This article will describe and classify AD and examine the current evidence and theories on its pathogenesis. It is surprising how little is still known and understood about the aetiology, pathogenesis, treatment, management and prevention of AD.
This article will describe and classify AD and examine the current evidence and theories on its pathogenesis. It is surprising how little is still known and understood about the aetiology, pathogenesis, treatment, management and prevention of AD.
This article will describe and classify AD and examine the current evidence and theories on its pathogenesis. It is surprising how little is still known and understood about the aetiology, pathogenesis, treatment, management and prevention of AD.
July 2013 | Volume 23 | Number 6 PRIMARY HEALTH CARE 32
Continuing professional development
Aims and intended learning outcomes This article explores the reasons Alzheimers disease (AD) challenges scientists, current medical thinking on pathogenesis and, most importantly, patients and their families, and why effective treatments or a cure remain elusive. This article will describe and classify AD, and will examine the current evidence and theories on its pathogenesis. After reading the article you should be able to: Classify the different types of AD and describe the pathological profile of the disease. Identify the theories on causes and pathogenesis of AD, including risk factors. Outline the reasons why there is a lack of progress in a cure for AD. Describe the strategies for new drug treatment approaches for AD. Discuss the social and moral dilemmas that face families of patients with AD and how they can be addressed. Identify personal learning needs on understanding AD in your professional role. Now do time out 1 Introduction More than a century ago Alois Alzheimer characterised a disease in a patient who had died from an unusual mental illness (Alzheimer 1907). It is surprising how little is still known and understood about the aetiology, pathogenesis, treatment, management and prevention of AD (Goedert 2009). Diagnosis is difficult, particularly in the early stages, with confirmed diagnosis only possible once dementia has manifested to the point where the distinction between mild cognitive impairment (MCI), arguably a normal part of the ageing process, and AD is not so subtle, precluding any confusion or overlap in symptoms. So, why has there been such little progress in advancing our understanding of this devastating and incurable disease? The answers may lie in the complexity of human beings and assumptions about normal ageing compared with what constitutes AD and the differences between the two. Experiments on mice have demonstrated significant success in possible drug treatment strategies based on current understanding of pathophysiological mechanisms, yet have failed in clinical trials. Bapineuzumab, for example, demonstrated clear benefits in mice but failed to improve cognition and daily function compared with placebo in patients (Castillo 2012). Now do time out 2. 1 Understanding of the condition T i m e
o u tBefore reading the account of AD, write down a paragraph summary of the condition, such as you might use to teach a nursing student. Refer to this as you read on, identifying where your understanding is challenged or supplemented. Reflect on where your ideas on the disease come from. Correspondence info@yaso-shan.co.uk Yaso Shan is a medical writer and health consultant at Vinings Natural Health Centre in West Sussex Keywords Alzheimers disease, dementia, mental illness, ageing These keywords are based on the subject headings from the British Nursing Index. For related articles visit our online archive and search using the keywords Peer review This article has been subject to double-blind review and has been checked using antiplagiarism software Conflict of interest None declared Author guidelines www.primaryhealthcare.net Abstract Alzheimers disease was first identified more than 100 years ago but still relatively little is known and understood about the aetiology, pathogenesis, treatment, management and prevention of the disease. Diagnosis is difficult, particularly in the early stages, and effective treatments remain elusive. This article reviews the evidence and theories on the pathogenesis of the disease, outlines risk factors and treatment options and examines some of the ethical dilemmas that nurses and patients face. PHC788 Shan Y (2013) Treatment of Alzheimers disease. Primary Health Care. 23, 6, 32-38. Date of submission: August 24 2012. Date of acceptance: December 12 2012. Treatment of Alzheimers disease PHC JULY 2013 32-38.indd 32 25/06/2013 10:57 PRIMARY HEALTH CARE July 2013 | Volume 23 | Number 6 33 Continuing professional development
