Alzheimer's disease overview

# Overview
Alzheimer's disease is the most common cause of dementia among older people. Dementia is a loss of thinking, remembering, and reasoning skills that interferes with a person's daily life and activities. Other causes of dementia include blood vessel disease in the brain (called vascular dementia), Parkinson's disease, frontotemporal dementia, and Lewy body dementia. The first case of Alzheimer's disease was described by a German psychiatrist named Alois Alzheimer in the year 1901. For many decades after Alzheimer's original description, there was little progress in defining the pathogenesis of AD occurred. In the mid 1970's, it was found that the levels of acetylcholine decrease in brains of individuals undergoing neurodegeneration due to Alzheimer's disease. In early 1980's major advances in biochemistry and molecular genetics allowed the use of compositional analyses and immunocytochemistry to explain the structure of tangles and plaques found in the brains of Alzheimer patients. The term Alzheimer's disease was subsequently formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology. Alzheimer's disease may be classified according to severity into mild, moderate and severe dementia. It may also be classified based on age of onset into early onset and late onset Alzheimer's disease. Another method of classification of Alzheimer's disease is based on the course of disease into pre-dementia, early dementia, moderate dementia and advanced dementia. Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of A peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. The microscopic histopathological features of alzheimer's disease consist of neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy. Alzheimer's disease may be caused by trisomy of chromosome 21, familial inheritance of mutations in either presenilin 1 gene, presenilin 2 gene or APOE4 gene. Presenilin mutations are associated with early onset Alzheimer's disease, whereas APOE mutations are associated with late onset disease. Environmental factors, such as aging, low level of education and head trauma may also contribute to the development of Alzheimer's disease. An estimated 5.5 million Americans of all ages have Alzheimer's disease. An estimated 10,000 per 100,000 individuals aged greater than 65 years have been known to be living with Alzheimer's disease in the United States. The diagnosis of Alzheimer's disease (AD) is made on the basis of clinical criteria described by either the National Institute on Aging and the Alzheimer's Association (NIA-AA) or DSM-V (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Histopathologic examination for diagnosis of Alzheimer's disease is rarely done. Elderly patients presenting with progressive decline in memory and other cognitive impairments such as aphasia, agnosia or apraxia should be suspected for Alzheimer's disease. In these patients, mental status examination (MSE) and neuropsychological testing should be performed to further evaluate the status of cognitive abilities. Diagnostic tools for the examination of the patient include mini- mental status examination (MMSE), Montreal Cognitive Assesment (MOCA) and instruments of activities of dailing living (IADL).  Characteristic findings on MRI suggestive of Alzheimer's disease include reduced hippocampal volume and medial temporal lobe atrophy. There is no known cure for Alzheimer's disease (AD). Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmacological, psychosocial, and caregiving. Acetylcholine esterase inhibitors increase the amount of acetylcholine in the brain and are a major part of pharmacotherapy for Alzheimer's disease. Major drugs include, donepezil, rivastigmine and galantamine, these drugs help with the cognitive symptoms of the disease. Associated psychosis and depression may be managed with antipsychotics and selective serotonin reuptake inhibitors (SSRIs). Caregiving plays a pivotal role in the management of patients suffering from Alzheimer's disease.

# Historical Perspective
The first case of Alzheimer's disease was described by a German psychiatrist named Alois Alzheimer in the year 1901. For many decades after Alzheimer's original description, there was little progress in defining the pathogenesis of AD occurred. In the mid 1970's, it was found that the levels of acetylcholine decrease in brains of individuals undergoing neurodegeneration due to Alzheimer's disease. In early 1980's major advances in biochemistry and molecular genetics allowed the use of compositional analyses and immunocytochemistry to explain the structure of tangles and plaques found in the brains of Alzheimer patients. The term Alzheimer's disease was subsequently formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.

# Classification
Alzheimer's disease may be classified according to severity into mild, moderate and severe dementia. It may also be classified based on age of onset into early onset and late onset Alzheimer's disease. Another method of classification of Alzheimer's disease is based on the course of disease into pre-dementia, early dementia, moderate dementia and advanced dementia.

