INTRODUCTION:

Alzheimer's disease is a neurological disorder in which the death of brain cells causes memory loss and cognitive decline. A neurodegenerative type of dementia, the disease starts mild and gets progressively worse.

It was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.^[1] Most often, AD is diagnosed in people over 65 years of age,^[2] although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.^[3]

The likelihood of having Alzheimer's disease increases substantially after the age of 70 and may affect around 50% of persons over the age of 85. ^[4]

SYMPTOMS:

The symptoms of Alzheimer’s disease progress slowly over several years. However, the rate at which they progress will differ for each individual. No two cases of Alzheimer's disease are ever the same because different people react in different ways to the condition. However, generally, there are three stages of the condition, ^[35]

· Mild

· Moderate

· Severe

These stages are described below.

Mild Alzheimer's disease:

Common symptoms of mild Alzheimer's disease include,

· Forgetfulness

· Mood swings

· Speech problems

These symptoms are a result of a gradual loss of brain function. The first section of the brain to start deteriorating is often the part that controls the memory and speech functions.

Moderate Alzheimer's disease:

As Alzheimer's disease develops into the moderate stage, it can also cause:

· Disorientation

· Difficulty performing spatial tasks (such as judging distances or finding your way around)

· Problems with eyesight which could lead to poor vision, or in some cases, hallucinations (where you hear or see things that are not there)

· Delusions – believing things that are untrue

· Obsessive or repetitive behaviour

· A belief that you have done or experienced something that never happened

· Disturbed sleep

· Incontinence – where you unintentionally pass urine (urinary incontinence) or stools (faecal or bowel incontinence)

During the moderate stage, you may have difficulty remembering very recent things. Problems with language and speech could also start to develop at this stage. This can make you feel frustrated and depressed, leading to mood swings.

Severe Alzheimer's disease:

Someone with severe Alzheimer's disease may seem very disorientated and is likely to experience hallucinations and delusions. They may think that they can smell, see or hear things that are not there, or believe that someone has stolen from them or attacked them when they have not. This can be distressing for friends and family, as well as for the person with Alzheimer's disease. The hallucinations and delusions are often worse at night, and the person with Alzheimer's disease may start to become violent, demanding, and suspicious of those around them.

As Alzheimer's disease becomes severe, it can also cause a number of other symptoms such as:

· Dysphagia (difficulty swallowing)

· Difficulty changing position or moving from place to place without assistance

· Weight loss or a loss of appetite

· Increased vulnerability to infection

· Complete loss of short-term and long-term memory

It is important to note that infections or medication can sometimes be responsible for an increase in symptoms of disorientation or disturbed behaviour. People with any stage of Alzheimer's disease with symptoms that rapidly increase should be investigated to rule out these causes.

During the severe stage of Alzheimer's disease, people often start to neglect their personal hygiene. At this stage that most people with the condition will need to have full-time care because they will be able to do very little on their own. ^[35]

CAUSES:

Although it is still unknown what causes the deterioration of brain cells, there are several factors that are known to affect the development of Alzheimer's disease. These are described in more detail below.

Age:

Age is the greatest factor in the development of Alzheimer's disease. The likelihood of developing the condition doubles every five years after you reach 65 years of age.

Family history:

Genetic factors contribute to the risk of developing Alzheimer’s disease. Though in most cases, if you have a close family member with the condition, your risk of developing it is only slightly increased.

However, in a few families, Alzheimer’s disease is caused by the inheritance of a single gene, and the risks are much greater. If several of your family members over the generations have developed dementia, it may be appropriate to seek genetic advice and counselling.

Down's syndrome:

People with Down's syndrome are at a higher risk of developing Alzheimer's disease. This is because people with Down's syndrome have an extra copy of chromosome 21, which codes for a protein involved in the cause of Alzheimer's disease. Therefore, people with Down's syndrome produce more abnormal protein, which could contribute to developing Alzheimer's disease. ^[5,6]

Whiplash and head injuries:

People who have had a severe head injury, or severe whiplash, (a neck injury caused by a sudden movement of the head forwards, backwards or sideways) have been found to be at a higher risk of developing Alzheimer's disease.

Vascular disease:

Research shows that several lifestyle factors and conditions associated with vascular disease can increase the risk of Alzheimer’s disease.

