Alzheimer's disease

Alzheimer's disease

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Alzheimer's disease also known in medical literature as Alzheimer disease (AD) is the most common form of dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

. There is no cure for the disease, which worsens as it progresses
Degenerative disease
A degenerative disease, also called neurodegenerative disease, is a disease in which the function or structure of the affected tissues or organs will progressively deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits...

, and eventually leads to death
Terminal illness
Terminal illness is a medical term popularized in the 20th century to describe a disease that cannot be cured or adequately treated and that is reasonably expected to result in the death of the patient within a short period of time. This term is more commonly used for progressive diseases such as...

. It was first described by German psychiatrist and neuropathologist Alois Alzheimer
Alois Alzheimer
Aloysius "Alois" Alzheimer, was a German psychiatrist and neuropathologist and a colleague of Emil Kraepelin. Alzheimer is credited with identifying the first published case of "presenile dementia", which Kraepelin would later identify as Alzheimer's disease....

 in 1906 and was named after him.

Most often, AD is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

Although Alzheimer's disease develops differently for every individual, there are many common symptoms. Early symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most common symptom is difficulty in remembering recent events. When AD is suspected, the diagnosis is usually confirmed with tests that evaluate behaviour and thinking abilities, often followed by a brain scan
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...

 if available.

As the disease advances, symptoms can include confusion
Mental confusion
Confusion of a pathological degree usually refers to loss of orientation sometimes accompanied by disordered consciousness and often memory Confusion (from Latin confusĭo, -ōnis, noun of action from confundere "to pour together", also "to confuse") of a pathological degree usually refers to loss...

, irritability and aggression, mood swing
Mood swing
-Associated disorders:Mood swings are commonly associated with mood disorders including bipolar disorder and depression. In patients with cases of bipolar disorder, the patient experiences serious mood swings that last for days or even weeks...

s, trouble with language, and long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

 loss. As the sufferer declines they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Since the disease is different for each individual, predicting how it will affect
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...

 the person is difficult. AD develops for an unknown and variable amount of time before becoming fully apparent, and it can progress undiagnosed for years. On average, the life expectancy following diagnosis is approximately seven years. Fewer than three percent of individuals live more than fourteen years after diagnosis.

The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques
Senile plaques
Senile plaques are extracellular deposits of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures and an abundance of microglia and astrocytes...

 and tangles in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

. Current treatments only help with the symptoms of the disease. There are no available treatments that stop or reverse the progression of the disease. , more than 500 clinical trials have been conducted to find ways to treat the disease, but it is unknown if any of the tested treatments will work. Mental stimulation
Mental exercise
Mental exercise is the act of performing a mentally stimulating task that is considered beneficial to warding off Alzheimer’s disease and dementia. This practice is accepted by many cultures worldwide...

, exercise, and a balanced diet have been suggested as possible ways to delay symptoms in healthy older individuals, but they have not been been proven as effective.

Because AD cannot be cured and is degenerative, the sufferer relies on others for assistance. The role of the main caregiver
Caregiver
Caregiver may refer to:* Caregiver or carer - an unpaid person who cares for someone requiring support due to a disability, frailty, mental health problem, learning disability or old age...

 is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers
Caregiving and dementia
As populations age, caregiving and dementia become more common aspects of life. In most mild to medium cases of dementia the primary caregiver is a family member, usually a spouse or adult child...

; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregiver's life. In developed countries
Developed country
A developed country is a country that has a high level of development according to some criteria. Which criteria, and which countries are classified as being developed, is a contentious issue...

, AD is one of the most costly diseases to society.

Characteristics


The disease course is divided into four stages, with progressive patterns of cognitive and functional
Functional symptom
A functional symptom is a medical symptom in an individual which is very broadly conceived as arising from a problem in nervous system 'functioning' and not due to a structural or pathologically defined disease cause...

 impairments
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...

.

Pre-dementia


The first symptoms are often mistakenly attributed to aging or stress. Detailed neuropsychological
Neuropsychology
Neuropsychology studies the structure and function of the brain related to specific psychological processes and behaviors. The term neuropsychology has been applied to lesion studies in humans and animals. It has also been applied to efforts to record electrical activity from individual cells in...

 testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...

 of AD. These early symptoms can affect the most complex daily living activities
Activities of daily living
Activities of Daily Living is a term used in healthcare to refer to daily self-care activities within an individual's place of residence, in outdoor environments, or both...

. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.

Subtle problems with the executive functions
Executive functions
The executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is responsible for processes that are sometimes referred to as the executive function, executive functions, supervisory attentional system, or cognitive control...

 of attentiveness
Attention
Attention is the cognitive process of paying attention to one aspect of the environment while ignoring others. Attention is one of the most intensely studied topics within psychology and cognitive neuroscience....

, planning
Planning
Planning in organizations and public policy is both the organizational process of creating and maintaining a plan; and the psychological process of thinking about the activities required to create a desired goal on some scale. As such, it is a fundamental property of intelligent behavior...

, flexibility, and abstract thinking
Abstraction
Abstraction is a process by which higher concepts are derived from the usage and classification of literal concepts, first principles, or other methods....

, or impairments in semantic memory
Semantic memory
Semantic memory refers to the memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences. The conscious recollection of factual information and general knowledge about the world is generally thought to be independent of context and personal relevance...

 (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...

 can be observed at this stage, and remains the most persistent neuropsychiatric
Neuropsychiatry
Neuropsychiatry is the branch of medicine dealing with mental disorders attributable to diseases of the nervous system. It preceded the current disciplines of psychiatry and neurology, in as much as psychiatrists and neurologists had a common training....

 symptom throughout the course of the disease. The preclinical stage of the disease has also been termed mild cognitive impairment
Mild cognitive impairment
Mild cognitive impairment is a brain-function syndrome involving the onset and evolution of cognitive impairments beyond those expected based on the age and education of the individual, but which are not significant enough to interfere with their daily activities...

, but whether this term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.

Early


In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, difficulties with language, executive functions, perception
Perception
Perception is the process of attaining awareness or understanding of the environment by organizing and interpreting sensory information. All perception involves signals in the nervous system, which in turn result from physical stimulation of the sense organs...

 (agnosia
Agnosia
Agnosia is a loss of ability to recognize objects, persons, sounds, shapes, or smells while the specific sense is not defective nor is there any significant memory loss...

), or execution of movements (apraxia
Apraxia
Apraxia is a disorder caused by damage to specific areas of the cerebrum. Apraxia is characterized by loss of the ability to execute or carry out learned purposeful movements, despite having the desire and the physical ability to perform the movements...

) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

 of the person's life (episodic memory
Episodic memory
Episodic memory is the memory of autobiographical events that can be explicitly stated. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory...

), facts learned (semantic memory
Semantic memory
Semantic memory refers to the memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences. The conscious recollection of factual information and general knowledge about the world is generally thought to be independent of context and personal relevance...

), and implicit memory
Implicit memory
Implicit memory is a type of memory in which previous experiences aid in the performance of a task without conscious awareness of these previous experiences. Evidence for implicit memory arises in priming, a process whereby subjects show improved performance on tasks for which they have been...