Definition and prevalence AD is the most common form of dementia. It is a degenerative, incurable and terminal disease. It is the most common form of senile dementia and, along with cerebrovascular disorders, the leading cause of dementia in our population (Alzheimers Society 2012). On a biological level, AD is described as a clinicopathological state literally meaning the loss of the ability to think (Gandy 2005). Clinically, patients exhibit progressive cognitive failure including loss of the ability to form and retrieve new memories, changes in personality and a loss of the ability to navigate even the most familiar environments. Ultimately, all cortical function is lost and death occurs as a complication of the terminally bed-bound state, for example, with pneumonia or sepsis (Lublin and Gandy 2010). There is also a decline in reasoning, which involves establishing connections, forming judgements and making decisions. However, there is disagreement about the extent of some of these symptoms prior to diagnosis and about the basic nature of the disease itself even among AD specialists. That controversy is no better illustrated than in contemplation of how the disease is initiated at the molecular level (Gandy 2005). Ageing populations have increased the prevalence of AD. The disease constitutes 62 per cent of all cases of dementia and there were 800,000 people in the UK with a form of dementia in 2012 (more than 17,000 of whom were under 65) (Alzheimers Society 2012); the number of cases is expected to rise to more than 1.7 million by 2051. Now do time out 3. Pathology AD is defined by a characteristic loss of hippocampal and cerebrocortical neurons (Lublin and Gandy 2010). These regions control memory, thought, language, attention, perception and consciousness. The structural changes in this neurodegenerative process involve the accumulation of a protein called amyloid (which deposits outside the neurones) and neurofibrillary tangles (NFTs), which accumulate inside the neurones. The cerebral amyloid in AD is deposited as military structures known as plaques, which primarily consist of the amyloid-beta (A) peptide (Lublin and Gandy 2010). A peptide was identified in 1984 as the major constituent that characterises AD (Lublin and Gandy 2010). These amyloid plaques and NFTs have long been regarded as the signature pathological lesions of AD (Armstrong 2011). The discovery of A (Glenner and Wong 1984) as the most important molecular constituent of these plaques resulted in the formulation of the Amyloid Cascade Hypothesis or ACH (Hardy and Higgins 1992), the most important model of the molecular pathology of AD developed over the last 20 years. Essentially, the ACH proposes that the deposition of A is the initial pathological event in the disease leading to the formation of NFTs, cell death and, ultimately, dementia (Armstrong 2009). ACH has a number of limitations that arise from a lack of understanding of the association between plaques and NFTs (if one exists at all). Of the two original cases described by Alzheimer, both had numerous plaques but only one of them had significant numbers of NFTs (Graeber et al 1997), thus creating a controversy that persists to this day as to the relative significance of the two lesions. Armstrong (2011) challenges the ACH with questions on the relationship between the pathogenesis of amyloid plaques and NFTs, and the relationship and significance of these lesions to disease pathogenesis, and suggests limitations to the hypothesis: Amyloid plaques and NFTs may be reactive products resulting from neurodegeneration in AD rather than being its cause. There is no generally accepted mechanism to explain how the deposition of A leads to the formation of NFTs. Classification AD does not develop in a characteristic pattern for all those affected, notably in its onset. Therefore, the disease is classified according to the following (Armstrong 2011): Early onset (<65 years) Late onset/sporadic AD (SAD) Familial AD (FAD) 2 Normal ageing or Alzheimers? T i m e
o u tWith a colleague discuss normal ageing and its effects on reasoning and memory. The purpose of your conversation is to establish your individual ideas on what constitutes expected deterioration in aspects of cognitive ability as people age. Did you find that you both shared norms of disability? If you found that your ideas differed, could this help explain why it is harder to agree what counts as AD and to agree when to intervene? 3 Statistical evidence T i m e
o u tThinking beyond the statistics, what in your practice has demonstrated a growth in the incidence and the care demands associated with AD recently? Is the profile of your work or the percentage of your time that you spend with this group of patients changing? If AD-related work is not on the increase locally, determine why you think that is. Make notes you can use to discuss care requirements and best use of resources with colleagues.
