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Alzheimer’s disease: Characteristics and Causes of a serious neurodegenerative disease


Alzheimer’s disease (AD) is the most common of all dementia diagnoses, has become a major public health concern as our population ages, and it has been estimated by the American National Institute of Health that 8.5 million people will be affected by the year 2030 in the United States alone. [1] So far, no preventive drugs have been discovered, but a well controlled blood pressure and an active life, both mentally and socially, are known to delay or lower the risk of AD [2]



Alzheimer’s disease (AD), first described by German psychiatrist Alois Alzheimer in 1906, is a progressive neurodegenerative disease characterized by cognitive deterioration together with behavioral disturbances and declining activities of daily living[3] Alzheimer’s disease is typically divided into three stages, based on severity of cognitive impairment: the early, middle, and late stage.[4]


In the early stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas. [5]-[7] While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they are commonly unnoticed. [5] As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities. [5]


In the Middle stage, speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. [5],[7] During this phase, memory problems worsen, and the person may fail to recognize close relatives.[5] Long-term memory, which was previously intact, becomes impaired.[5] Approximately 30% of patients develop illusionary misidentifications and other delusional symptoms.[5] Subjects also lose insight of their disease process and limitations (anosognosia).[5] Urinary incontinence can develop.[5] These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.[5],[8]


During the last stage of AD, the patient is completely dependent upon caregivers.[5] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[5],[7] Despite the loss of verbal language abilities, patients can often understand and return emotional signals.[5] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results.[5] Patients will ultimately not be able to perform even the most simple tasks without assistance.[5] Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves.[5] AD is a terminal illness with the cause of death typically being an external factor such as infection of pressure ulcers or pneumonia, not the disease itself.[5]




Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, [9] which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. Cholinergic systems are involved in normal memory functions, [10] and cholinergic deficiency has been implicated in the cognitive and behavioral manifestations of AD.[11] Activity of the synthetic enzyme choline acetyltransferase (CAT) and the catabolic enzyme acetylcholinesterase (ACE) are significantly reduced in the cerebral cortex,[12],[13] hippocampus, and amygdala in AD patients.[14] The nucleus basalis of Meynert, medial septum, and diagonal band of Broca, which provide the main cholinergic input to the hippocampus, amygdala, and neocortex, demonstrate a fairly selective pattern of neuronal degeneration in AD.[15] Loss of cortical CAT[16] and decline in acetylcholine synthesis in biopsy specimens have been found to correlate with cognitive impairment[17] and reaction time performance.[18] The relationship between basal forebrain dysfunction and amyloid precursor protein metabolism remains poorly understood.

The effects of cholinergic agents on APP release have yielded conflicting results in animal studies. [19] The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, [20] leading to generalized neuroinflammation. [21]

In 1991, the amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease.[22],[23] Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.[24],[25] Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise.

A 2004 study found an observation that supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. [23] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. [26] When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. [27] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells. [28] Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene. [29]

Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau. [30]- [32] Aging is the major risk factor of AD in the general population. Recent research has identified 2 potential mechanisms related to aging that may contribute to the development of the disease. One is the concept that free radicals (reactive oxygen species) produced during cellular respiration may play an important role in the process of aging and in the development of AD.[33] Ample evidence has accumulated that oxidative damage to proteins and membrane lipids and an up-regulation of antioxidant enzymes is associated with AD.[34],[35] The toxic effects of β-amyloid are mediated, at least in part,through the generation of free radicals by the peptide.[36],[37] The recent demonstration of redox-active iron deposits associated with senile plaques and neurofibrillary tangles is relevant in this respect because iron can catalyze the formation of damaging free radicals.[38]

Oxidative stress is a significant cause in the formation of the pathology. [39] Oxidative stress is believed to be a critical factor in normal aging [40] and neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis. There is evidence that oxidative stress is also implicated in AD. Formation of free carbonyls [41] and thiobarbituric acid-reactive products, [42] an index of oxidative damage, are significantly increased in AD brain tissue compared with age-matched controls. Plaques and tangles display immunoreactivity to antioxidant enzymes.[43] There are multiple mechanisms by which cellular alterations may be induced by oxidative stress, including production of reactive oxygen species (ROS) in the cell membrane (lipid peroxidation).

