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[2]. 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[3]. Alzheimer’s disease affects language and memory skills as well as other vital functions[3]. 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[6]. 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[18]. Interestingly, Davis et al. showed that older individuals can have extensive plaque deposition while having no symptoms of Alzheimer’s disease[19].
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[23]. 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[111] 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[112].
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[115]. 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)[77]. We have reported that high shear stress (exceeding the physiological value) may potentially damage the endothelium[77] 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[77]. 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[112].
References
[1] Butler RN. The longevity revolution. edn. New York: Public Affairs, 2008.
[2] Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88(9):1337-42.
[3] Waldemar G, Dubois B, Emre M et
al. Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007; 14(1):e1-26.
Notes: CORPORATE NAME: EFNS
[4] Molsa PK, Marttila RJ, Rinne UK. Survival and cause of death in Alzheimer's disease and multi-infarct dementia. Acta Neurol Scand 1986; 74(2):103-7.
[5] Molsa PK, Marttila RJ, Rinne UK. Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia. Acta Neurol Scand 1995; 91(3):159-64.
[6] Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999; 66(2):137-47.
[7] Schmitz C, Rutten BP, Pielen A et al. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Am J Pathol 2004; 164(4):1495-502.
[8] Goedert M, Spillantini MG, Crowther RA. Tau proteins and neurofibrillary degeneration. Brain Pathol 1991; 1(4):279-86.
[9] Bartzokis G. Alzheimer's disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging 2009.
[10] Bartzokis G, Lu PH, Mintz J. Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer's disease. J Alzheimers Dis 2004; 6(6 Suppl):S53-9.
[11] Su B, Wang X, Nunomura A et al. Oxidative stress signaling in Alzheimer's disease. Curr Alzheimer Res 2008; 5(6):525-32.
[12] Pardridge WM, Vinters HV, Yang J et al. Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-dalton peptide isolated from cortical microvessels. J Neurochem 1987; 49(5):1394-401.
[13] Pardridge WM, Vinters HV, Miller BL et al. High molecular weight Alzheimer's disease amyloid peptide immunoreactivity in human serum and CSF is an immunoglobulin G. Biochem Biophys Res Commun 1987; 145(1):241-8.
[14] Vinters HV. Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18(2):311-24.
[15] Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991; 12(10):383-8.
[16] Wong SH, Robbins PD, Knuckey NW, Kermode AG. Cerebral amyloid angiopathy presenting with vasculitic pathology. J Clin Neurosci 2006; 13(2):291-4.
[17] van Horssen J, de Jong D, de Waal RM et al. Cerebral amyloid angiopathy with severe secondary vascular pathology: a histopathological study. Dement Geriatr Cogn Disord 2005; 20(5):321-30.
[18] de la Torre JC. Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease. Ann N Y Acad Sci 1997; 826:75-91.
[19] Davis DG, Schmitt FA, Wekstein DR, Markesbery WR. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 1999; 58(4):376-88.
[20] de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease? Neurol Res 1993; 15(3):146-53.
[21] de la Torre JC. Impaired cerebromicrovascular perfusion. Summary of evidence in support of its causality in Alzheimer's disease. Ann N Y Acad Sci 2000; 924:136-52.
[22] de la Torre JC. Impaired brain microcirculation may trigger Alzheimer's disease. Neurosci Biobehav Rev 1994; 18(3):397-401.
[23] de la Torre JC. Cerebral hypoperfusion, capillary degeneration, and development of Alzheimer disease. Alzheimer Dis Assoc Disord 2000; 14 Suppl 1:S72-81.
[24] Du AT, Jahng GH, Hayasaka S et al. Hypoperfusion in frontotemporal dementia and Alzheimer disease by arterial spin labeling MRI. Neurology 2006; 67(7):1215-20.
[25] Johnson NA, Jahng GH, Weiner MW et al. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 2005; 234(3):851-9.
[26] Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 2004; 5(5):347-60.
[27] Silvestrini M, Pasqualetti P, Baruffaldi R et al. Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke 2006; 37(4):1010-5.
[28] Honig LS, Tang MX, Albert S et al. Stroke and the risk of Alzheimer disease. Arch Neurol 2003; 60(12):1707-12.
[29] Meier-Ruge W, Bertoni-Freddari C. The significance of glucose turnover in the brain in the pathogenetic mechanisms of Alzheimer's disease. Rev Neurosci 1996; 7(1):1-19.
[30] Guo Z, Viitanen M, Fratiglioni L, Winblad B. Blood pressure and dementia in the elderly: epidemiologic perspectives. Biomed Pharmacother 1997; 51(2):68-73.
[31] Pasquier F, Leys D. Why are stroke patients prone to develop dementia? J Neurol 1997; 244(3):135-42.
[32] Skoog I. The relationship between blood pressure and dementia: a review. Biomed Pharmacother 1997; 51(9):367-75.
[33] van Kooten F, Bots ML, Breteler MM et al. The Dutch Vascular Factors in Dementia Study: rationale and design. J Neurol 1998; 245(1):32-9.
[34] Kalaria RN, Ballard C. Stroke and cognition. Curr Atheroscler Rep 2001; 3(4):334-9.
[35] Roher AE, Esh C, Kokjohn TA et al. Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer's disease. Arterioscler Thromb Vasc Biol 2003; 23(11):2055-62.
[36] Buee L, Hof PR, Bouras C et al. Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders. Acta Neuropathol 1994; 87(5):469-80.
[37] de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology 1997; 43(1-2):26-43.
[38] Mancardi GL, Perdelli F, Rivano C, Leonardi A, Bugiani O. Thickening of the basement membrane of cortical capillaries in Alzheimer's disease. Acta Neuropathol 1980; 49(1):79-83.
[39] Moody DM, Brown WR, Challa VR, Ghazi-Birry HS, Reboussin DM. Cerebral microvascular alterations in aging, leukoaraiosis, and Alzheimer's disease. Ann N Y Acad Sci 1997; 826:103-16.
[40] Perlmutter LS, Myers MA, Barron E. Vascular basement membrane components and the lesions of Alzheimer's disease: light and electron microscopic analyses. Microsc Res Tech 1994; 28(3):204-15.
[41] De Jong GI, Farkas E, Stienstra CM et al. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience 1999; 91(1):203-10.