PHC JULY 2013 32-38.indd 33 25/06/2013 10:57 July 2013 | Volume 23 | Number 6 PRIMARY HEALTH CARE 34 Continuing professional development Early onset AD (<65 years) is usually caused by autosomal dominant mutations in the genes for amyloid precursor protein (APP), presenilin 1 (PS1 or PSE1) and presenilin 2 (PS2 or PSE2). This form of AD accounts for approximately 2-5 per cent of all AD cases (Blennow et al 2006). First degree relatives of patients with AD are at higher lifetime risk of developing the disease than the rest of the population (Green et al 2002). The risk may be partly due to the presence of the allele Apo4 (apolipoprotein 4), which is the only proven genetic factor of risk so far identified in the development of both the early- and late-onset forms of AD (Corder et al 1994). The factor increases susceptibility to AD but it is neither necessary nor sufficient for the development of the disease. Now do time out 4. Late onset AD or sporadic AD (SAD) is the most common form of AD, accounting for more than 90 per cent of cases and usually occurs after 65 years of age. SAD affects almost 50 per cent of people over the age of 85 and may or may not be hereditary (Alzheimers Disease Health Center 2012). Familial AD (FAD) is a rare form of AD that is known to be entirely inherited. In affected families, members of at least two generations have had AD, with a much earlier onset (often in the 40s) (Alzheimers Disease Health Center 2012). Some sources categorise this along with early-onset AD (Alzheimers Society 2013). The total known number of cases of FAD worldwide is about 200 people with mutations in three genes shown to be causative of FAD (alzheimersillness.com 2013). The three genes involved account for 30-50 per cent of all autosomal dominant early-onset cases, or around 10 per cent of familial early onset cases (Binetti 2009). The genetic link in some late onset cases of AD (in people aged 65 and over) is more complex than the link for younger people. The presence of a positive family history in the late onset cases is considered as a risk factor, but a clear autosomal dominant pattern of inheritance is rare (Binetti 2009). Recent experiments in mice have added weight to the idea that AD is driven by an infection-like spread of protein aggregates in the brain, as the history of theories in Table 1 (Schnabel 2012) shows. Now do time out 5 Table 1 History of theories about Alzheimers disease (1970s to present) Date/Theory Comment 1970s-1980s: Alzheimers disease is a suspected prion disease Researchers noted similarities between AD and transmissible spongiform encephalopathies such as scrapie and CreutzfeldtJakob disease. 1980s-1990s: Plaques cause AD Alzheimers plaque proteins were successfully isolated in 1984 and referred to as amyloid beta (A). It was shown to be quite different to scrapie amyloids. A was determined as a fragment of a larger neuronal membrane protein called amyloid precursor protein (APP) coded by a gene on chromosome 21. Early 1990s-early 2000s: Confusion and debate Many of the transgenic mice that over-expressed APP developed the typical brain plaques associated with AD but they did not develop the other major AD amyloid (NFTs), which are made of tau protein, found inside the neurones. These mice also failed to show the profound neuronal losses and memory failures seen in human AD. The NFTs correlated better with dementia. Late 1990s-present: The oligomeric prion hypothesis Early experiments showed that A, besides forming plaques can also cluster into soluble oligomers made of comparatively few copies of A. Oligomers were thought to exist only fleetingly as intermediate aggregates on the way to form complex plaques. Circumstantial evidence suggests that build-up of A aggregation occurs over decades; it is this which represents the last, lethal stage of disease. 4 Genetic predisposition T i m e
o u tLook back to your time out 1 description of AD and note whether genetic predisposition featured. What is the significance of this if you discuss the disease with anxious members of the public? 5 Slow scientific progress T i m e
