Understanding Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder with an uncertain pathogenesis. It is characterised by symptoms of memory impairment, executive dysfunction and visuospatial impairment. Management goals and interventions should be based on a solid alliance with the patient and family and on thorough psychiatric, neurological and general medical evaluations of the nature and cause of cognitive deficits and associated non-cognitive symptoms. There are currently three cholinesterase inhibitors and one N-methyl-D-aspartate (NMDA) antagonist indicated in the treatment of AD as monotherapy or in combination. Cholinesterase inhibitors remain the first-line therapy in patients with mild to moderate AD, which may stabilise the symptomatic cognitive and functional decline. Other pharmacotherapy options include the use of memantine which may be used by itself or in combination with cholinesterase inhibitors. These treatments are for symptomatic relief and are not disease modifying in preventing the progression of the disease


Introduction
Alzheimer disease (AD) is a neurodegenerative disorder with a pathogenesis and causes that are uncertain. 1It affects older adults and is the most common cause of dementia. 1AD's early clinical manifestation is selective memory impairment, but there are exceptions to this.The incidence of AD increases exponentially with age over 65 years. 2AD before the age of 65 years is unusual and may be familial in nature.Familial early-onset AD accounts for approximately 1% of cases and follows a pattern of autosomal dominant inheritance. 3,4Treatment is available that may ameliorate some of the symptoms but currently there is no cure or disease-modifying therapy available and the disease will inevitably progress. 1

Pathophysiology
As discussed above, the pathogenesis of AD is uncertain. 1ome of the early neuropathological changes in AD include the following [5][6][7][8] : 1. Neuritic plaques, which are associated with neuronal injury and may be characterised by amyloid which is formed from amyloid beta plus dystrophic neurites which frequently has phospho-tau immunoreactivity.
3. Neurofibrillary degeneration which is best illustrated by neurofibrillary tangles.
Table I describes other pathological changes commonly observed in association with AD. [9][10][11][12][13][14][15][16] The pathogenesis of all forms of AD seems to share the commonality of an overproduction and/or a decreased clearance of amyloid beta peptides. 17These peptides are produced by cleavage of mature protein translated from the amyloid precusor protein (APP) gene and cleaved by beta-secretase and gamma-secretase.Presenillin forms part of the gamma-secretase complex and mutations of the presenilin 1 (PSEN 1) or presenilin 2 (PSEN 2) genes tend to favour the production of amyloid beta.Amyloid beta or the forms that are produced through mutations of PSEN 1 or PSEN 2 are neurotoxic. 17second protein involved in the pathogenesis of AD is tau.18- 20 Tau is a microtubule-associated protein which aids in microtubule assembly and stabilisation.In AD, these proteins become hyperphosphorylated and aggregate to form paired Table I.Several other pathological changes found with AD [9][10][11][12][13][14] In addition to the essential features discussed above, several other pathological features are observed in patients with AD.These include: 1. Cerebral amyloid angiopathy is often found in patients with parenchymal amyloid beta deposits 9,10 2. Inclusions of abnormal alpha-synucle in accumulation called Lewy bodies, are common in the setting of intermediate-to-high levels of AD neuropathologic change. 11,12Lewy bodies may also be found in some cases of early-onset familial AD. 13,14 3. Pathological changes of vascular brain injury are caused by oligaemia, hypoxaemia, or ischaemia involving different calibre vessels in different regions of the brain.
4. Hippocampal sclerosis (HS), defined by pyramidal cell loss and gliosis in the hippocampal formation that is out of proportion to AD neuropathological change, can be observed alone or in the context of AD, frontotemporal lobar degeneration, or vascular brain injury. 15 Immunoreactive inclusions of transactive response DNA binding protein 43 kD (TDP-43) are also commonly observed in cases with AD neuropathological change 16 The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd29 helical filament (PHF) tau.These are a major component of neurofibrillary tangles within the neuronal cytoplasm.Experimental models have suggested that the accumulations of these altered proteins are neurotoxic.Additionally, pathological forms of tau between neurons have been proposed as a mechanism by which AD spreads in the brain.[18][19][20] Various other genes and proteins have been implicated in the pathogenesis of AD but that is beyond the scope of this review.