 (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories.

Language problems
Semantic memory
Semantic memory refers to the memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences. The conscious recollection of factual information and general knowledge about the world is generally thought to be independent of context and personal relevance...

 are mainly characterised by a shrinking vocabulary
Vocabulary
A person's vocabulary is the set of words within a language that are familiar to that person. A vocabulary usually develops with age, and serves as a useful and fundamental tool for communication and acquiring knowledge...

 and decreased word fluency
Fluency
Fluency is the property of a person or of a system that delivers information quickly and with expertise.-Speech:...

, which lead to a general impoverishment of oral and written language
Written language
A written language is the representation of a language by means of a writing system. Written language is an invention in that it must be taught to children, who will instinctively learn or create spoken or gestural languages....

. In this stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas. While performing fine motor tasks
Fine motor skill
Fine motor skills are the coordination of small muscle movements which occur e.g., in the fingers, usually in coordination with the eyes. In application to motor skills of hands the term dexterity is commonly used....

 such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia
Apraxia
Apraxia is a disorder caused by damage to specific areas of the cerebrum. Apraxia is characterized by loss of the ability to execute or carry out learned purposeful movements, despite having the desire and the physical ability to perform the movements...

) may be present but they are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.

Moderate


Progressive deterioration eventually hinders independence; with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasia
Paraphasia
Paraphasia is a feature of aphasia in which one loses the ability of speaking correctly, substitutes one word for another, and changes words and sentences in an inappropriate way. It often develops after a stroke or brain injury. The patient's speech is fluent but is error-prone, e.g...

s). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

, which was previously intact, becomes impaired.

Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering
Wandering (dementia)
Wandering, in persons with dementia, is a common behavior that can cause great risk for the person, and is often the major priority for caregivers. It is estimated to be the most common form disruption from people with dementia within institutions. Although it occurs in several types of...

, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....

 and labile affect, leading to crying, outbursts of unpremeditated aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...

, or resistance to caregiving. Sundowning
Sundowning (dementia)
In medicine, sundowning, also known as sundown syndrome, is a syndrome involving the occurrence or increase of one or more abnormal behaviors in a circadian rhythm. Sundowning typically occurs during the late afternoon, evening, and night, hence the name. It occurs in persons with certain forms of...

 can also appear. Approximately 30% of people with AD develop illusionary misidentifications
Delusional misidentification syndrome
Delusional misidentification syndrome is an umbrella term, introduced by Christodoulou for a group of delusional disorders that occur in the context of mental or neurological illness. They all involve a belief that the identity of a person, object or place has somehow changed or has been altered...

 and other delusion
Delusion
A delusion is a false belief held with absolute conviction despite superior evidence. Unlike hallucinations, delusions are always pathological...

al symptoms. Subjects also lose insight of their disease process and limitations (anosognosia
Anosognosia
Anosognosia /æˌnɒsɒgˈnəʊsɪə/ is a condition in which a person who suffers disability seems unaware of the existence of his or her disability. Unlike denial, which is a defense mechanism, anosognosia is rooted in physiology...

). Urinary incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...

 can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care
Home care
Home Care, , is health care or supportive care provided in the patient's home by healthcare professionals Home Care, (also referred to as domiciliary care or social care), is health care or supportive care provided in the patient's home by healthcare professionals Home Care, (also referred to as...

 to other long-term care facilities
Nursing home
A nursing home, convalescent home, skilled nursing unit , care home, rest home, or old people's home provides a type of care of residents: it is a place of residence for people who require constant nursing care and have significant deficiencies with activities of daily living...

.

Advanced


During this last stage of AD, the person is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results.
People with AD will ultimately not be able to perform even the simplest tasks without assistance. Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers
Bedsore
Bedsores, more properly known as pressure ulcers or decubitus ulcers, are lesions caused by many factors—such as unrelieved pressure, friction, humidity, shearing forces, temperature, age, continence, and medication—to any part of the body, especially portions over bony or cartilaginous areas such...

 or pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

, not the disease itself.

Causation



The cause for most Alzheimer's cases is still essentially unknown (except for 1% to 5% of cases where genetic differences have been identified).
Several competing hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...

 hypothesis
, which proposes that AD is caused by reduced synthesis of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

 acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.

In 1991, the amyloid
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...

 hypothesis
postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid beta precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

 (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...

) who have an extra gene copy
Gene dosage
Gene dosage is the number of copies of a gene present in a cell or nucleus. An increase in gene dosage can cause higher levels of gene product if the gene is not subject to regulation from elsewhere in the body....

 almost universally exhibit AD by 40 years of age. Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD. Further evidence comes from the finding that transgenic
Genetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...

 mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.

An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.
One receptor for Aβ oligomers may be the prion protein
PRNP
Major prion protein also known as CD230 is a protein that in humans is encoded by the PRNP gene...

, the same protein that has been linked to mad cow disease
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...

 and the related human condition, Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease
Creutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...

, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21
TNFRSF21
Tumor necrosis factor receptor superfamily, member 21, also known as TNFRSF21, is a protein which in humans is encoded by the TNFRSF21 gene.- Function :...

). DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain
Aging brain
Age is a major risk factor for most common neurodegenerative diseases, including Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. Other risk factors, including genetic mutations, low educational attainments and head injury contribute much less to the risk...

 to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.

A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss. This observation supports the tau hypothesis, the idea that tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...

 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.

Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...

 gene.

Another hypothesis asserts that the disease may be caused by age-related myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...

 breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.

Oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

 and dys-homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

 of biometal (biology)
Biometal (biology)
The term Biometal refers to the role of metal ions in biology, biochemistry and medicine. The metals copper, zinc, iron and manganese are examples of metals that are essential for the normal functioning of the body. It is also a term used to describe a living machine.-External links:*...

 metabolism may be significant in the formation of the pathology.

AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous antiinflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ. This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.

Pathophysiology




Neuropathology


Alzheimer's disease is characterised by loss of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s and synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

s in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

 and certain subcortical regions. This loss results in gross atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...

 of the affected regions, including degeneration in the temporal lobe
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....

 and parietal lobe
Parietal lobe
The parietal lobe is a part of the Brain positioned above the occipital lobe and behind the frontal lobe.The parietal lobe integrates sensory information from different modalities, particularly determining spatial sense and navigation. For example, it comprises somatosensory cortex and the...

, and parts of the frontal cortex and cingulate gyrus. Studies using MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

 and PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 have documented reductions in the size of specific brain regions in people with AD as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.

Both amyloid plaques and neurofibrillary tangle
Neurofibrillary tangle
Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...

s are clearly visible by microscopy
Microscopy
Microscopy is the technical field of using microscopes to view samples and objects that cannot be seen with the unaided eye...

 in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 and cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....

 are not rare in the brains of people with AD.

Biochemistry



Alzheimer's disease has been identified as a protein misfolding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....

 disease (proteopathy
Proteopathy
In medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body...

), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s, 39–43 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

 (APP), a transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...

 that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...

. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques
Senile plaques
Senile plaques are extracellular deposits of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures and an abundance of microglia and astrocytes...