o u tStudy Table 1 and decide what investigative process is under way here. You might refer to it as a process of elimination or the search for causes of the condition. Summarise how you might explain this scientific endeavour to family members who feel impatient with the progress of science and why it takes so long. (Adapted from Schnabel 2012) PHC JULY 2013 32-38.indd 34 25/06/2013 10:57 PRIMARY HEALTH CARE July 2013 | Volume 23 | Number 6 35 Continuing professional development Current evidence and theories Those working on AD research study not only the oligomer theory (Table 1) but also other aspects that may influence the disease profile: Oxidative stress. Mitochondrial dysfunction. Prion/transmission. Genetics. Inflammation and immune mechanisms. Amyloid proteins (A, tau, oligomers). Cerebrovascular events and other risk factors. Oxidative stress Free radicals formation can occur as part of normal metabolism. Sometimes, the immune system purposefully creates them to neutralise pathogens (Knight 2000). Normally, the body can handle free radicals, but if antioxidants are unavailable, or if the free radical production becomes excessive, damage can occur (Christen 2000). Of particular importance to AD is that free radical damage accumulates with age. The oxidative stress (OS) hypothesis proposes that the ageing process in the brain is associated with a progressive imbalance between the anti-oxidant defences and the pro-oxidative species. This imbalance can occur as a result of either an increase in free radical production or a decrease in antioxidant defence (Gella and Bolea 2011). Mitochondrial dysfunction Mitochondria are regulators of both energy metabolism and cell death pathways. Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of AD (Moreira et al 2010). Prion/transmission There is the possibility that some of the SAD cases may arise from an infectious process which occurs with other neurological diseases caused by prions such as CJD. Recent studies (Morales et al 2012) on intracellular and extracellular protein aggregation suggest that those aggregates are capable of crossing cellular membranes and can directly contribute to the pathogenesis including AD. Once initiated, neuropathological changes might spread in a prion-like manner and disease progression is associated with intracellular transfer of pathogenic protein (Brundin et al 2010). Genetics Most AD lacks a predictable, autosomal dominant mode of inheritance (Gandy 2005). While APP and the presenilins (PS1 and PS2) constitute the only known AD genes, at least one important generic risk factor is known for about 25 per cent of the population with AD, and that is the Apo4 genotype (Mayeux et al 1993). However, efforts to link Apo4 with A accumulation have produced mixed results (Gandy 2005). Inflammation and immune mechanisms Evidence for the involvement of inflammatory processes in the pathogenesis of AD has been documented for some time (Zotova et al 2010). However, it is only recently that inflammation itself has been hypothesised in AD pathology. Much of the data relates to outcomes of two major inflammation-relevant treatment strategies in AD: the use of anti-inflammatory drugs and immunisation against A (Zotova et al 2010). For any inflammatory response, there has to be a challenge; the immune systems inflammatory response is after all the bodys defence mechanism to a challenge, insult or injury. The type of inflammation in the AD brain is not well defined; it could be a consequence of the disease with the production of A as a direct immune response to a challenge (unknown at present), pointing to an inability of microglia (the brains immune cells) to clear away ever-growing neuronal debris due to extensive neurodegeneration and synaptic loss. Mixed and often contradictory findings with respect to inflammation in AD indicate the complexity and multifunctional role of the immune system (Zotova et al 2010). Inflammation in the CNS (as in the periphery) is a mixture of both destructive and rebuilding processes. It is this balance between the two processes that determines the overall integrity of the tissue or the whole organism (Rogers et al 2002). Therefore inflammation should not be viewed as wholly detrimental or wholly beneficial in AD. Amyloid proteins (A, tau, oligomers) The build-up of amyloid plaques has characterised AD and has received the bulk of the attention in this pathology. However, there is a gulf in opinion as to whether these plaques are toxic, protective or inert. Of great interest more recently is the significance of the free-floating oligomers (intermediary amyloid proteins), which is gaining prominence as the real culprit in the neurotoxicity that is characteristic of AD (Gandy et al 2010). Cerebrovascular events It has been suggested that patients with a clinical history of stroke have an increased risk of developing AD particularly in the presence of vascular risk factors (Honig et al 2003). Furthermore, silent cerebral or brain infarcts or silent brain ischemia (SBI) (identified by neuroimaging techniques), even in patients with no history of transient ischaemic attacks (TIAs) or stroke, can contribute to the loss of memory and cognitive function in the elderly. It was found that SBI more than doubles the risk of