Know Alzheimer’s?

Alzheimer’s disease (AD) is also known as Alzheimer’s. It is prolonged neurodegenerative disease. It starts very slowly and gets worsen. 60-70% dementia is caused by it. Short memory loss is common in Alzheimer’s patients. With the passage of time the symptoms vary and include mood swings, careless about him, loss of motivation, and even forgetting the language. The patient’s behavior is changed and he feels alone with his family and friends. Slowly, body functions are disturbed. All these symptoms eventually lead to death. The cases may vary according to start of diagnosis and the life of patients under diagnosis may vary from three to nine years. [1]

Causes of Alzheimer

The cause is poorly understood. More than 70% cases are reported due to genetic causes. But physical injury especially head injury is also involved to trigger the disease. Depression and hypertension may also involve the process. All the process of disease is associated with the brain mainly. The diagnosis of disease is based on different tests including imaging and blood tests. Aging causes some symptoms to appear. But final diagnosis is made by studying the brain tissues. It can be avoided by maintaining the mental health and by doing exercises both physical and mental. There are no recommended medicines available in market that decreases the risk of disease. There is no any treatment that stops its progression but improve some symptoms only temporarily. The patients should be treated with intense care as they suffer from different symptoms. The memory loss can only be cured by psychotics. Exercise proves beneficial in this regard. [1] [2]

Signs and Symptoms

Due to ageing, many memory related complications arise in AD patients. These may include forgetting things occasionally, short term memory loss, misplacing things, and even forgetting the main incidents. This disease includes three stages. These stages are divided into early, middle and last stage. [3]

Early stage of disease

Early stage can only be evicted by close friends and relatives. The patient forgets the names of his family members and always stays confused in different issues. He forgets about the detail of any extraordinary incident and has a short term memory loss. He also forgets about his forgetfulness and blames others. [3][4]

Middle stage of disease

Middle stage is somewhat more complicated than early stage. The patient suffers more difficulty in remembering the current issue. His confusion is more increased about everything and issue. He suffers problems with his sleep. He feels confliction in his life and tries hard to be not a part of it but fails.[3]

Last stage of disease

The final stage of disease includes poor ability of patient to think. He suffers problems during speech. He may repeats some conversations and may be uses some abusive and annoying words. He even forgets about where he is now. [3][4]

Pre-dementia

When the early stage is appeared, disappointingly it is associated with ageing and stress. The disease is neglected and not diagnosed at correct time. Neuropsychological testing reveals mild cognitive symptoms. [4] The disease could be otherwise diagnosed up to eight years. The early symptoms affect the complex activities of life. Short memory loss is a common symptom. He becomes unable to get new information. He cannot pay attention to any issue. He is unable to make plans due to impaired semantic memory. The preclinical stage is also termed as mild cognitive impairment. It is an overlapping stage between normal ageing and dementia. It has a wide array of symptoms. Memory loss is a dominant symptom. It is known as amnestic MCI.[5]

Moderate symptoms

The patient suffers with acute disturbance in language and cannot recall vocabulary. Reading and writing skills are also diminished. It leads to common incorrect words changes. Complex motor activities are not coordinated. Risk of disease increase with time and symptoms become more severe. Behavioral changes become more obvious. [5] Common signs are aggression, crying, irritating and wandering. Usually, patient becomes so irritating and aggressive to his family members that he is moved from house to long term care departments. [6]

Advanced

Advanced level includes final stage of disease. The patient is unable to take care of himself. Due to difficulty in memorizing vocabulary, he is overlaid to simple phrases and may be single words. In some cases, patient becomes speechless. [8] Patient only contacts through some emotional signals. But aggressiveness is still a dominant factor of his personality. He stays at most the times aggressive and exhausted. He cannot perform any task. He becomes immobile due to muscle mobility deterioration. He becomes unable to take his food. The caregiver is always there to do all his activities of life. The disease may not prove cause of death itself and patient may die due to pneumonia and ulcers. [7] [8]

Causes

The cause of disease may vary in different patients. It may be due to genetic causes and may not be. Different hypothesis are given to describe the cause of disease but nothing is still proved. In cases of 1-5 % genetic variations are found to be a discrete cause of disease. [10]