.
AD is also considered a tauopathy
Tauopathy
Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain.The best known of these illnesses is Alzheimer's disease , where tau protein is deposited within neurons in the form of neurofibrillary tangles...

 due to abnormal aggregation of the tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...

. Every neuron has a cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

 and back. A protein called tau stabilizes the microtubules when phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

, and is therefore called a microtubule-associated protein
Microtubule-associated protein
In cell biology, microtubule-associated proteins are proteins that interact with the microtubules of the cellular cytoskeleton.-Function:...

. In AD, tau undergoes chemical changes, becoming hyperphosphorylated
Hyperphosphorylation
Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signalling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems or cancer are a likely outcome...

; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.

Disease mechanism


Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibril
Fibril
Fibril is a fine fiber approximately 1 nm in diameter.Cytoplasmic fibrils are observed on the protoplasmic cylinders found in most spirochetal species, although no function of the cytoplasmic fibrils has been ascribed....

s, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...

 homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

, induces programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...

 (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

). It is also known that Aβ selectively builds up in the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...

 in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 functions and the utilisation of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 by neurons.

Various inflammatory processes and cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s may also have a role in the pathology of Alzheimer's disease. Inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 is a general marker of tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

 damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.

Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain derived neurotrophic factor (BDNF) have been described in AD.

Genetics


The vast majority of cases of Alzheimer's disease are sporadic, meaning that they are not genetically inherited although some genes may act as risk factors. On the other hand, around 0.1% of the cases are familial forms of autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...

 dominant (not sex-linked) inheritance, which usually have an onset before age 65. This form of the disease is known as Early onset familial Alzheimer's disease.

Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

 (APP) and presenilin
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex...

s 1 and 2. Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques
Senile plaques
Senile plaques are extracellular deposits of amyloid in the gray matter of the brain. The deposits are associated with degenerative neural structures and an abundance of microglia and astrocytes...

. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—e.g., Aβ40—without increasing Aβ42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than Aβ.

Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD. Nevertheless genetic differences may act as risk factors
Risk factors
A risk factor is a concept in finance theory such as the CAPM, APT and other theories that use pricing kernels. In these models, the rate of return of an asset is a random variable whose realization in any time period is a linear combination of other random variables plus a disturbance term or...

. The best known genetic risk factor is the inheritance of the ε4 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...

 of the apolipoprotein E
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...

 (APOE). Between 40 and 80% of people with AD possess at least one apoE4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. However, it must be noted that this "genetic" effect is not necessarily purely genetic. For example, certain Nigerian populations have no relationship between presence or dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease.
Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer's disease, but results such as the Nigerian studies and the incomplete penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...

 for all genetic risk factors associated with sporadic Alzheimers indicate a strong role for environmental effects. Over 400 genes have been tested for association with late-onset sporadic AD, most with null results.

Diagnosis



Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...

 and neuropsychological
Neuropsychology
Neuropsychology studies the structure and function of the brain related to specific psychological processes and behaviors. The term neuropsychology has been applied to lesion studies in humans and animals. It has also been applied to efforts to record electrical activity from individual cells in...

 features and the absence of alternative conditions
Diagnosis of exclusion
A diagnosis of exclusion is a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from examination or testing...

. Advanced medical imaging
Medical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...

 with computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...

 (CT) or magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

 (MRI), and with single photon emission computed tomography
Single photon emission computed tomography
Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information...

 (SPECT) or positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.

Assessment of intellectual functioning
Neuropsychological assessment
Neuropsychological assessment was traditionally carried out to assess the extent of impairment to a particular skill and to attempt to locate an area of the brain which may have been damaged after brain injury or neurological illness...

 including memory testing can further characterise the state of the disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...

 when brain material is available and can be examined histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

.

Criteria


The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association
Alzheimer's Association
The Alzheimer's Association, incorporated on April 10, 1980 as the Alzheimer’s Disease and Related Disorders Association, Inc., is a non-profit American voluntary health organization which focuses on care, support and research for Alzheimer's disease....

) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria
NINCDS-ADRDA Alzheimer's Criteria
The NINCDS-ADRDA Alzheimer's Criteria were proposed in 1984 by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and are among the most used in the diagnosis of Alzheimer's disease...

 for diagnosis in 1984, extensively updated in 2007. These criteria require that the presence of cognitive impairment
Developmental disability
Developmental disability is a term used in the United States and Canada to describe lifelong disabilities attributable to mental or physical impairments, manifested prior to age 18. It is not synonymous with "developmental delay" which is often a consequence of a temporary illness or trauma during...

, and a suspected dementia syndrome, be confirmed by neuropsychological testing
Neuropsychological assessment
Neuropsychological assessment was traditionally carried out to assess the extent of impairment to a particular skill and to attempt to locate an area of the brain which may have been damaged after brain injury or neurological illness...

 for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic
Microscopic
The microscopic scale is the scale of size or length used to describe objects smaller than those that can easily be seen by the naked eye and which require a lens or microscope to see them clearly.-History:...

 examination of brain tissue is required for a definitive diagnosis. Good statistical reliability
Reliability (statistics)
In statistics, reliability is the consistency of a set of measurements or of a measuring instrument, often used to describe a test. Reliability is inversely related to random error.-Types:There are several general classes of reliability estimates:...

 and validity
Validity (statistics)
In science and statistics, validity has no single agreed definition but generally refers to the extent to which a concept, conclusion or measurement is well-founded and corresponds accurately to the real world. The word "valid" is derived from the Latin validus, meaning strong...

 have been shown between the diagnostic criteria and definitive histopathological confirmation. Eight cognitive domains are most commonly impaired in AD—memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....

, language
Language
Language may refer either to the specifically human capacity for acquiring and using complex systems of communication, or to a specific instance of such a system of complex communication...

, perceptual skills
Perception
Perception is the process of attaining awareness or understanding of the environment by organizing and interpreting sensory information. All perception involves signals in the nervous system, which in turn result from physical stimulation of the sense organs...

, attention
Attention
Attention is the cognitive process of paying attention to one aspect of the environment while ignoring others. Attention is one of the most intensely studied topics within psychology and cognitive neuroscience....

, constructive abilities, orientation
Orientation (mental)
Orientation is a function of the mind involving awareness of three dimensions: time, place and person. Problems with orientation lead to disorientation, and can be due to various conditions, from delirium to intoxication...

, problem solving
Problem solving
Problem solving is a mental process and is part of the larger problem process that includes problem finding and problem shaping. Consideredthe most complex of all intellectual functions, problem solving has been defined as higher-order cognitive process that requires the modulation and control of...

 and functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders
Diagnostic and Statistical Manual of Mental Disorders
The Diagnostic and Statistical Manual of Mental Disorders is published by the American Psychiatric Association and provides a common language and standard criteria for the classification of mental disorders...

(DSM-IV-TR) published by the American Psychiatric Association
American Psychiatric Association
The American Psychiatric Association is the main professional organization of psychiatrists and trainee psychiatrists in the United States, and the most influential worldwide. Its some 38,000 members are mainly American but some are international...

.