These include:

· Smoking

· Obesity

· Diabetes

· High blood pressure

· High cholesterol

Amyloid cascade hypothesis:

The "amyloid cascade hypothesis" is the most widely discussed and researched hypothesis about the cause of Alzheimer's disease. The strongest data supporting the amyloid cascade hypothesis comes from the study of early-onset inherited (genetic) Alzheimer's disease.^[7,8] Mutations associated with Alzheimer's disease have been found in about half of the patients with early-onset disease. In all of these patients, the mutation leads to excess production in the brain of a specific form of a small protein fragment called ABeta (Aβ). Many scientists believe that in the majority of sporadic (for example, non-inherited) cases of Alzheimer's disease (these make up the vast majority of all cases of Alzheimer's disease) there is too little removal of this Aβ protein rather than too much production. ^[9,10] In any case, much of the research in finding ways to prevent or slow down Alzheimer's disease has focused on ways to decrease the amount of Aβ in the brain. ^[11-13]

Cholinergic hypothesis:

The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.^[14,15]

Tau hypothesis:

The tau hypothesis is the idea that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.^[16,17]

Pathophysiology:

Alzheimer’s disease (AD) is a progressive dementia with loss of neurons and the presence of two main microscopic neuropathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles.^[18]

Early onset AD, the rare familial form, is the result of a mutation in one of three genes, APP (amyloid precursor protein), PS1 (PSEN1, presenilin 1) or PS2 (PSEN2, presenilin 2). The sporadic form occurs usually after 65 years of age and accounts for most cases; it most likely results from a combination of genetic and environmental influences

The only confirmed risk factors for sporadic AD are age and the presence of the E4 allele of APOE (apolipoprotein E)^[19]

Amyloid plaques comprise mainly of the neurotoxic peptide amyloid (Aβ, Abeta), cleaved sequentially from a larger precursor protein (APP) by two enzymes: β-secretase (also called BACE1) and γ-secretase (comprising four proteins, one of which is presenilin). If APP is first cleaved by the enzyme α-secretase rather than β-secretase then Aβ is not formed.

Neurofibrillary tangles comprise mainly of the protein tau which binds microtubules, thereby facilitating the neuronal transport system. Uncoupling of tau from microtubules and aggregation into tangles inhibits transport and results in microtubule disassembly. Phosphorylation of tau may play an important role in this.

Selective vulnerability of neuronal systems such as the cholinergic, serotonergic, noradrenergic and glutamatergic systems form the basis of current rational pharmacological treatment. ^[20,21]

EPIDEMIOLOGY:

More than 25 million people in the world today are affected by dementia, most suffering from Alzheimer's disease. In both developed and developing nations.

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at any given time.

Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person–years for all dementias and 5–8 for AD, ^[22,23] which means that half of new dementia cases each year are AD. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every five years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years.^[22,23] There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.^[24] The risk of dying from Alzheimer’s disease is twenty-six percent higher among the non-Hispanic white population than among the non-Hispanic black population, whereas the Hispanic population has a thirty percent lower risk than the non-Hispanic white population.^[25]

Prevalence of AD in populations is dependent upon different factors including incidence and survival. Since the incidence of AD increases with age, it is particularly important to include the mean age of the population of interest. In the United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall and in the 65–74 age group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than 84 group.^[25] Prevalence rates in less developed regions are lower.^[26] The World Health Organization estimated that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would increase to 0.441% in 2015 and to 0.556% in 2030.^[27] Other studies have reached similar conclusions. Another study estimated that in 2006, 0.40% of the world population (range 0.17–0.89%; absolute number 26.6 million, range 11.4–59.4 million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by 2050.^[28,29]

DIAGNOSIS:

Tests:

There is no simple, reliable test for diagnosing Alzheimer's disease, so the diagnosis is usually based on ruling out other conditions. You may have blood tests and a physical examination to rule out other medical conditions that could be causing your symptoms.

If your GP suspects Alzheimer's disease, you may also be given a brain scan, which will look for changes in your brain. This could be:

· A computerized tomography (CT) scan – where several X-rays of your brain are taken at slightly different angles, and a computer is used to put the images together

· A magnetic resonance imaging (MRI) scan – where a strong magnetic field and radio waves are used to produce detailed images of the inside of your brain ^[30,,31]

Cognitive tests have changed little since being established by work from the likes of Professor Henry Hodkinson in the 1970s. The following example list of questions reveals the types of memory loss and areas of cognition that are tested and may indicate Alzheimer's.