Risk factors for developing Alzheimer's disease
Aside from genetics as a risk factor for AD, a variety of different factors may influence a patient's risk for developing AD. 21Risk factors for vascular disease such as hypertension, diabetes and obesity may increase the risk of developing AD, particularly if these diseases are present in midlife. 213][34][35][36] It is clear, however, that cerebrovascular disease and AD do frequently co-exist. 379][40] Cerebrovascular disease is associated with worse cognitive performance in patients with AD and studies have suggested that cerebrovascular disease lowers the threshold for clinical dementia in patients with a diagnosis of AD. [41][42][43][44][45][46] Clinical features Some of the cardinal symptoms of AD include memory impairment, executive dysfunction and visuospatial impairment. 47,48The last two symptoms tend to present relatively early, while language and behavioural symptoms tend to manifest later in the course of the disease.Less common symptoms include language deficits and visuospatial abnormalities. 47,48Table II describes the signs and symptoms of AD with their relevant description.  Tabl.Signs and symptoms of AD with a clinical description

Cardinal Signs and Symptoms
Memory impairment 1. Pattern in AD is distinctive. 49. Memory of events occurring at a particular time and place (declarative memory) is profoundly affected. 49. Procedural memory and motor learning is spared until quite late into disease progression. 49][52] 5. Immediate memory (e.g.[52] Executive function and judgement

Diagnosis
Alzheimer's disease is diagnosed based on clinical assessment and neuroimaging studies and is suspected in any older adult with insidious onset, a progressive decline in memory and in at least one other cognitive domain. 47,73The two commonest used criteria in the diagnosis of AD include the clinical criteria established by the National Institute on Aging and the Alzheimer's Association (NIA-AA) and the Diagnostic and Statistical Manual of Mental Disorders (DSM). 73,48Table III outlines the criteria in diagnosis of AD as established by the NIA-AA. 73e DSM clinical criteria for AD has been expanded beyond the previous five domains (memory, aphasia, apraxia, agnosia, and executive function) to include learning, language, complex attention, perceptual motor and social cognition. 48While less validated when compared to the NIA-AA, the DSM criteria appear to have similar accuracy. 74,75e NIA-AA recent diagnostic guidelines have defined three stages of AD 76 : • Preclinical phase: neuropathological changes occur, no overt (or only subtle) symptoms • Phase of mild cognitive impairment: symptoms become apparent; ADLs are preserved; patient does not have dementia

• Dementia phase: ADLs are impaired
There may be preclinical neurologic changes in the form of cerebrospinal fluid or amyloid imaging biomarkers. 76However, AD diagnosis is principally based on clinical criteria (Table III). 73

Differential diagnosis
The most common disorders considered in the differential diagnosis of AD are vascular dementia and neurodegenerative dementias.The most common neurodegenerative dementias after AD include dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). 77,78

Pharmacological therapy
Management goals and interventions should be based on a solid alliance with the patient and family as well as thorough psychiatric, neurological and general medical evaluations of the nature and cause of cognitive deficits and associated noncognitive symptoms.There are currently three cholinesterase inhibitors and one N-methyl-D-aspartate (NMDA) antagonist indicated in the treatment of AD as monotherapy or in combination. 79

Pharmacological therapy: Memantine
Memantine is a NMDA receptor antagonist which is proposed to be neuroprotective by preventing glutamatergic excitotoxicity in blocking excessive stimulation of NMDA receptors. 80This action protects the neurons from further damage and restores the physiological function of remaining neurons resulting in symptomatic improvement. 81Glutamate stimulation of NMDA receptors has been implicated in memory processes and dementia. 82Memantine appears to have modest benefits in patients with moderate to severe AD based on a 28-week randomised trial of 252 patients. 82This study found that memantine reduced deterioration on multiple scales of clinical efficacy (Table V). 82Memantine appears to have fewer sideeffects than the cholinergic agents, with dizziness being the most common adverse effect. 82However, there is a lack of evidence that patients with milder AD benefit from memantine, with no effect on behaviour or ADLs. 82Memantine may be introduced in moderate to severe disease stages and can be used as monotherapy or in combination with a cholinesterase inhibitor. 83