Techniques


Neuropsychological test
Neuropsychological test
Neuropsychological tests are specifically designed tasks used to measure a psychological function known to be linked to a particular brain structure or pathway. Tests are used for research into brain function and in a clinical setting for the diagnosis of deficits. They usually involve the...

s such as the mini-mental state examination
Mini-mental state examination
The mini–mental state examination or Folstein test is a brief 30-point questionnaire test that is used to screen for cognitive impairment. It is commonly used in medicine to screen for dementia...

 (MMSE), are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Neurological examination
Neurological examination
A neurological examination is the assessment of sensory neuron and motor responses, especially reflexes, to determine whether the nervous system is impaired...

 in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia.

Further neurological examinations are crucial in the differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...

 of AD and other diseases. Interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function
Mental function
Mental processes, mental functions and cognitive processes are terms often used interchangeably to mean such functions or processes as perception, introspection, memory, creativity, imagination, conception, belief, reasoning, volition, and emotion—in...

. A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits
Anosognosia
Anosognosia /æˌnɒsɒgˈnəʊsɪə/ is a condition in which a person who suffers disability seems unaware of the existence of his or her disability. Unlike denial, which is a defense mechanism, anosognosia is rooted in physiology...

. Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.

Another recent objective marker of the disease is the analysis of cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 for amyloid beta or tau proteins, both total tau protein and phosphorylated tau181P protein concentrations. Searching for these proteins using a spinal tap
Lumbar puncture
A lumbar puncture is a diagnostic and at times therapeutic procedure that is performed in order to collect a sample of cerebrospinal fluid for biochemical, microbiological, and cytological analysis, or very rarely as a treatment to relieve increased intracranial pressure.-Indications:The...

 can predict the onset of Alzheimer's with a sensitivity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...

 of between 94% and 100%. When used in conjunction with existing neuroimaging
Functional neuroimaging
Functional neuroimaging is the use of neuroimaging technology to measure an aspect of brain function, often with a view to understanding the relationship between activity in certain brain areas and specific mental functions...

 techniques, doctors can identify people with significant memory loss who are already developing the disease. Spinal fluid tests are commercially available, unlike the latest neuroimaging technology. Alzheimer's was diagnosed in one-third of the people who did not have any symptoms in a 2010 study, meaning that disease progression occurs well before symptoms occur.

Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....

s can identify other causes for dementia than AD—causes which may, in rare cases, be reversible. It is common to perform thyroid function tests
Thyroid function tests
Thyroid function tests is a collective term for blood tests used to check the function of the thyroid.TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism , or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy...

, assess B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...

, rule out syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...

, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g. lead, mercury) and anemia. (See differential diagnosis for Dementia). (It is also necessary to rule out delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...

).

Psychological tests
Psychological testing
Psychological testing is a field characterized by the use of samples of behavior in order to assess psychological construct, such as cognitive and emotional functioning, about a given individual. The technical term for the science behind psychological testing is psychometrics...

 for depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

 are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease
Depression of Alzheimer disease
Depression is one of the most common psychiatric symptoms in Alzheimer's disease, but it often appears in a different form than other depressive disorders. In 2002, a workgroup of the U.S...

), an early sign of cognitive impairment, or even the cause.

Imaging


When available as a diagnostic tool, single photon emission computed tomography
Single photon emission computed tomography
Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information...

 (SPECT) and positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 (PET) neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination
Mental status examination
The mental status examination in the USA or mental state examination in the rest of the world, abbreviated MSE, is an important part of the clinical assessment process in psychiatric practice...

. In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history
Medical history
The medical history or anamnesis of a patient is information gained by a physician by asking specific questions, either of the patient or of other people who know the person and can give suitable information , with the aim of obtaining information useful in formulating a diagnosis and providing...

 analysis. Advances have led to the proposal of new diagnostic criteria.

A new technique known as PiB PET
Pittsburgh compound B
Pittsburgh compound B is a fluorescent analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue...

 has been developed for directly and clearly imaging beta-amyloid deposits in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

 using a tracer
Radioactive tracer
A radioactive tracer, also called a radioactive label, is a substance containing a radioisotope that is used to measure the speed of chemical processes and to track the movement of a substance through a natural system such as a cell or tissue...

 that binds
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...

 selectively to the A-beta deposits. The PiB-PET compound uses carbon-11 PET scanning. Recent studies suggest that PiB-PET is 86% accurate in predicting which people with mild cognitive impairment will develop Alzheimer's disease within two years, and 92% accurate in ruling out the likelihood of developing Alzheimer's.

A similar PET scanning radiopharmaceutical compound called (E)-4-(2-(6-(2-(2-(2-([18F]-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine, or 18F AV-45, or florbetapir-fluorine-18, or simply florbetapir, contains the longer-lasting radionuclide fluorine-18
Fluorine-18
Fluorine-18 is a fluorine radioisotope which is an important source of positrons. It has a mass of 18.0009380 u and its half-life is 109.771 minutes....

, has recently been created, and tested as a possible diagnostic tool in Alzheimer's disease. Florbetapir, like PiB, binds to beta-amyloid, but due to its use of fluorine-18 has a half-life of 110 minutes, in contrast to PiB's radioactive half life of 20 minutes. Wong et al. found that the longer life allowed the tracer to accumulate significantly more in the brains of people with AD, particularly in the regions known to be associated with beta-amyloid deposits.

One review predicted that amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative.

Volumetric MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

 can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study.

Non-Imaging biomarkers


Recent studies have shown that people with AD had decreased glutamate (Glu) as well as decreased Glu/creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...

 (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to normal people. Both decreased NAA/Cr and decreased hippocampal
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

 glutamate may be an early indicator of AD.

Early research in mouse models may have identified markers for AD. The applicability of these markers is unknown.

A small human study in 2011 found that monitoring blood dehydroepiandrosterone
Dehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....

 (DHEA) variations in response to an oxidative stress could be a useful proxy test: the subjects with MCI did not have a DHEA variation, while the healthy controls did.

Prevention


At present, there is no definitive evidence to support that any particular measure is effective in preventing AD. Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results.
However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD.

Although cardiovascular risk factors, such as hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...

, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 lowering drugs, have not been effective in preventing or improving the course of the disease. The components of a Mediterranean diet
Mediterranean diet
The Mediterranean diet is a modern nutritional recommendation inspired by the traditional dietary patterns of southern Italy, Crete and much of the rest of Greece in the 1960s....

, which include fruit and vegetables, bread
Bread
Bread is a staple food prepared by cooking a dough of flour and water and often additional ingredients. Doughs are usually baked, but in some cuisines breads are steamed , fried , or baked on an unoiled frying pan . It may be leavened or unleavened...

, wheat
Wheat
Wheat is a cereal grain, originally from the Levant region of the Near East, but now cultivated worldwide. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...

 and other cereal
Cereal
Cereals are grasses cultivated for the edible components of their grain , composed of the endosperm, germ, and bran...

s, olive oil
Olive oil
Olive oil is an oil obtained from the olive , a traditional tree crop of the Mediterranean Basin. It is commonly used in cooking, cosmetics, pharmaceuticals, and soaps and as a fuel for traditional oil lamps...

, fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...

, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Its beneficial cardiovascular effect has been proposed as the mechanism of action. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.

Reviews on the use of vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

s have not found enough evidence of efficacy to recommend vitamin C, E, or folic acid with or without vitamin B12, as preventive or treatment agents in AD. Additionally vitamin E is associated with important health risks. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Docosahexaenoic acid
Docosahexaenoic acid
Docosahexaenoic acid is an omega-3 fatty acid that is a primary structural component of the human brain and retina. In chemical structure, DHA is a carboxylic acid with a 22-carbon chain and six cis double bonds; the first double bond is located at the third carbon from the omega end...

, an Omega 3 fatty acid, has not been found to slow decline.

Long-term usage of non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

 (NSAIDs) is associated with a reduced likelihood of developing AD. Human postmortem studies, in animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...

s, or in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

 investigations also support the notion that NSAIDs can reduce inflammation related to amyloid plaques. However trials investigating their use as palliative treatment have failed to show positive results while no prevention trial has been completed. Curcumin
Curcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...

 from the curry
Curry
Curry is a generic description used throughout Western culture to describe a variety of dishes from Indian, Pakistani, Bangladeshi, Sri Lankan, Thai or other Southeast Asian cuisines...

 spice turmeric
Turmeric
Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive...

 has shown some effectiveness in preventing brain damage
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...

 in mouse models due to its anti-inflammatory properties. Hormone replacement therapy
Hormone therapy
Hormone therapy, or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also referred to as hormonal therapy...

, although previously used, is no longer thought to prevent dementia and in some cases may even be related to it. There is inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia, and a recent study concludes that it has no effect in reducing the rate of AD incidence. A 21-year study found that coffee drinkers of 3–5 cups per day at midlife had a 65% reduction in risk of dementia in late-life.

People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instrument
Musical instrument
A musical instrument is a device created or adapted for the purpose of making musical sounds. In principle, any object that produces sound can serve as a musical instrument—it is through purpose that the object becomes a musical instrument. The history of musical instruments dates back to the...

s, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the cognitive reserve
Cognitive reserve
The term cognitive reserve describes the mind's resilience to neuropathological damage of the brain. The mind's resilience is evaluated behaviorally, whereas the neuropathological damage is evaluated histologically, although damage may be estimated using blood-based markers and imaging methods...

 theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of AD syndrome, but is not related to earlier death after diagnosis. Learning a second language even later in life seems to delay getting Alzheimer disease.
Physical activity is also associated with a reduced risk of AD.

Two studies have shown that medical marijuana may be effective in inhibiting the progress of AD. The active ingredient in marijuana, THC
THC
THC commonly refers to tetrahydrocannabinol, the main active chemical compound in Cannabis.THC may also refer to:* Tan Holdings Corporation...

, may prevent the formation of deposits in the brain associated with Alzheimer's disease. THC was found to inhibit acetylcholinesterase more effectively than commercially marketed drugs. A recent review of the clinical research has found no evidence that cannabinoids are effective in the improvement of disturbed behavior or in the treatment of other symptoms of AD or dementia.

Some studies have shown an increased risk of developing AD with environmental factor
Environmental factor
Environmental factor or ecological factor or ecofactor is any factor, abiotic or biotic, that influences living organisms.- Environmental factors inducing diseases :...

s such the intake of metal
Metal
A metal , is an element, compound, or alloy that is a good conductor of both electricity and heat. Metals are usually malleable and shiny, that is they reflect most of incident light...

s, particularly aluminium
Aluminium
Aluminium or aluminum is a silvery white member of the boron group of chemical elements. It has the symbol Al, and its atomic number is 13. It is not soluble in water under normal circumstances....

, or exposure to solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

s. The quality of some of these studies has been criticised, and other studies have concluded that there is no relationship between these environmental factors and the development of AD.

While some studies suggest that extremely low frequency
Extremely low frequency
Extremely low frequency is a term used to describe radiation frequencies from 3 to 300 Hz. In atmosphere science, an alternative definition is usually given, from 3 Hz to 3 kHz...

 electromagnetic fields may increase the risk for Alzheimer's disease, reviewers found that further epidemiological and laboratory investigations of this hypothesis are needed. Smoking is a significant AD risk factor.
Systemic markers of the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...

 are risk factors for late-onset AD.

Management


There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but remain palliative
Palliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...

 in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

Pharmaceutical




Five medications are currently approved by regulatory agencies such as the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) and the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...

 (EMA) to treat the cognitive manifestations of AD: four are acetylcholinesterase inhibitor
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...

s (Tacrine
Tacrine
Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist . It was the first centrally-acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the...

, Rivastigmine
Rivastigmine
Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...

, Galantamine
Galantamine
Galantamine is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin...

 and Donepezil
Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...

) and the other (memantine) is an NMDA receptor antagonist
NMDA receptor antagonist
NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...

. No drug has an indication for delaying or halting the progression of the disease.

Reduction in the activity of the cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...

 neurons is a well-known feature of Alzheimer's disease. Acetylcholinesterase inhibitor
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...

s are employed to reduce the rate at which acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. , the cholinesterase inhibitors approved for the management of AD symptoms are donepezil
Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...

 (brand name Aricept), galantamine
Galantamine
Galantamine is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin...

 (Razadyne), and rivastigmine
Rivastigmine
Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...

 (branded as Exelon and Exelon Patch). There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease, and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia. The use of these drugs in mild cognitive impairment
Mild cognitive impairment
Mild cognitive impairment is a brain-function syndrome involving the onset and evolution of cognitive impairments beyond those expected based on the age and education of the individual, but which are not significant enough to interfere with their daily activities...

 has not shown any effect in a delay of the onset of AD. The most common side effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 are nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

 and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users and are mild to moderate in severity. Less common secondary effects include muscle cramps, decreased heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....

 (bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

), decreased appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...

 and weight, and increased gastric acid
Gastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...

 production.

Glutamate is a useful excitatory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

 of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...

, although excessive amounts in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 can lead to cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 death through a process called excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...

 which consists of the overstimulation of glutamate receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

 and multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

. Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda), is a noncompetitive NMDA receptor antagonist
NMDA receptor antagonist
NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...

 first used as an anti-influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

 agent. It acts on the glutamatergic system by blocking NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

s and inhibiting their overstimulation by glutamate. Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer's disease. Its effects in the initial stages of AD are unknown. Reported adverse events with memantine are infrequent and mild, including hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...

s, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...

, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

 and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....

 but clinically marginal effectiveness".

Antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

 drugs are modestly useful in reducing aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...

 and psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...

 in Alzheimer's disease with behavioural problems, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use. When used in the long-term, they have been shown to associate with increased mortality.

People with Alzheimer’s disease who have taken Huperzine A
Huperzine A
Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the plant firmoss Huperzia serrata. and in varying quantities in other Husperzia spp.including H. elmeri, H. carinat, H. aqualupian,...

 may have improved general cognitive function, global clinical status, functional performance and reduced behavioural disturbance compared to people taking placebos, according to a Cochrane Review, however, the poor methodological quality of the small trials, including problems with blinding and randomization, led reviewers to conclude "There is currently insufficient evidence of the effects of Huperzine A for Alzheimer's disease (AD)."