The "abbreviated mental test score" (AMTS):

1. What is your age?

2. What is the time, to the nearest hour?

3. Repeat an address at the end of the test that I will give you now (e.g. "42 West Street")

4. What is the year?

5. What is the name of the hospital or town we are in?

6. Can you recognize two people (e.g. the doctor, nurse, home help, etc.)?

7. What is your date of birth?

8. In what year did World War 1 begin? (Other widely known dates in the past can be used.)

9. Name the president/prime minister/monarch.

10. Count backwards from 20 down to 1.

The general practitioner assessment of cognition (GPCOG) test is a website-based assessment designed to be an early reliable indicator for use in initial consultations with GPs. ^[31,32]

The mini mental state examination (MMSE) is a fuller cognitive test to help diagnose Alzheimer's disease. It is also sensitive to the severity of the disorder and helps to indicate when drug treatment could ease symptoms appearing later in the course of the disease ^[32,33]

· Normal cognitive health - score above 26

· Mild-to-moderate Alzheimer's - below 26

· Moderate - below 20 but above 10

· Severe - score under 10.

TREATMENT:

Cholinesterase inhibitors:

In patients with Alzheimer's disease there is a relative lack of a brain chemical neurotransmitter called acetylcholine. (Neurotransmitters are chemical messengers produced by nerves that the nerves use to communicate with each other in order to carry out their functions.) Substantial research has demonstrated that acetylcholine is important in the ability to form new memories. The cholinesterase inhibitors (ChEIs) block the breakdown of acetylcholine. As a result, more acetylcholine is available in the brain, and it may become easier to form new memories.

Four ChEIs have been approved by the FDA, but only donepezil hydrochloride (Aricept), rivastigmine (Exelon), and galantamine (Razadyne - previously called Reminyl) are used by most physicians because the fourth drug, tacrine (Cognex) has more undesirable side effects than the other three. Most experts in Alzheimer's disease do not believe there is an important difference in the effectiveness of these three drugs. Several studies suggest that the progression of symptoms of patients on these drugs seems to plateau for six to 12 months, but inevitably progression then begins again. of the three widely used AchEs, rivastigmine and galantamine are only approved by the FDA for mild to moderate Alzheimer's disease, whereas donepezil is approved for mild, moderate, and severe Alzheimer's disease. It is not known whether rivastigmine and galantamine are also effective in severe Alzheimer's disease, although there does not appear to be any good reason why they shouldn't.^[34]

Partial glutamate antagonists:

Glutamate is the major excitatory neurotransmitter in the brain. One theory suggests that too much glutamate may be bad for the brain and cause deterioration of nerve cells. Memantine (Namenda) works by partially decreasing the effect of glutamate to activate nerve cells. It has not been proven that memantine slows down the rate of progression of Alzheimer's disease. Studies have demonstrated that some patients on memantine can care for themselves better than patients on sugar pills (placebos). Memantine is approved for treatment of moderate and severe dementia, and studies did not show it was helpful in mild dementia. It is also possible to treat patients with both AchEs and memantine without loss of effectiveness of either medication or an increase in side effects. ^[34]

Potential and future therapies for Alzheimer's disease:

A variety of clinical research trials are underway with agents that try either to decrease the amount of _Aβ1-42 produced or increase the amount of _Aβ1-42 removed. It is hoped that such therapies may slow down the rate of progression of Alzheimer's disease.

PREVENTION:

There is some evidence suggesting that rates of dementia are lower in people who remain as mentally, physically, and socially active as possible throughout their lives, and also among those who enjoy a wide range of different activities and hobbies. ^[35]

Some activities that may reduce the risk of developing dementia include,

· Reading

· Writing for pleasure

· Learning foreign languages

· Playing musical instruments

· Taking part in adult education courses

· Playing tennis

· Playing golf

· Swimming

· Group sports, such as bowling

· Walking.

REFERENCES:

1. Berchtold NC, Cotman CW. Evolution in the Conceptualization of Dementia and Alzheimer's Disease: Greco-Roman Period to the 1960s. Neurobiol. Aging. 1998;19(3):173–89.

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. American Journal of Public Health. 1998;88(9):1337–42.

3. Brookmeyer R, Johnson E, Ziegler-Graham K, MH Arrighi. Forecasting the global burden of Alzheimer's disease. Alzheimer's and Dementia. 2007 [Retrieved 2008-06-18];3(3):186–91.

4. World population prospects: the 2006 revision, highlights [PDF]. 2007 [Retrieved 2008-08-2

5. Nistor M. 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.

6. Lott IT, Head E. Alzheimer Disease and Down Syndrome: Factors in Pathogenesis. Neurobiol Aging. 2005;26(3):383–89

7. 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.