Genetic

Usually the disease is dominant autosomal inherited. It involves onset of age before 65. It is called as early onset familial Alzheimer disease. The mutations of genes mainly occur at three different genes. These genes may be Amyloid precursor encoding gene or presenilin 1 and 2. [11] These genes are encoded in a way to increase the production of Aβ42. This protein is main component of senile plaques. Other mutations alter the ratio of production of major and minor proteins. Aβ42 is minor protein while Aβ40 is major protein. The change in rate of production of these proteins may result autosomal genetic defect to cause the disease.  [12]

In other cases, the disease may not be due to genetic causes but due to other environmental or geographical causes. Then it is referred to as Sporadic AD. The rate of different exposure acts as risk factor of disease. It is indirectly due to some genetic changes. [13]

Cholinergic hypothesis

Cholinergic hypothesis is the oldest hypothesis. Many drug therapies are based on it. It occurs due to reduction in synthesis of neurotransmitters named as acetylcholine. The medications designed to fulfill the deficiency of acetylcholine is not proved effective. [15]

Amyloid hypothesis

Amyloid hypothesis was presented in 1991. It postulates that the deposits of extracellular amyloid beta are the basic cause of disease. This hypothesis is considered much important. It finds its significance as the gene defect in amyloid precursor protein encoding gene is present on chromosome 21. The patients of Down’s syndrome show trisomy and are more sensitive towards disease even at the age of 40.experiments were performed in laboratory revealed that transgenic mice expressing mutant form of human APP gene was developed fibrillar plaques of amyloid. The brain suffered with pathology of learning deficiency. [14]

A vaccine in clinical trial was made to clear the plaque formation in human trials. But unluckily, it was not proved helpful to remove these plaques and no significant role in dementia. Some researchers suspect that A_β as primary pathogenic form of A_β. Amyloid-derived diffusible ligands (ADDLs) are toxic oligomers. These oligomers bind to a receptor present on surface of neurons. The change in structure of synapse occurs. It disrupts the communication of neurons that is mainly occurred by synapses. The synapses are junctions between neurons through which they mainly communicate with the help of releasing specific chemicals known as neurotransmitters. A_β oligomer receptor is a prion protein. [7] [15] Mad cow disease is a common and worse disease of humans is caused by same kind of prion protein. This kind of prion protein is known as Creutzfeldt-Jakob disease. In this way, a link is detected in the mechanism of neurodegenerative illnesses and the disorders and pathophysiology of Alzheimer disease. [12] [16]

In 2009, amyloid hypothesis undergone a change and slightly updated by some new concepts. It was suggested that the major culprit of the disease is beta amyloid protein. Before it, it was considered that beta amyloid is the major cause of the disease. But beta amyloid does not play any role in pathology. The neuronal connections are disturbed due to ageing and cause withered neuronal junctions of Alzheimer disease. The amyloid beta protein is adjacent to the N termini of N-APP. The amyloid beta protein is cleaved from APP. When it is cleaved, APP undergoes destructive pathway and binds to death receptor 6.  TNFRSF21 is another name commonly used for death receptor 6. It is expressed in human brain. Brain regions are mostly affected by this high expression of death receptor. The pathway may be disturbed by the ageing process. In this way, beta amyloid plays crucial role in depression of synaptic functions. [12] [17]

In 2017, an experiment was performed of verubecestat. It inhibits beta secretase protein. This protein is a major cause of production of amyloid protein. This experiment was also uncompleted like always because there was no positive clue for the treatment of Alzheimer’s disease. [8]

Tau hypothesis

Fig (A)

The tau hypothesis defines the role of tau protein. The abnormalities in tau protein initiate the disease process. In figure, it is shown that tau is present in hyperphosphorylated form at the beginning. It is used to pair with threads of tau protein. In this way, neurofibrillary tangles formation takes place. This formation is occurred in nerve cell bodies. The consequences of the upper described process result in way that microtubules disintegration occurs, cytoskeleton is disrupted. It collapses the transport system of neurons. This complicated process results in more complications. It affects the communication of neurons at early stages. Later on, it results in death of individual. [12]

