Alzheimer's disease (AD) is an irreversible, progressive, neurodegenerative disease of the brain cells (neurons). AD was first identified in 1906 by German physician Alois Alzheimer, thus the name Alzheimer's disease. AD initially affects the nerve cells in the memory areas of the brain such as the cerebral cortex and hippocampus. Gradually other parts of the brain are also affected. AD primarily presents with loss of memory, cognitive functions, judgment and reasoning, movement coordination and pattern recognition.
AD usually develops in elderly over the age of 65 years. More than 10% of people over the age of 65 and more than 50% people over the age of 85 develop Alzheimer's. A very small percentage of people develop Alzheimer's in their fifties, forties or even their thirties. Alzheimer's is known to be a hereditary disease but researchers have found that cases do exist without any family history. Alzheimer's is the main cause of dementia and the fourth leading cause of death in developed countries. The most extensive European epidemiological study â€“ The Rotterdam study â€“ shows that 72% of all dementia patients suffer from AD. It is estimated that there are more than 2 million Alzheimer's sufferers in the major countries of the European Union. Of the persons suffering from undiagnosed AD, it is estimated that 47% suffer from mild AD, 29% are in the moderate stage, and 24% have severe AD. Of the diagnosed group of patients 20% suffer from mild Alzheimer's, 40% from the moderate form and 40% from the severe form.
The main histopathological findings in Alzheimer's are brain lesions of abnormal, insoluble protein deposits of amyloid plaques, and neurofibrillary tangles.
An adult human brain contains about 100 billion nerve cells, or neurons, with branches that connect each other. Signals traveling through these neurons are responsible for memory, thoughts and feelings. AD affects both the signal transmission in the cell and also the activity of neurotransmitters. Scientists found two important causes of cell death in AD, deposition of amyloid plaques and formation of neurofibrillary tangles.
Beta amyloid is a peptide protein formed by the enzyme clipping of the normal neuron membrane protein known as amyloid precursor protein (APP). APP is a natural neuroprotective protein. The amyloid beta protein clusters into plaques on blood vessels and on the outer surface of the neurons leading to their death. The formation of beta amyloid plaques is followed by two processes which ultimately are responsible for the destruction of neurons. These processes are inflammation and neurofibrillary tangles.
The two major types of cells that take part in the inflammatory response are astrocytes and microglia. In AD astrocytes increase in number and are activated to produce prostaglandin/arachidonic acid mediated inflammation. The microglial cells are also activated and produce damaging free radicals. The combined activities of these two cells lead to the death of neurons.
The substances for nutrition and cell-regulation are transported via the microtubules in the neurons. The structural integrity of these microtubules is maintained by a protein called Tau. In AD this Tau protein undergoes hyper-phosphorylation and looses the capacity to bind to microtubules, and instead bind to each other tying themselves into knots known as the Neurofibrillary Tangles (NFTs). The neurons are filled with these NFTs and thus destroyed.
Other changes observed in the brain affected by AD are neuronal degeneration of nucleus basalis of Meynert and decreased levels of acetylcholine.
3 Causes & Risk factors
AD is one of the greatest mysteries in modern medicine. Currently, lot of research is being done in an effort to find out the causes of AD. Increase in age is the first and foremost risk factor in the development of AD.
- Chemical Causes
- A decline in growth promoting factor such as the nerve growth factor (NGF) and spontaneous increase in factors that are toxic to brain cells contribute to the dysfunction or death of the nerve cells.
- Nerve cells communicate with each other through chemicals called neurotransmitters. It has been found that patients with AD have decreased levels of neurotransmitters that influenced intellectual functioning and behavior. One such neurotransmitter extensively studied is acetylcholine.
- Accumulation of chemical toxic substances in the brain such as aluminum and mercury.
- Genetic causes AD can be divided into two types
- Familial Alzheimer's disease (FAD): this is genetically inherited. FAD has an early onset between the ages 30 to 60. Most of the FAD cases are accounted for by the Pre-Senilin 1 (PS1) gene located on chromosome 14. Abnormal proteins from the PS1 and PS2 genes influence gamma-secretase enzyme causing more beta amyloid peptide formation. The mutation on chromosome 21 is on the amyloid precursor protein (APP) gene, resulting in abnormal APP protein that is cleaved by sectretases to form more beta amyloid peptide.