Psychosocial intervention



Psychosocial
Psychosocial
For a concept to be psychosocial means it relates to one's psychological development in, and interaction with, a social environment. The individual needs not be fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of...

 interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general.

Behavioural interventions
Behavior modification
Behavior modification is the use of empirically demonstrated behavior change techniques to increase or decrease the frequency of behaviors, such as altering an individual's behaviors and reactions to stimuli through positive and negative reinforcement of adaptive behavior and/or the reduction of...

 attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning,
but can help to reduce some specific problem behaviours, such as incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...

. There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.

Emotion-oriented interventions include reminiscence therapy
Reminiscence therapy
Reminiscence therapy is used to counsel and support older people, and is an intervention technique with brain-injured patients. This form of therapeutic intervention respects the life and experiences of the individual with the aim to help the patient maintain good mental health.Often utilised in...

, validation therapy
Validation therapy
Validation therapy was developed by Naomi Feil for older people with cognitive impairments and dementia. Feil's own approach classifies individuals with cognitive impairment as having one of four stages in a continuum of dementia...

, supportive psychotherapy
Psychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...

, sensory integration
Sensory integration
Sensory integration is defined as the neurological process that organizes sensation from one’s own body and the environment, thus making it possible to use the body effectively within the environment. Specifically, it deals with how the brain processes multiple sensory modality inputs into usable...

, also called snoezelen
Snoezelen
Snoezelen or controlled multisensory Environment relates to the interdependence of both the space and the "client-centered" approach of the practitioner...

, and simulated presence therapy
Simulated presence therapy
Simulated presence therapy is an emotion-oriented non pharmacological intervention for people with dementia. It is based in psychological attachment theories and is normally carried out playing a recording with voices of the closests relatives of the patient. There are preliminary evidences...

. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired people adjust to their illness. Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT, it may be beneficial for cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...

 and mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....

.
Simulated presence therapy (SPT) is based on attachment theories
Attachment theory
Attachment theory describes the dynamics of long-term relationships between humans. Its most important tenet is that an infant needs to develop a relationship with at least one primary caregiver for social and emotional development to occur normally. Attachment theory is an interdisciplinary study...

 and involves playing a recording with voices of the closest relatives of the person with Alzheimer's disease. There is partial evidence indicating that SPT may reduce challenging behaviour
Challenging behaviour
Challenging behaviour is defined as "culturally abnormal behaviour of such intensity, frequency or duration that the physical safety of the person or others is placed in serious jeopardy, or behaviour which is likely to seriously limit or deny access to the use of ordinary community...

s.
Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate sense
Sense
Senses are physiological capacities of organisms that provide inputs for perception. The senses and their operation, classification, and theory are overlapping topics studied by a variety of fields, most notably neuroscience, cognitive psychology , and philosophy of perception...

s. There is little evidence to support the usefulness of these therapies.

The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining
Rehabilitation (neuropsychology)
Rehabilitation of sensory and cognitive function typically involves methods for retraining neural pathways or training new neural pathways to regain or improve neurocognitive functioning that has been diminished by disease or traumatic injury....

, is the reduction of cognitive deficit
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...

s. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his or her place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities, although in some studies these effects were transient and negative effects, such as frustration, have also been reported.

Stimulation-oriented treatments include art
Art therapy
Because of its dual origins in art and psychotherapy, art therapy definitions vary. They commonly either lean more toward the ART art-making process as therapeutic in and of itself, "art as therapy," or focus on the psychotherapeutic transference process between the therapist and the client who...

, music
Music therapy
Music therapy is an allied health profession and one of the expressive therapies, consisting of an interpersonal process in which a trained music therapist uses music and all of its facets—physical, emotional, mental, social, aesthetic, and spiritual—to help clients to improve or maintain their...

 and pet
Animal-Assisted Therapy
Animal-assisted therapy is a relatively new field of study, although the human-animal bond has existed for thousands of years. AAT is a type of therapy that involves animals as a form of treatment. The goal of AAT is to improve a patient’s social, emotional, or cognitive functioning...

 therapies, exercise
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...

, and any other kind of recreational activities
Recreational therapy
Recreational therapy, also referred to as recreation therapy and therapeutic recreation, is a treatment service that provides treatments and recreation activities to individuals with illnesses or disabling conditions to improve or maintain physical, mental and emotional well-being and help reduce...

. Stimulation has modest support for improving behaviour, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.

Caregiving


Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.

During the early and moderate stages, modifications to the living environment and lifestyle can increase patient safety
Patient safety
Patient safety is a new healthcare discipline that emphasizes the reporting, analysis, and prevention of medical error that often leads to adverse healthcare events. The frequency and magnitude of avoidable adverse patient events was not well known until the 1990s, when multiple countries reported...

 and reduce caretaker burden. Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labelling of household items to cue the person with the disease or the use of modified daily life objects. The patient may also become incapable of feeding themselves, so they require food in smaller pieces or pureed. When swallowing difficulties
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

 arise, the use of feeding tube
Feeding tube
A feeding tube is a medical device used to provide nutrition to patients who cannot obtain nutrition by swallowing. The state of being fed by a feeding tube is called gavage, enteral feeding or tube feeding...

s may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with AD or their caregivers.

As the disease progresses, different medical issues can appear, such as oral and dental disease
Dental disease
Dental diseases may affect the teeth, the gums, or other tissues and parts of the mouth. Dental diseases can cause much more serious problems than a toothache; they can affect our ability to chew, smile, or speak properly. Their severity may range from a simple aphthous ulcer, to a common tooth...

, pressure ulcers
Bedsore
Bedsores, more properly known as pressure ulcers or decubitus ulcers, are lesions caused by many factors—such as unrelieved pressure, friction, humidity, shearing forces, temperature, age, continence, and medication—to any part of the body, especially portions over bony or cartilaginous areas such...

, malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....

, hygiene
Hygiene
Hygiene refers to the set of practices perceived by a community to be associated with the preservation of health and healthy living. While in modern medical sciences there is a set of standards of hygiene recommended for different situations, what is considered hygienic or not can vary between...

 problems, or respiratory
Respiratory system
The respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...

, skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...

, or eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...

 infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s. Careful management can prevent them, while professional treatment is needed when they do arise. During the final stages of the disease, treatment is centred on relieving discomfort until death.

A small recent study in the US concluded that people whose caregivers had a realistic understanding of the prognosis and clinical complications of late dementia were less likely to receive aggressive treatment near the end of life.

Feeding tubes


There is strong evidence that feeding tubes do not help people with advanced Alzheimer's dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

 gain weight, regain strength or function, prevent aspiration pneumonias, or improve quality of life.

Prognosis


The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living.

Life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...

 of the population with the disease is reduced. The mean life expectancy following diagnosis is approximately seven years. Fewer than 3% of people live more than fourteen years. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...

, diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

 or history of alcohol abuse
Alcohol abuse
Alcohol abuse, as described in the DSM-IV, is a psychiatric diagnosis describing the recurring use of alcoholic beverages despite negative consequences. Alcohol abuse eventually progresses to alcoholism, a condition in which an individual becomes dependent on alcoholic beverages in order to avoid...

 are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.