Other hypotheses

• Blood brain barriers can also play as a causative agent of the disease. This is a neurovascular hypothesis. If the blood brain barriers are damaged and they are unable to play their role in the control of homeostasis. Then complications arise.
• If the biometals named as iron, zinc, copper are disrupted and failed to maintain their normal range. The ions of these metals cause impaired regulation and affects homeostasis. This hypothesis is very much controversial.
• Smoking also plays role in AD. It acts as a risk factor of the disease.
• Air pollution may act as a risk factor of the disease. It is a tentative hypothesis.
• Spirochetes may cause gum infection. This kind of gum infection is not normal and may cause the state of dementia. Similarly, fungal infection may also acts as a risk factor of disease.
• Oligodendrocytes malfunctioning results in axon damage. It causes amyloid production and tau protein is hyperphosphorylated.
• Reterogenesis is also a common hypothesis about AD. It is very important at medical point of view. The fetus goes through the process of neurulation. During this, the neural development of fetus occurs. The brains of patients go through a reverse process. Neurodegeneration occurs. The death of axons results death of white and grey matter.

Fig (B)

Neurofibrillary tangles are formed due to defect in neurons. This figure illustrates it well.

Normal brain having no defection is shown.

Neuropathology

Alzheimer’s disease basically is caused by loss of synapses and impaired working of neurons in cerebral cortex area. This impaired working and loss results in atrophy of cerebral cortex. It results in degeneration of parietal and temporal lobes. The parts of frontal cortex, subcortex and cingulate gyrus are also affected. Locus coeruleus is known as brainstem nuclei are also degenerated. Magnetic resonance imaging revealed that the specific parts of brains are reduced in their sizes in AD patients. While, healthy do not show the symptoms. Amyloid plaques formation is also observed in these patients.  Neurofibrils in tangled forms are also made visible. These plaques resemble in form with insoluble, dense deposits of beta amyloid. Tangles are basically aggregates of tau protein. This tau protein is hyperphosphorylated and is accumulated in cells to form tangles. [16]

Biochemistry

Fig (C)

Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.

Alzheimer’s disease is also well known due to protein misfolding. In this way, it is referred to as proteopathy. The plaques formation takes place by amyloid beta protein. This protein is accumulated in cells at abnormal levels leading to pathology. Plaques are generally small peptides; 39-43 aminoacids are present in an abnormal manner to form plaques.  A_β is fragment of amyloid precursor protein. APP is a transmembrane protein and passes through the membrane of neuron. APP is necessary for growth and survival of injury repair. Gamma secretase and beta secretase work together to cause proteolytic cleavage of APP. These cleaved parts are clumped together to form smaller fragments and forms senile plaques.

AD may also be correlated with taupathy. The abnormal aggregation of tau protein is a leading cause of disease. The microtubules form the inner support of a cell also a neuron. The cytoskeleton is made by microtubules and provides a support system.  These structures act as tracks leading and guiding to many important structures and functions. Tau protein stabilizes the structure of microtubules, phosphorylation occurs. These are also reffered as microtubule associated proteins. If these proteins are tangled in a way to become hyperphosphorylated. The hyperphosphorylated form is responsible to interaction of threads with each other creating neurofibrillary tangles. It causes neuronal death and leads to pathology. [3] [16]

Fig (D)

Diagnosis

Alzheimer’s disease is diagnosed on the basis of medical and disease history of a patient. Usually, it is diagnosed on the behavioral conditions of patients. Magnetic resonance imaging known as MRI, positron emission tomography known as PET, computed tomography known as CT, and single photon emission computed tomography known as SPECT are different diagnosing techniques developed to diagnose AD patients with clear symptoms. These techniques may also able to predict the stage of pathology mostly mild cognitive impairment to AD. The stage of disease can be further elaborated by different types of tests. The intellectual functions of AD patients are assessed to predict the mental state of patient. Memory testing is used to test memory of patient. For practicing physicians, it is much easier to diagnose the patient after death. It is determined with high accuracy post mortem because brain materials can be easily studied histologically now. [17] [18]

Criteria

The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) are two international institutes working on AD. They were established in 1984 for diagnosis of AD patients. They updated that dementia symptoms are confirmed that they lead to disease or not by psychological testing. Through this testing, it is confirmed that the AD is found or not. Through this testing, the patient goes through a sequence of clinical trials. Brain tissues are diagnosed to confirm the disease. Different eight domains are disturbed in AD patients. These eight domains include language, focusing to any problem or view, memory, problem resolving, attention, functional abilities, self-care, and orientation. [12] [16]

Medication

Many cardiovascular threat issues as hypercholesterolaemia and hypertension are associated with the AD. Statin is a drug used to lower the level of cholesterol in blood. This drug is still not proved effective to improve or prevent the symptoms associated with AD.