# Pathophysiology
Alzheimer disease (AD), is a progressive neurodegenerative disorder. The dysfunction of amyloid precursor protien (APP) metabolism and the resulting build up of of A peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals have been considered pivotal for neurodegeneration in the disease. Cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic system. In familial forms of AD, mutations result in an increased A production or aggregation, in sporadic AD, failure of the clearance mechanisms might play a key role. Loss of mature neurons and alterations in neural progenitor cells (NPCs) in areas such as the dentate gyrus (DG) of the hippocampus have been found to be responsible for manifestations of AD. On gross pathology, temporal atrophy (hippocampus in particular), dilation of lateral ventricles and third ventricle are characteristic findings of Alzheimer's disease. The microscopic histopathological features of alzheimer's disease consist neurofibrillary tangles, senile plaques, neuronal loss, and with or without cerebral amyloid angiopathy.

# Causes
Alzheimer's disease may be caused by trisomy of chromosome 21, familial inheritance of mutations in either presenilin 1 gene, presenilin 2 gene or APOE4 gene. Presenilin mutations are associated with early onset Alzheimer's disease, whereas APOE mutations are associated with late onset disease. Environmental factors, such as aging, low level of education and head trauma may also contribute to the development of Alzheimer's disease.

# Differentiating alzheimer's disease from Other Diseases
Alzheimer's disease must be differentiated from other causes of dementia which may share common characteristics of cognitive impairment. The differentials include, vascular dementia, Lewy body dementia and frontotemporal dementia.

# Epidemiology and Demographics
Alzheimer's disease is the most frequently observed form of dementia, and it typically develops in elderly patients. An estimated 5.5 million Americans of all ages have Alzheimer's disease. An estimated 10,000 per 100,000 individuals aged greater than 65 years have been known to be living with Alzheimer's disease in the United States. Alzheimer's disease has been known to affect females more than males. African Americans and Hispanics are more likely to develop Alzheimer's disease than older whites. AD is diagnosed in people over 65 years of age, although the less prevalent early-onset Alzheimer's can occur much earlier.

# Risk Factors
The most potent risk factors for the development of Alzheimer's disease (AD) are age and genetic mutations. Females are more prone to development of Alzheimer's disease. Inhabitants of Central African Republic, East Africa, Southern Africa, Malaysia, Australia, and Papua New Guinea are more predisposed to the development of Alzheimer's disease. Stroke increases the risk of Alzheimer's dementia.

# Natural History, Complications, and Prognosis
Alzheimer's disease (AD) is a slow-progressing condition that involves complications such as the inability to take care of oneself. If left untreated, Alzheimer's disease progresses from pre-clinical stage to advanced dementia. Common complications of Alzheimer's disease include anosmia, bedsores, psychosis, malnutrition and dehydration. There is no cure for Alzheimer's disease currently and the treatment focuses on symptomatic management of the disease.

# Diagnosis

## Diagnostic Criteria
The diagnosis of Alzheimer's disease (AD) is made on the basis of clinical criteria described by either the National Institute on Aging and the Alzheimer's Association (NIA-AA) or DSM-V (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Histopathologic examination for diagnosis of Alzheimer's disease is rarely done. Elderly patients presenting with progressive decline in memory and other cognitive impairments such as aphasia, agnosia or apraxia should be suspected for Alzheimer's disease. In these patients, mental status examination (MSE) and neuropsychological testing should be performed to further evaluate the status of cognitive abilities. Laboratory investigation are not required to diagnose Alzheimer's and are done to exclude other conditions which may present with similar symptoms as seen in Alzheimer's disease (such as vit B12 deficiency, syphilis, or tuberculosis). Patients with atypical clinical presentation may also be tested for biomarkers such as  A and total and phosphorylated tau protein.

## History and Symptoms
Obtaining patient's history is an important aspect of making a diagnosis of Alzheimer's disease. Alzheimer's disease patients may be disoriented and therefore the patient interview may be difficult.  In such cases history from the care givers or the family members may need to be obtained.  Specific histories about the symptoms (duration, onset, progression), associated symptoms, drug usage have to be obtained.