dementia including AD (Vermeer et al 2003, 2007) and AD patients with SBI have lower global cognitive function scores than patients with pure PHC JULY 2013 32-38.indd 35 25/06/2013 10:57 July 2013 | Volume 23 | Number 6 PRIMARY HEALTH CARE 36 Continuing professional development AD (Song et al 2007). Other risk factors are identified in Table 2. Now do time out 6. Treatment There are no drug treatments available that can cure AD (Table 3). At best, medicines abate or improve symptoms, temporarily slow down progression and manage the various symptoms associated with the disease and this may be unique to each patient. Early detection is always advised to delay progression as treatments work best in the early stages of the disease (Hartz et al 2010). Acetylcholine (ACh) is a key neurotransmitter in the brain signalling short-term memory and learning. It is broken down by the enzyme acetylcholinesterase, which is in excess in the AD brain. Glutamate is the most common neurotransmitter in the brain and is involved in learning and memory. Dying brain cells in AD release excess amounts of glutamate that causes harm to the brain by over-stimulating healthy brain cells. The choice of drug for any given patient is mostly determined by the stage of the disease with donepezil, rivastigmine and galantamine prescribed for mild to moderate AD and memantine for moderate to severe AD, who are intolerant to or have a contraindication to cholinesterase inhibitors (National Institute for Health and Care Excellence (NICE) Guidelines March 2011). Now do time out 7. New approaches The following list summarises the various treatment strategies currently being considered in light of recent advancements in AD research (Lane et al 2012): Anti-plaque strategies with monoclonal Ab (anti-A42 Ab: oligomeric A42 (for example, Bapineuzumab, Solanezumab, Crenezumab). Attack or disrupt the prion-like transmissibility of protein aggregates. Target inflammatory pathways/mechanisms on the basis that inflammation is deleterious not beneficial as a result of an initial trigger or immune challenge (if so, identify that challenge). Treatments that mimic the APP gene variant that confers protection against AD. Monoclonal Ab or gene therapy/strategy to target the Apo4 variant. Disrupt or inhibit the enzymatic cleavage of APP into amyloid. For example, to inhibit the secretases, BACE1, PS1 or PS2 (such as Semagacestat a -secretase inhibitor). Correct or target mitochondrial dysfunction. Antioxidant therapy to tackle oxidative stress. Table 2 Risk factors associated with Alzheimers disease 7 Drug treatments T i m e
o u tIdentify the drug treatments that your patients are using locally. What is their understanding of the ways in which the drugs are meant to work? 6 Explanations T i m e
o u tLook at some of the ventured explanations of why AD occurs. Summarise each, forming an aide memoire that you might use to discuss with colleagues or students. At this stage the explanations are speculative. Anticipating student questions about this, why is it vital that scientists speculate regarding the origins of AD? What can a practitioner add to the speculation that might help scientists develop interesting lines of future enquiry? (Adapted from Povova et al 2012) Risk factor hypothesis Comment Smoking Increased risk of Alzheimers disease (AD) (meta-analysis). Alcohol Increased risk of AD. Overweight and obesity The higher the BMI, the higher the risk of AD. BP and management of hypertension Increased BP, increased risk (observational studies). Antihypertensive drugs offer a protective effect. Hypercholesterlaemia and statin therapy Increased risk in middle-aged people 20 years later. Statins reduce risk. Nutritional factors Increased antioxidant intake, reduced risk. Increased saturated fat diet, reduced risk. Increased omega 3 EFAs, reduced risk. Diabetes Mellitus Diabetes increased risk of AD. Also increased risk of vascular dementia. CVS and cerebrovascular diseases Increased risk in stroke patients. Increased incidence of AD in CVD patients. Psychosocial factors Education and socioeconomic status Low status increased risk. Social network and social engagement Poor network and engagement leads to reduced cognitive function & dementia. Social isolation leads to an increased risk. Physical activity Physical activity delays onset of dementia and AD (reduced risk). Mental activity Protective effect against dementia and AD (reduced risk). PHC JULY 2013 32-38.indd 36 25/06/2013 10:57 PRIMARY HEALTH CARE July 2013 | Volume 23 | Number 6 37 Continuing professional development Table 3 Current drug treatments for Alzheimers disease 8 Multidisciplinary work T i m e