8. Polvikoski T. Apolipoprotein E, Dementia, and Cortical Deposition of Beta-amyloid Protein. N Engl J Med. 1995;333(19):1242–47.

9. Games D. Alzheimer-type Neuropathology in Transgenic Mice Overexpressing V717F Beta-amyloid Precursor Protein. Nature. 1995;373(6514):523–27.

10. Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. Comparison of Neurodegenerative Pathology in Transgenic Mice Overexpressing V717F Beta-amyloid Precursor Protein and Alzheimer's Disease. J Neurosci. 1996;16(18):5795–811.

11. Hsiao K. Correlative Memory Deficits, Abeta Elevation, and Amyloid Plaques in Transgenic Mice. Science. 1996;274(5284):99–102.

12. Lauren J. Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers. Nature. 2009; 457 (7233): 1128–32.

13. Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M. APP Binds DR6 to Cause Axon Pruning and Neuron Death via Distinct Caspases. Nature. 19 February 2009;457(7232):981–989. Goedert M, Spillantini MG, Crowther RA. Tau Proteins and Neurofibrillary Degeneration. Brain Pathol. 1991;1(4):279–86.

14. 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.

15. Shen ZX. Brain Cholinesterases: II. The Molecular and Cellular Basis of Alzheimer's Disease. Med Hypotheses. 2004;63(2):308–21.

16. Iqbal K. Tau Pathology in Alzheimer Disease and Other Tauopathies. Biochim Biophys Acta. 2005;1739(2–3):198–210.

17. Chun W, Johnson GV. The Role of Tau Phosphorylation and Cleavage in Neuronal Cell Death. Front Biosci. 2007;12:733–56

18. Kotzbauer PT, Trojanowsk JQ, Lee VM. Lewy Body Pathology in Alzheimer's Disease. J Mol Neurosci. 2001;17(2):225–32

19. Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of Protein Aggregation in Mitochondrial Dysfunction and Neurodegeneration in Alzheimer's and Parkinson's Diseases. Neuromolecular Med.. 2003;4(1–2):21–36.

20. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. Synapse Formation and Function is Modulated by the Amyloid Precursor Protein. J. Neurosci. 2006;26(27):7212–21.

21. Turner PR, O'Connor K, Tate WP, Abraham WC. Roles of Amyloid Precursor Protein and its Fragments in Regulating Neural Activity, Plasticity and Memory. Prog. Neurobiol.. 2003; 70(1):1–32.

22. Bermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC. Incidence and subtypes of dementia in three elderly populations of central Spain. J. Neurol. Sci.. 2008; 264(1–2):63–72.

23. Di Carlo A. Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. J Am Geriatr Soc. 2002; 50(1):41–8.

24. Andersen K. Gender Differences in the Incidence of AD and Vascular Dementia: The Eurodem Studies. Eurodem Incidence Research Group. Neurology. 1999;53(9):1992–7.

25. Tejada-Vera, B. (2013). Mortality from Alzheimer’s Disease in the United States: Data for 2000 and 2010. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics.

26. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer Disease in the US population: Prevalence Estimates Using the 2000 census. Arch. Neurol.. 2003;60(8):1119–22.

27. "Profiles of General Demographic Characteristics, 2000 Census of Population and Housing, United States" (PDF). U.S. Census Bureau. 2001. Archived from the original on 19 August 2008. Retrieved 2008-08-27.

28. Ferri CP. Global Prevalence of Dementia: A Delphi Consensus Study. Lancet. 2005;366(9503):2112–7.

29. World Health Organization (2006). Neurological Disorders: Public Health Challenges. Switzerland: World Health Organization. pp. 204–207.

30. Hodkinson HM. Evaluation of a mental test score for assessment of mental impairment in the elderly. Age and Ageing, 2012, volume 41, supplement 3, pages iii35-40. Reprint of original 1972 paper published online

31. Alzheimer’s Association. Cognitive assessment. Information on Alzheimer’s disease for healthcare professionals. Published online, accessed November 1st, 2013.

32. NICE. Diagnosis and assessment of dementia. In: Dementia: Supporting people with dementia and their carers in health and social care, NICE clinical guideline. London, UK: National Institute for Health and Care Excellence, November 2006.

33. Alzheimer’s Society. The mini mental state examination (MMSE). Fact sheet published online, accessed November 1st, 2013.

34. Medicinenet.comPrevention

35. www.nhs.uk

Received on 02.02.2014 Modified on 01.03.2014

Res. J. Pharmacology & P’dynamics. 6(1): Jan.-Mar. 2014; Page 59-63