Pharmacological therapy: Cholinesterase inhibitors
Patients with AD have reduced cerebral content of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cholinergic function.Cholinesterase inhibitors used in the treatment of AD increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft and provide modest benefit in patients with dementia.Unlike memantine, cholinesterase inhibitors are considered symptomatic therapies which are not neuroprotective. 83To date, three cholinesterase inhibitors are indicated in mild to moderate AD; donepezil, galantamine and rivastigmine, while donepezil is also indicated in moderate to severe AD (Table IV). 83High dose rivastigmine patch is approved for mild to moderate and severe AD based on the positive findings of recent studies. 83,84,85The cholinesterase inhibitors have demonstrated clinical benefits on cognitive The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd7][88][89][90][91][92][93] There are no clinically meaningful differences between the efficacy of the individual agents. 834][85] The agents have similar tolerability profiles, with nausea, vomiting and diarrhoea being the most common adverse effects. 94Patients with bradycardias or bradyarrhythmia's should be carefully monitored if treated with cholinesterase inhibitors, as they have an increased risk of syncope or dizziness. 76reatment is individualised; patients can be switched from one cholinesterase inhibitor to another if the initial agent is poorly tolerated or ineffective. 83Systematic reviews and meta-analyses of cholinesterase inhibitors illustrate that they delay the decline in function as measured by the AD Assessment Scalecognitive subscale (ADAS-cog), global clinical rating, behaviour and ADLs over 6-12-month periods.These benefits seem to be applicable to mild, moderate and severe AD. 95 Pivotal six month placebo-controlled studies further highlight the beneficial effects of cholinesterase inhibitors in patients with mild to moderate AD, on cognitive and global functioning (Table V). 86- 93Extended 6-12 month trials provide evidence that patients receiving cholinesterase inhibitors can be maintained near pretreatment baseline levels for at least 12 months of therapy and then decline, but appear to maintain higher levels of function than expected if untreated. 96

Pharmacological therapy: Combination therapy
The combination therapy of memantine with a cholinesterase inhibitor, which affect separate neurotransmitter systems in AD, is useful in patients with advanced disease conferring independent clinical benefits.The combination leads to modest improvements in cognition and global outcomes in patients with advanced disease. 97A study in which patients treated with memantine plus donepezil resulted in significantly better outcomes than placebo plus donepezil on measures of cognition, ADLs, global outcome and behaviour (Table V). 98These results together with previous studies, suggest that combination therapy of memantine with a cholinesterase inhibitor represents a new approach for the treatment of patients with moderate to severe AD which may improve efficacy relative to single-agent therapy and may ameliorate gastrointestinal adverse effects of cholinesterase inhibitors.

Nonpharmacological therapy
Behavioural disturbances can profoundly affect patients with dementia as well as their families and caregivers.Recognition and treatment of behavioural symptoms and mood disorders are important aspects of the care of patients with dementia. 83  Inadequate nutrition is common in patients with AD and is associated with increased morbidity and mortality. 101nterventions such as oral nutritional supplements may improve weight and fat-free mass. 102Nonpharmacological aims in helping cognitive function in AD involves cognitive rehabilitation.This involves cognitive stimulation programmes to maintain memory and higher cognitive function. 103In terms of improving physical functioning, studies have demonstrated that formal exercise programmes may improve physical functioning or at least slow the progression of functional decline in patients with AD. [103][104][105] However, exercise programmes do not appear to improve any cognitive functioning in adults with AD. [104][105][106][107] In addition to exercise, individualised occupational therapy sessions focused on training patients and caregivers in the use of aids, coping behaviours, and strategies to compensate for functional deficits, demonstrated improvements in motor and process skills in daily activities. 108These multidisciplinary, nonpharmacological approaches to management of dementia have significant advantages in having none of the side-effects that significantly complicate drug treatment in patients with AD.

Conclusion
The benefits of early investigating and diagnosis of AD include instigation of pharmacological symptomatic treatments and the initiation of psychosocial support processes.Cholinesterase inhibitors remain the first-line therapy in patients with mild to moderate AD, which may stabilise symptomatic cognitive and functional decline.Memantine, a glutamatergic partial antagonist, has shown to be beneficial in the treatment of moderate to severe cases of AD either alone or in combination with a cholinesterase inhibitor.However, these treatments are for symptomatic relief and are not disease modifying in preventing the progression of the disease.

Table III .
73e NIA-AA clinical assessment characteristics in confirming diagnosis of AD73

AD dementia is a syndrome of dementia defined by the following characteristics:
83

Table IV .
83proved AD therapies83 Table VI describes the nonpharmacological approaches to manage common behavioural symptoms.

Table VI .
83npharmacological approaches to manage behavioural symptoms and mood disorders in patients with AD83