The subsequent increase in intracellular calcium, along with the accumulation of ROS, damages various cellular components such as proteins, DNA, and lipids and may result in apoptotic cellular death.[44],[45] Increased intracellular calcium may also alter calcium-dependent enzyme activity[46] such as the implication of protein kinase C in amyloid protein metabolism and the phosphorylation of tau. Therefore, blocking the increase in free intracellular calcium may diminish neuronal injury

The finding that monozygotic twins may not both develop AD suggests that environmental factors also play a role in the development of AD. [47] One hypothesis is that AD may represent a chronic active inflammatory disease. The brains of AD patients show evidence of mild active inflammation, including microglial and complement activation, and the presence of inflammatory cytokines.[48] Moreover, the recruitment and activation of microglia is associated with maturation of plaques in elderly individuals.[49] Although the inflammation is likely secondary to more fundamental injuries, it may participate in a morbid cycle of tissue damage, as it does in systemic diseases like rheumatoid arthritis. Epidemiological retrospective studies have been conducted to determine the risk of developing AD among patients receiving anti-inflammatory drugs or having conditions such as rheumatoid arthritis in which these drugs are routinely used. More than 21 independent studies, including the Canadian Study of Health and Aging, [50] have reported a decreased prevalence of AD among patients taking anti-inflammatory agents on a long-term basis, although these findings are not universal. [51]


[1]National Institutes of Health. Progress Report on Alzheimer’s Disease. Washington, DC: US Department of Health and Human Services; 1999.

[2]Scalco MZ, van Reekum R. Prevention of Alzheimer disease. Encouraging evidence. Can Fam Physician. 2006; 52:200-207.

[3]Burns A, Byrne EJ, Maurer K. Alzheimer’s disease. Lancet 2002; 360:163–5.

[4]Kaufman DM: Dementia, in Clinical Neurology for Psychiatrists. New York, WB Saunders, 1995, pp 123–167

[5]Förstl H, Kurz A. "Clinical features of Alzheimer's disease". European Archives of Psychiatry and Clinical Neuroscience 1999; 249 (6): 288–290

[6]Taler V, Phillips NA. "Language performance in Alzheimer's disease and mild cognitive impairment: a comparative review". J Clin Exp Neuropsychol 2008; 30 (5): 501–56

[7]Frank EM. "Effect of Alzheimer's disease on communication function". J S C Med Assoc 1994; 90 (9): 417–23

[8]Gold DP, Reis MF, Markiewicz D, Andres D. "When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia". J Am Geriatr Soc 1995; 43 (1): 10–6

[9]Francis PT, Palmer AM, Snape M, Wilcock GK. "The cholinergic hypothesis of Alzheimer's disease: a review of progress". J. Neurol. Neurosurg. Psychiatr. 1999; 66 (2): 137–47.

[10]Kesner RP: Reevaluation of the contribution of the basal forebrain cholinergic system to memory. Neurobiol Aging 1988; 9:609–616

[11]Cummings JL, Kaufer D: Neuropsychiatric aspects of Alzheimer’s disease: the cholinergic hypothesis revisited. Neurology 1996; 47:876–883

[12]Bowen DM, Smith CB, White P, et al: Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976; 99:459–496

[13]Dekosky ST, Scheff SW, Markesbery WR: Laminar organization of cholinergic circuits in human frontal cortex in Alzheimer’s disease and aging. Neurology 1985; 35:1425–1431

[14]Davies P, Maloney AJF: Selective loss of central cholinergic neurons in Alzheimer’s disease (letter). Lancet 1976; 2:1403

[15]Whitehouse PJ, Price DL, Struble RG, et al: Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 1982; 215:1237–1239

[16]Perry EK, Tomlinson BE, Blessed G, et al: Correlations of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 1978; 2:1457–1459

[17]Francis PT, Palmer AM, Sims NR, et al: Neurochemical studies of early-onset Alzheimer’s disease. Possible influence on treatment. N Engl J Med 1985; 313:7–11

[18]Sims NR, Bowen DM, Smith CCT, et al: Glucose metabolism and acetylcholine synthesis in relation to neuronal activity in Alzheimer’s disease. Lancet 1980; 1:333–336

[19]Olivier Felician, Thomas A. Sandson. The Neurobiology and pharmacotherapy of Alzheimer’s disease. J. Neuropsychiatry Clin Neurosci. 1999; 11:1

[20]Shen ZX. "Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease". Med Hypotheses 2004; 63 (2): 308–21

[21]Wenk GL. "Neuropathologic changes in Alzheimer's disease". J Clin Psychiatry 2003; 64 Suppl 9: 7–10