## Physical Examination
Patients with Alzheimer's disease usually appear disoriented and disorganized. When a doctor or physician has been notified, and AD is suspected, the diagnosis is usually further supported by behavioral assessments and cognitive tests, often followed by a brain scan if available. Physical examination of Alzheimer's disease consists of a thorough neurological assessment of the patient. Patient may be disoriented to time, place and person. Diagnostic tools for the examination of the patient include mini- mental status examination (MMSE), Montreal Cognitive Assesment (MOCA) and instruments of activities of dailing living (IADL).

## Laboratory Findings
There are no specific diagnostic laboratory findings associated with Alzheimer's disease. However, laboratory findings are done to rule out other conditions which may mimic Alzheimer's disease symptoms. These include CSF analysisfor A 2 and tau protein, 14-3-3 protein, vitamin B12 levels, thyroid hormones, electrolytes, HIV serology,  complete blood count, blood glucose, renal function test, liver function test, and urine screen for drug abuse.

## Electrocardiogram
ECG has minimal diagnostic value in diagnosing Alzheimer's disease but plays a role in diagnosing concurrent conduction abnormalities and monitoring side effects of medications. Electrocardiogram of a patient with Alzheimer's disease may show QT dispersion and heart rate variability abnormalities.

## X-ray
There are no x-ray findings associated with Alzheimer's disease.

## Ultrasound
Focused ultrasound is a non-invasive, therapeutic technology aiming to improve the quality of life at lower costs for patients with Alzheimers disease.

## CT scan
CT scan of the brain may be helpful in the diagnosis of Alzheimer's disease. Findings include enlargement of cerebral sulci, loss of gyral volume and mild dilation of the ventricular system.

## MRI
Structural MRI of the brain may be helpful in the diagnosis of Alzheimer's disease. Characteristic finding on MRI suggestive of Alzheimer's disease include reduced hippocampal volume and medial temporal lobe atrophy.

## Other Imaging Findings
Other imaging studies in Alzheimer's include positron emission tomography (PET) and single photon emission computed tomography (SPECT) scan. PET and SPECT scan are not routinely done in Alzheimer's disease. However, patients with atypical presentation may be evaluated with either a PET or SPECT scan to assess for any underlying condition. In these patients, use of amyloid  PET scan will reveal lower FDG (fluorine-18 fluorodeoxyglucose) metabolism and higher PiB (Pittsburgh compound B) deposition in areas of the brain affected by Alzheimer's disease. On SPECT scan patients with Alzheimer's disease have low relative regional cerebral blood flow (rCBF) in the parietal and prefrontal cortices.

## Other Diagnostic Studies
Genotyping for Apolipoprotein (APOE) -4, APOE -3, amyloid precursor protein (APP), presenilin PSEN1 and PSEN 2 genes may be helpful in the diagnosis of Alzheimer's disease (AD), although it is not routinely recommended. They may be helpful in the diagnosis of Alzheimer's dementia. However, genetic study is reserved for research purposes or for those who have presenile dementia.

# Treatment

## Medical Therapy
There is no known cure for Alzheimer's disease (AD). Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmacological, psychosocial, and caregiving. Acetylcholine esterase inhibitors increase the amount of acetylcholine in the brain and are a major part of pharmacotherapy for Alzheimer's disease. Major drugs include, donepezil, rivastigmine and galantamine, these drugs help with the cognitive symptoms of the disease. Associated psychosis and depression may be managed with antipsychotics and selective serotonin reuptake inhibitors (SSRIs). Caregiving plays a pivotal role in the management of patients suffering from Alzheimer's disease.

## Surgery
Surgical intervention is not recommended for the management of Alzheimer's disease.

## Primary Prevention
Primary prevention of Alzheimer's disease includes mental stimulation, exercise, and the maintenance of a balanced diet are often recommended as both a possible prevention and a sensible way of managing the disease.

## Secondary Prevention
Secondary prevention of Alzheimer's disease is similar to primary prevention.