The disease is the underlying cause of death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....

 in 70% of all cases. Pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

 and dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

 are the most frequent immediate causes of death, while cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 is a less frequent cause of death than in the general population.

Epidemiology

Incidence rates
after age 65
Age New affected
per thousand
person–years
65–69  3
70–74  6
75–79  9
80–84 23
85–89 40
90–     69


Two main measures are used in epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...

 studies: incidence and prevalence. Incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...

 is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 is the total number of cases of the disease in the population at any given time.

Regarding incidence, cohort
Cohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...

 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, 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. There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.

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. Prevalence rates in less developed regions are lower. The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 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. 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 , range ) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by 2050.

History



The ancient Greek and Roman
Classical antiquity
Classical antiquity is a broad term for a long period of cultural history centered on the Mediterranean Sea, comprising the interlocking civilizations of ancient Greece and ancient Rome, collectively known as the Greco-Roman world...

 philosophers and physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...

s associated old age with increasing dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

. It was not until 1901 that German psychiatrist
Psychiatry
Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...

 Alois Alzheimer
Alois Alzheimer
Aloysius "Alois" Alzheimer, was a German psychiatrist and neuropathologist and a colleague of Emil Kraepelin. Alzheimer is credited with identifying the first published case of "presenile dementia", which Kraepelin would later identify as Alzheimer's disease....

 identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D
Auguste D
Auguste Deter is the first person diagnosed with Alzheimer's disease. Her maiden name is unknown. She married Karl Deter in the 1880s and together they had one daughter. Auguste had a normal life. However, during the late 1890s, she started showing symptoms of dementia, such as: loss of memory,...

. Alzheimer followed her until she died in 1906, when he first reported the case publicly. During the next five years, eleven similar cases were reported in the medical literature
Medical literature
Medical literature refers to articles in journals and texts in books devoted to the field of medicine.Contemporary and historic views regarding diagnosis, prognosis and treatment of medical conditions have been documented for thousands of years. The Edwin Smith papyrus is the first known medical...

, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by Emil Kraepelin
Emil Kraepelin
Emil Kraepelin was a German psychiatrist. H.J. Eysenck's Encyclopedia of Psychology identifies him as the founder of modern scientific psychiatry, as well as of psychopharmacology and psychiatric genetics. Kraepelin believed the chief origin of psychiatric disease to be biological and genetic...

 after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D. He included Alzheimer's disease, also named presenile dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

 by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 1910.

For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes. This eventually led to the diagnosis of Alzheimer's disease independently of age. The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature
Nomenclature
Nomenclature is a term that applies to either a list of names or terms, or to the system of principles, procedures and terms related to naming - which is the assigning of a word or phrase to a particular object or property...

 to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology
Neuropathology
Neuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole autopsy brains. Neuropathology is a subspecialty of anatomic pathology, neurology, and neurosurgery...

.

Social costs


Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in Europe and the United States, while their cost in other countries such as Argentina
Argentina
Argentina , officially the Argentine Republic , is the second largest country in South America by land area, after Brazil. It is constituted as a federation of 23 provinces and an autonomous city, Buenos Aires...

, or South Korea
South Korea
The Republic of Korea , , is a sovereign state in East Asia, located on the southern portion of the Korean Peninsula. It is neighbored by the People's Republic of China to the west, Japan to the east, North Korea to the north, and the East China Sea and Republic of China to the south...

, is also high and rising. These costs will probably increase with the ageing
Ageing
Ageing or aging is the accumulation of changes in a person over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline...

 of society, becoming an important social problem
Social issues
Social issues are controversial issues which relate to people's personal lives and interactions. Social issues are distinguished from economic issues...

. AD-associated costs include direct medical costs such as nursing
Nursing
Nursing is a healthcare profession focused on the care of individuals, families, and communities so they may attain, maintain, or recover optimal health and quality of life from conception to death....

 home care
Home care
Home Care, , is health care or supportive care provided in the patient's home by healthcare professionals Home Care, (also referred to as domiciliary care or social care), is health care or supportive care provided in the patient's home by healthcare professionals Home Care, (also referred to as...

, direct nonmedical costs such as in-home day care
Day care
Child care or day care is care of a child during the day by a person other than the child's legal guardians, typically performed by someone outside the child's immediate family...

, and indirect costs such as lost productivity
Productivity
Productivity is a measure of the efficiency of production. Productivity is a ratio of what is produced to what is required to produce it. Usually this ratio is in the form of an average, expressing the total output divided by the total input...

 of both patient and caregiver. Numbers vary between studies but dementia costs worldwide have been calculated around $160 billion, while costs of Alzheimer in the United States may be $100 billion each year.

The greatest origin of costs for society is the long-term care
Long-term care
Long-term care is a variety of services which help meet both the medical and non-medical need of people with a chronic illness or disability who cannot care for themselves for long periods of time....

 by health care professionals
Health care provider
A health care provider is an individual or an institution that provides preventive, curative, promotional or rehabilitative health care services in a systematic way to individuals, families or communities....

 and particularly institutionalisation, which corresponds to 2/3 of the total costs for society. The cost of living
Cost-of-living index
Cost of living is the cost of maintaining a certain standard of living. Changes in the cost of living over time are often operationalized in a cost of living index. Cost of living calculations are also used to compare the cost of maintaining a certain standard of living in different geographic areas...

 at home is also very high, especially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.

Costs increase with dementia severity and the presence of behavioural disturbances, and are related to the increased caregiving time required for the provision of physical care. Therefore any treatment that slows cognitive decline, delays institutionalisation or reduces caregivers' hours will have economic benefits. Economic evaluations of current treatments have shown positive results.

Caregiving burden



The role of the main caregiver
Caregiving and dementia
As populations age, caregiving and dementia become more common aspects of life. In most mild to medium cases of dementia the primary caregiver is a family member, usually a spouse or adult child...

 is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects. Home care is usually preferred by people with AD and their families. This option also delays or eliminates the need for more professional and costly levels of care. Nevertheless two-thirds of nursing home residents have dementias.

Dementia
Depression of Alzheimer disease
Depression is one of the most common psychiatric symptoms in Alzheimer's disease, but it often appears in a different form than other depressive disorders. In 2002, a workgroup of the U.S...

 caregivers are subject to high rates of physical and mental disorders. Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviours of the cared person such as depression, behavioural disturbances, hallucinations, sleep problems or walking disruptions and social isolation
Social isolation
Social isolation refers to a lack of contact with society for members of social species. There may be many causes and individuals in numerous generally social species are isolated at times, it need not be a pathological condition. In human society, in those cases where it is viewed as a pathology,...

. Regarding economic problems, family caregivers often give up time from work to spend 47 hours per week on average with the person with AD, while the costs of caring for them are high. Direct and indirect costs of caring for an Alzheimer's patient average between $18,000 and $77,500 per year in the United States, depending on the study.