[22]Hardy J, Allsop D. "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends Pharmacol. Sci. 1991; 12 (10): 383–88

[23]Mudher A, Lovestone S. "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci. 2002; 25 (1): 22–26

[24]Nistor M, Don M, Parekh M, et al. "Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain". Neurobiol Aging 2007; 28 (10): 1493–1506

[25]Lott IT, Head E. "Alzheimer disease and Down syndrome: factors in pathogenesis". Neurobiol Aging 2005; 26 (3): 383–89

[26]Goedert M, Spillantini MG, Crowther RA. "Tau proteins and neurofibrillary degeneration". Brain Pathol 1991; 1 (4): 279–86

[27]Iqbal K, Alonso Adel C, Chen S, et al. "Tau pathology in Alzheimer disease and other tauopathies". Biochim Biophys Acta 2005; 1739 (2–3): 198–210.

[28]Chun W, Johnson GV. "The role of tau phosphorylation and cleavage in neuronal cell death". Front Biosci 2007; 12: 733–56

[29]Ithaki RF, Wozniak MA. "Herpes simplex virus type 1 in Alzheimer's disease: the enemy within". J Alzheimers Dis 2008; 13 (4): 393–405

[30]Bartzokis G. "Alzheimer's disease as homeostatic responses to age-related myelin breakdown". Neurobiology of Aging. 2009

[31]Bartzokis G, Lu PH, Mintz J. "Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer's disease". Journal of Alzheimer's disease. 2004; 6 (6 Suppl): S53–9

[32]Bartzokis G, Lu, P, Mintz J. "Human brain myelination and amyloid beta deposition in Alzheimer’s disease". Alzheimer's and Dementia 2007; 3: 122

[33]Smith MA, Sayre LM, Monnier VM, Perry G. Radical aging in Alzheimer’s disease. Trends Neurosci 1995; 18:172-6

[34]Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 1997; 68:2092-7

[35]Smith MA, Richey HP, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 1997; 17:2653-7

[36]Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, et al. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci 1994; 91:3270-4

[37]Harris ME, Hensley K, Butterfield DA, Leedle RA, Carney JM. Direct evidence of oxidative injury produced by the Alzheimer’s beta-amyloid peptide (1–40) in cultured hippocampal neurons. Exp Neurol 1995; 131:193-202

[38]Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci 1997; 94:9866-8

[39]Su B, Wang X, Nunomura A, Moreira PI, Lee HG, Perry G, Smith MA, Zhu X. "Oxidative stress signaling in Alzheimer's disease". Current Alzheimer research 2008; 5 (6): 525–32

[40]Sohal RS,Weindruch R: Oxidative stress, caloric restriction, and aging. Science 1996; 273:59–63

[41]Smith CD, Carney JM, Starke-Reed PE, et al: Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer’s disease. Proc Natl Acad Sci USA 1991; 88:10540–10543

[42]Subbarao KV, Richardson JS, Ang LC: Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J Neurochem 1990; 55:342–345

[43]Pappolla MA, Omar RA, Kim KS, et al: Immunohistochemical evidence of oxidative stress in Alzheimer’s disease. Am J Pathol 1992; 140:621–628

[44]Mark RJ, Hensley K, Butterfield DA, et al: Amyloid betapeptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2` homeostasis and cell death. J Neurosci 1995; 15:6239–6249

[45]Mattson MP, Rydel RE: Amyloid ox-tox transducers. Nature 1996; 382:674–675

[46]Disterhoft JF, Moyer JR Jr, Thompson LT: The calcium rationale in aging and Alzheimer’s disease. Ann NY Acad Sci 1994; 747:382–406

[47]Rapoport SI, Pettigrew KD, Schapiro MB. Discordance and concordance of dementia of the Alzheimer type (DAT) in monozygotic twins indicate heritable and sporadic forms of Alzheimer’s disease. Neurology 1991; 41:1549-53

[48]McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195-218

[49]Mackenzie IR, Miller LA. Senile plaques in temporal lobe epilepsy. Acta Neuropathol (Berl) 1994; 87:504-10

[50]The Canadian Study of Health and Aging. The Canadian Study of Health and Aging: risk factors for Alzheimer’s disease. Neurology 1994; 44:2073-80

[51]McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 1996; 47:425-32

Article By: Cosette NGARAMBE, Guy-Armel BOUNDA
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