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) was considered in 2007 to reduce the prevalence of AD. Mechanism behind this is that it is used to reduce the inflammation caused by amyloid plaque formation. But trials of this medication again were disappointing. It was not proved beneficial to cure the AD in trials.

Generally five medicines are currently in use to treat cognitive problems of AD. There are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit observed is very small. There is no any medicine that is used to stop the progression of disease still.

Cholinergic neurons are reduced in activity in Alzheimer’s disease. Acetylcholinesterase inhibitors are used to decrease the rate of breakdown of acetylcholine. It increases the concentration of acetylcholine in brain area. In this way, it combats the causes involved in reduction and death of cholinergic neurons. Most common side effects in users are observed as nausea and vomiting. Both of these symptoms are indirectly associated with the excess of cholinergic. Very less users suffer from the secondary side effects of this drug. The symptoms

may involve cramps, loss of appetite, weight loss, decreased heart rate, and acidity in stomach. [13] [15] [17]

References:

1. Burns A, Iliffe S (February 2009). “Alzheimer’s disease”. BMJ. 338: b158
2. “Dementia Fact sheet”. World Health Organization. 12 December 2017
3. Mendez MF (November 2012). “Early-onset Alzheimer’s disease: nonamnestic subtypes and type 2 AD”
4. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (March 2011). “Alzheimer’s disease”. Lancet. 377 (9770): 1019–31.
5. “Dementia diagnosis and assessment” (PDF). National Institute for Health and Care Excellence (NICE). Archived from the original (PDF) on 5 December 2014. Retrieved 30 November 2014.
6. Commission de la transparence. Médicaments de la maladie d’Alzheimer [Drugs for Alzheimer’s disease: best avoided. No therapeutic advantage]. Prescrire International. June 2012;21(128):150.
7. The possible role of antioxidant vitamin C in Alzheimer’s disease treatment and prevention. American Journal of Alzheimer’s Disease & Other Dementias. March 2013;28(2):120–25.
8. Vitamin C and Vitamin E for Alzheimer’s Disease. The Annals of Pharmacotherapy. 2005;39(12):2073–80
9. Cholinesterase inhibitors for Alzheimer’s disease. The Cochrane Database of Systematic Reviews. 2006
10. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Medicine. 2007;4(11):e338
11. Clinical Features of Alzheimer’s Disease. European Archives of Psychiatry and Clinical Neuroscience. 1999;249(6):288–90.
12. Language Performance in Alzheimer’s Disease and Mild Cognitive Impairment: a comparative review. Journal of Clinical and Experimental Neuropsychology. July 2008;30(5):501–56.
13. Alzheimer Disease and Down Syndrome: Factors in Pathogenesis. Neurobiology of Aging. 2005;26(3):383–89.
14. Apolipoprotein E, Dementia, and Cortical Deposition of Beta-amyloid Protein. The New England Journal of Medicine. 1995;333(19):1242–47.
15. Regional Distribution of Neurofibrillary Tangles and Senile Plaques in the Cerebral Cortex of Elderly Patients: A Quantitative Evaluation of a One-year Autopsy Population from a Geriatric Hospital. Cerebral Cortex. 1994;4(2):138–50.
16. New insights into brain BDNF function in normal aging and Alzheimer disease. Brain R Early diagnosis of dementia: neuropsychology. Journal of Neurology. 1999;246(1):6–15. esearch Reviews. 2008;59(1):201–20
17. Awareness of Deficits and Anosognosia in Alzheimer’s Disease. L’Encéphale. 2004;30(6):570–77.
18. The Initial Symptoms of Alzheimer Disease: Caregiver Perception. Acta Médica Portuguesa. 2004;17(6):435–44. Portuguese.

References for figures:

A: Cholinesterase inhibitors for Alzheimer’s disease. The Cochrane Database of Systematic Reviews. 2006

B: Alzheimer Disease and Down Syndrome: Factors in Pathogenesis. Neurobiology of Aging. 2005;26(3):383–89.

C: Apolipoprotein E, Dementia, and Cortical Deposition of Beta-amyloid Protein. The New England Journal of Medicine. 1995;333(19):1242–47.

D: The possible role of antioxidant vitamin C in Alzheimer’s disease treatment and prevention. American Journal of Alzheimer’s Disease & Other Dementias. March 2013;28(2):120–25.