o u tIdentify the different professions involved locally in managing AD and portraying this as something that might be managed. What factors do you think are essential in conveying the challenge of AD and sustaining a positive multidisciplinary attitude to work in this area? Preventative strategies Little is known on whether AD can be prevented. Technological progress is being made on early detection that can make it possible for those with a family history of AD to be vigilant about symptoms and take advantage of assessments early on (McGuire et al 2006). This is really based on the premise that AD is a response to injury (Mcguire et al 2006); some go on to be healthy as clearing away of plaques is at a sufficient rate to prevent deleterious build-up and some go on to develop dementia and AD. Predicting risk The biggest risk factor is age. However, although risk increases with age, the mechanisms need clarifying so that measures can be taken to give those at risk a chance to plan for that eventuality. Genetic counselling is available for those at risk; given that there is little certainty of how genes link with disease onset, this may be counterproductive by creating a sense of worry unnecessarily. Now do time out 8. Dilemmas The task of professionals who come into contact with patients (psychiatrists, clinical psychologists, community nurses, mental health nurses, GPs, home helps/ healthcare assistants, social services, solicitors, police and other authorities) is not an easy one. This condition has a profound and devastating impact on patients and their families. There is the danger of relying on a lay persons prototype of mental decline where a family member, or carer, has ulterior motives (such as financial gain). Conversely, there may be those in the family who are eager to label a relative showing worrying signs of dementia as being perfectly normal, delaying any prompt treatment. Professionals should remember the vulnerability of patients facing a possible diagnosis of AD and the fear and anxiety that it invokes, not only in those affected but also family members who may worry about being at risk. Given the difficulties in making a diagnosis (especially in the early stages), there are a number of uncertainties and obstacles that make treatment and management of AD particularly difficult. Some of these dilemmas are: What is the best point at which power of attorney should be implemented? If there is a family history of AD and how worthwhile is genetic counselling? Knowledge can be devastating so can steps be taken to mitigate the risk. Is there sufficient progress in treatment strategies for people diagnosed as being at risk? What recourse is there for family members who disagree about the mental capacity of a patient when AD specialists and professionals cannot agree on diagnosis or whether the patient retains the ability to make decisions independent of family influence? How much emphasis is given to changes in personality and behaviour, including reasoning abilities, as a diagnostic tool given that most of the cognitive assessments focus on memory and recall? Should society be more sympathetic to those who leave or divorce their partner/spouse who has AD because they are no longer the person/personality they once were or should they stay and honour the in sickness and in health commitment of all relationships? How can society, and health and social care in particular, be better integrated to support the needs of people with AD so that they are not to be regarded as a burden? What is the right time to advise admitting someone to a care home even if they exhibit moments of extreme lucidity and clarity? What support services are available to the carers of AD patients who seek specialist help, counselling or even psychological intervention in a climate of cuts, efficiency savings and a recession? (Adapted from NICE 2011, Alzheimers Society 2012) Proprietary name (trade name) Pharmacological mode of action Cholinesterase inhibitors Donepezil hydrochloride Rivastigmine Galantamine
