocyte aggregation and rouleaux formation. As noted above, hyperviscosity may worsen the blood circulation and cause ischemia and local necrosis through deterioration in capillary perfusion.
The mechanism of the association between traumatic brain injury and Alzheimer’s disease is complex. For instance, genetic influence (i.e. having apolipoprotein E epsilon4) can worsen prognosis of Alzheimer’s disease after traumatic brain injury[113,114]. Animal-based experiments observed an increase of amyloid β peptide following traumatic brain injury. The vascular component of the mechanism of traumatic brain injury-related Alzheimer’s disease should take into account both direct and indirect trauma to brain vessels, and therefore changes to local hemodynamic and rheological factors. Traumatic compression of the vessel can lead to the appearance of zones with high shear stress (as the result of injury to part of the vessel) and low or zero shear stress (within the zone of boundary layer separation). We have reported that high shear stress (exceeding the physiological value) may potentially damage the endothelium and increase platelet aggregation[116,117], possibly leading to thrombus formation. On the other hand, trauma may lead to boundary layer separation, resulting in the appearance of a zone with zero shear stress and zero yield velocity. According to current research, this may result in an increase of blood viscosity through increased erythrocyte aggregation and rouleaux formation. As noted above, hyperviscosity may worsen the blood circulation and cause ischemia and local necrosis through deterioration in capillary perfusion.
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