- Sporadic Alzheimer's disease (SAD): this type does not show any clear pattern of inheritance and occurs typically after the age of 65. the mutation on chromosome 19 to the ApoLipoprotein E (APOE) gene poses a risk factor for SAD. Apolipoproteins play an important role in the transport of cholesterol and apolipoprotein E is a major lipoprotein for lipid transport in the cerebrospinal fluid and between cells in the brain tissue. A high level of cholesterol is associated with increased risk of AD.
- Inflammation and Immune causes as mentioned earlier the aggregation of beta amyloid peptide in brain is one of the typical findings found in AD. This peptide is aggregated into beta sheet structure of ordered fibrils. Acidic conditions that exist in lysosomes and inflammation enhance amyloid beta aggregation and this in turn mediates the activation of microglia via a positive feedback loop of immune/inflammatory activation. The microglial cells activated by the amyloid beta produce inflammatory cytokines like InterLeukin-1Î² (IL-1Î²) and Tumor Necrosis Factor alpha (TNF-alpha). The over expression of IL-1Î² may promote the phosphorylation of Tau protein, leading to the formation of NFTs and neuron death.
- Increase in blood pressure is studied to have association with the development of AD. Stroke and defects in blood vessels carrying blood to the brain may also cause AD. Serious head injuries with loss of consciousness may also be associated with later onset of AD.
- Elevated levels of an amino acid called homocysteine, a risk factor for heart disease, is also associated with an increased risk of developing AD.
AD has a very slow and gradual onset. The symptoms vary from person to person. The first symptom to be noticed is forgetfulness. The patient forgets the daily and simple tasks of life. As more and more nerve cells get damaged the symptoms worsen. AD can be divided into three stages depending on the severity of the symptoms.
- Early or Mild stage: forgetfulness, especially recent or short term memory loss, mild personality changes, cognitive impairment and difficulty in learning new things.
- Middle or Moderate stage: memory loss worsens, progressive cognitive impairment, the patient gets easily irritated, disoriented and agitated. Disturbances in behavior and appearance, problems in thinking and intellectual functioning develop; the patient tends to depend on family for making decisions.
- Late or Severe Stage: the individual becomes confused, disoriented, fails to describe or remember the current events or family members, loses control over bowel and bladder, increased agitation and irritability, becomes sedentary, frequent infections and seizures may occur and finally the individual requires constant care.
there is no specific clinical test for the diagnosis of AD. The definitive diagnosis can be made by examination of the brain usually during autopsy. The histopathological examination of the brain may reveal deposits of amyloid beta protein, neurofibrillary tangles, hirano bodies, granulovacuolar bodies of Simchowicz, pick bodies and Lewy bodies. The affected part of the brain may be atrophied.
There are many types of dementia presenting the same symptoms of AD. A thorough medical and neurological evaluation should be made to exclude other diseases with similar symptoms.
The following tests may be useful:
- History of the patient for any familial link.
- Thorough clinical examination for symptoms that is more specific for AD.
- Neurological and psychiatric examination
- Thyroid function tests and serum vitamin B12 and folic acid levels
- Toxic screening for heavy metals such as aluminum and mercury.
- Neuroimaging tests such as Computer-Assisted Tomography (CAT), Positron Emission Tomography (PET scan), Single Photon Emission Computerized Tomography (SPECT) and Magnetic Resonance Imaging (MRI). The CAT scan usually reveal changes characteristic to AD such as atrophied brain with widened sulci and enlarged cerebral ventricles.
- Examination of the cerebrospinal fluid.
- The cholinergic neurons which play an important role in learning and memory are specifically destroyed in AD. The breakdown of acetylcholine should be prevented. The only RDA approved drugs for the treatment of AD are inhibitors of the enzyme acetyl cholinesterase (AChE) such as tacrine, donezepil and galantamine. Rivastigmine is used instead of tacrine because of the side effects of the later.
- The activation of microglial cells which produce neurotoxins should be prevented. This is achieved to some extent by administration of non steroidal anti-inflammatory drugs (NSAIDS).
- Antioxidants such as Vitamin E and C can be used to prevent oxidative damage of the cells by free radicals. Melatonin may also be protective against AD.
- Ginkgo biloba maybe used to slow down the progression of AD. Especially the cognitive impairement.
- Estrogen used to treat the symptoms of menopause in women is also known to reduce the risk of development of AD. Estrogen increases alpha-secretase activity which reduces the formation of beta amyloid protein.
- DeHydroEpiAndrosterone (DHEA) supplement may reduce the risk of AD. DHEA is a natural hormone that increases the synthesis of APP which in turn reduces the formation of beta amyloid peptide.
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