Aricept Exelon Reminyl Inhibits the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine (ACh). ACh is essential for vital communication between the nerve cells in the brain; the loss of communication is directly linked to the severity of the symptoms associated with AD. NMDA receptor antagonists Memantine Exiba Memantine blocks glutamate, another neurotransmitter which is in excess in AD pathology. However, unlike ACh, excess glutamate further damages brain cells. Therefore, memantine protects brain cells by blocking these effects of excess glutamate. PHC JULY 2013 32-38.indd 37 25/06/2013 10:57 July 2013 | Volume 23 | Number 6 PRIMARY HEALTH CARE 38 Continuing professional development Alzheimer A (1907) On a peculiar disease of the cerebral cortex. Allgemeine Zeitschrift fur Psychiatrie und Psychish-Gerichtlich Medicin. 64, 146-148. Alzheimers Disease Health Center (2012) Types of Alzheimers Disease. www.webmd.com/ alzheimers/guide/alzheimers-types (Last accessed: June 4 2013.) alzheimersillness.com (2013) 2007-2009 Familial Alzheimers Disease Alzheimers What Is Familial Alzheimers Disease Early Onset Alzheimers? tinyurl.com/mtb8tuv (Last accessed: 4 June 2013.) Alzheimers Society (2012) Factsheets. tinyurl.com/kvwmqsy (Last accessed: June 11 2013.) Alzheimers Society (UK) (2013) Genetics of Dementia www.alzheimers.org.uk/ factsheet/405 (Last accessed: June 5 2013.) Armstrong RA (2009) Alzheimers Disease and the Eye. Journal of Optometry. 2, 3, 103-111. Armstrong RA (2011) The pathogenesis of Alzheimers disease: a reevaluation of the Amyloid Cascade Hypothesis. International Journal of Alzheimers Disease. February 7, 630865. doi: 10.4061/2011/630865 Binetti G (2009) Familial Alzheimers Disease. Alzheimer Europe. tinyurl.com/lr5ojvy (Last accessed: June 3 2012.) 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Hardy JA, Higgins GA (1992) Alzheimers disease: the amyloid cascade hypothesis. Science. 256, 5054, 184-185. Hartz AMD, Miller DS, Bauer B (2010) Restoring blood-brain barrier P-Glycoprotein reduces brain amyloid in a mouse model of Alzheimers Disease. Molecular Pharmacology. 77, 5, 715-723. Honig LS, Tang M-X, Albert S et al (2003) Stroke and the risk of Alzheimer disease. Archives of Neurology. 60, 1707-1712. Knight JA (2000) Review: free radicals, antioxidants, and the immune system. Annals of Clinical & Laboratory Science. 30, 2, 145-158. Lane RF, Shineman DW, Steele JW et al (2012) Beyond amyloid: the future of therapeutics for Alzheimers disease. Advances in Pharmacology. 64, 213-71. doi: 10.1016/B978-0- 12-394816-8.00007-6. Lublin AL, Gandy S (2010) Amyloid- oligomers: possible roles as key neurotoxins in Alzheimers disease. Mount Sinai Journal of Medicine. 77, 43-49. Mayeux R, Stern Y, Ottoman R et al (1993) The apolipoprotein epsilon 4 allele in patients with Alzheimers disease. Annals of Neurology. 34, 752-754. McGuire BE, Whyte N, Hardardottir D (2006) Alzheimers Diseaes in down syndrom and intellectual disability: a review. Irish Journal of Psychology. 27, 3/4, 114-129. Morales R, Duran-Aniotz C, Castilla J (2012) De novo induction of amyloid- deposition in vivo. Molecular Psychiatry 17, 1347-1353. Moreira PI, Carvalho C, Zhu X et al (2010) Mitochondrial dysfunction is a trigger of Alzheimers disease pathophysiology. Biochimica et Biophysica Acta. 1802, 1, 2-10. National Institute for Health and Care Excellence (2011) Alzheimers Disease Donepezil, Galantamine, Rivastigmine and Memantine (TA217) www.nice.org.uk/guidance/ TA217 (Last accessed: June 2 2013.) Povova J, Ambroz P, Bar M et al (2012) Epidemiological of and risk factors for Alzheimers disease: a review. Biomedical Papers. 156, 2, 108-114. Rogers J, Strohmeyer R, Kovelowski CJ et al (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia. 40, 260-269. Schnabel J (2012) Alzheimers Disease: Return of the Prion Hypothesis. The Dana Foundation http://dana.org/news/features/detail. aspx?id=35584 (Last accessed: June 2 2013.) Song I-U, Kim J-S, Kim Y-I et al (2007) Clinical significance of silent cerebral infarctions in patients with Alzheimer disease. Cognitive and Behavioral Neurology. 20, 93-98. Vermeer SE, Prins ND, den Heijer T et al (2003) Silent brain infarcts and the risk of dementia and cognitive decline. New England Journal of Medicine. 348, 2115-1222. Vermeer SE, Longstreth WT, Koudstaal PJ (2007) Silent brain infarcts: a systematic review. The Lancet Neurology. 6, 611-619. Zotova E, Nicholl JAA, Kalaria R et al (2010) Inflammation in Alzheimers disease: relevance to pathogenesis and therapy. Alzheimers Research & Therapy. 2, 1. References Conclusion AD presents a unique problem to an ageing society, not only in terms of cost of care but also in progressing towards effective treatments that can halt the advancement of the disease or reverse its damage to provide a notable quality of life for as long as possible. Questions on best care options will continue to dominate until sufficient progress can be made on the very nature of AD, its pathogenesis and treatments, or even a cure, which seem a long way off at present. 9 Practice profile T i m e
o u tNow that you have completed the article, you might like to write a practice profile of between 750 and 1,000 words. See page 39 or go to the Primary Health Care website: www.primaryhealthcare.net and follow the link to the Learning Zone. PHC JULY 2013 32-38.indd 38 25/06/2013 10:57