Cognitive behavioural therapy and the teaching of coping strategies
Coping (psychology)
Coping has been defined in psychological terms by Susan Folkman and Richard Lazarus as "constantly changing cognitive and behavioral efforts to manage specific external and/or internal demands that are appraised as taxing" or "exceeding the resources of the person".Coping is thus expending...

 either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.

Notable cases



As Alzheimer's disease is highly prevalent, many notable people have developed it. Well-known examples are former United States President Ronald Reagan
Ronald Reagan
Ronald Wilson Reagan was the 40th President of the United States , the 33rd Governor of California and, prior to that, a radio, film and television actor....

 and Irish writer Iris Murdoch
Iris Murdoch
Dame Iris Murdoch DBE was an Irish-born British author and philosopher, best known for her novels about political and social questions of good and evil, sexual relationships, morality, and the power of the unconscious...

, both of whom were the subjects of scientific articles examining how their cognitive capacities deteriorated with the disease. Other cases include the retired footballer Ferenc Puskas
Ferenc Puskás
Ferenc Puskás was a Hungarian footballer and manager. He scored 84 goals in 85 international matches for Hungary, and 514 goals in 529 matches in the Hungarian and Spanish leagues. He became Olympic champion in 1952 and was a World Cup finalist in 1954...

, the former Prime Minister
Prime minister
A prime minister is the most senior minister of cabinet in the executive branch of government in a parliamentary system. In many systems, the prime minister selects and may dismiss other members of the cabinet, and allocates posts to members within the government. In most systems, the prime...

s Harold Wilson
Harold Wilson
James Harold Wilson, Baron Wilson of Rievaulx, KG, OBE, FRS, FSS, PC was a British Labour Member of Parliament, Leader of the Labour Party. He was twice Prime Minister of the United Kingdom during the 1960s and 1970s, winning four general elections, including a minority government after the...

 (United Kingdom) and Adolfo Suárez
Adolfo Suárez
Adolfo Suárez y González, 1st Duke of Suárez, Grandee of Spain, KOGF is a Spanish lawyer and politician. Suárez was Spain's first democratically elected prime minister after the dictatorship of Francisco Franco, and the key figure in the country's transition to democracy.-Parents:He is a son of...

 (Spain
Spain
Spain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...

), the actress Rita Hayworth
Rita Hayworth
Rita Hayworth was an American film actress and dancer who attained fame during the 1940s as one of the era's top stars...

, the actor Charlton Heston
Charlton Heston
Charlton Heston was an American actor of film, theatre and television. Heston is known for heroic roles in films such as The Ten Commandments, Ben-Hur for which he won the Academy Award for Best Actor, El Cid, and Planet of the Apes...

, the novelist Terry Pratchett
Terry Pratchett
Sir Terence David John "Terry" Pratchett, OBE is an English novelist, known for his frequently comical work in the fantasy genre. He is best known for his popular and long-running Discworld series of comic fantasy novels...

, Indian politician George Fernandes
George Fernandes
George Mathew Fernandes is an Indian trade unionist, politician, journalist, agriculturist, and member of Rajya Sabha from Bihar. He is a key member of the Janata Dal , and was the founder of the Samata Party...

,
and the 2009 Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

 in Physics recipient Charles K. Kao
Charles K. Kao
The Honorable Sir Charles Kuen Kao, GBM, KBE, FRS, FREng is a pioneer in the development and use of fiber optics in telecommunications...

.

AD has also been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch
Iris Murdoch
Dame Iris Murdoch DBE was an Irish-born British author and philosopher, best known for her novels about political and social questions of good and evil, sexual relationships, morality, and the power of the unconscious...

;
The Notebook
The Notebook (film)
The Notebook is a 2004 romance film directed by Nick Cassavetes, based on the novel of the same name by Nicholas Sparks. The film stars Ryan Gosling and Rachel McAdams as a young couple who fall in love during the early 1940s...

(2004), based on Nicholas Sparks
Nicholas Sparks (author)
Nicholas Charles Sparks is an internationally-bestselling American novelist and screenwriter. He has 16 published novels, with thematic ideas that include cancer, death and love. Six have been adapted to film, including Message in a Bottle, A Walk to Remember, The Notebook, Nights in Rodanthe,...

' 1996 novel of the same name
The Notebook
The Notebook is a 1996 romantic novel by American novelist Nicholas Sparks, based on a true story. The novel was later adapted into a popular romance film by the same name in 2004.-Background:...

; A Moment to Remember
A Moment to Remember
A Moment to Remember is a 2004 South Korean film based on a 2001 Japanese television drama Pure Soul broadcast by Yomiuri Telecasting Corporation. It stars Son Ye-jin and Jung Woo-sung. A Moment to Remember follows the theme of discovery in a relationship and the burdens of loss caused by...

(2004);Thanmathra
Thanmathra
Thanmathra is a 2005 Malayalam film directed by Blessy, based on Padmarajan's short story Orma, which portrays the effects of Alzheimer's disease on the life of an individual and his family...

(2005); Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name; Away from Her
Away From Her
Away from Her is a 2006 Canadian film which debuted at the Toronto International Film Festival and also played in the Premier category at the 2007 Sundance Film Festival...

(2006), based on Alice Munro
Alice Munro
Alice Ann Munro is a Canadian short-story writer, the winner of the 2009 Man Booker International Prize for her lifetime body of work, a three-time winner of Canada's Governor General's Award for fiction, and a perennial contender for the Nobel Prize...

's short story
Short story
A short story is a work of fiction that is usually written in prose, often in narrative format. This format tends to be more pointed than longer works of fiction, such as novellas and novels. Short story definitions based on length differ somewhat, even among professional writers, in part because...

 "The Bear Came over the Mountain
Hateship, Friendship, Courtship, Loveship, Marriage
Hateship, Friendship, Courtship, Loveship, Marriage is a book of short stories by Alice Munro, published by McClelland and Stewart in 2001....

". Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon
Malcolm Pointon
Malcolm Pointon was a pianist and lecturer from Thriplow, England, and the subject the film Malcolm and Barbara - A Love Story shown in 1999 and, more recently of an Independent Television program entitled Malcolm and Barbara: Love’s Farewell, broadcast on Wednesday, August 8,...

.

Research directions


, the safety and efficacy of more than 400 pharmaceutical treatments had been or were being investigated in 858 clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s worldwide, and approximately a quarter of these compounds are in Phase III trials; the last step prior to review by regulatory agencies.

One area of clinical research is focused on treating the underlying disease pathology. Reduction of amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...

 levels is a common target of compounds (such as apomorphine
Apomorphine
Apomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...

) under investigation. Immunotherapy
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...

 or vaccination
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...

 for the amyloid protein is one treatment modality under study. Unlike preventative vaccination, the putative therapy would be used to treat people already diagnosed. It is based upon the concept of training the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 to recognise, attack, and reverse deposition of amyloid, thereby altering the course of the disease. An example of such a vaccine under investigation was ACC-001, although the trials were suspended in 2008. Another similar agent is bapineuzumab
Bapineuzumab
Bapineuzumab is a humanized monoclonal antibody that acts on the nervous system and has potential therapeutic value for the treatment of Alzheimer's disease and possibly glaucoma....

, an antibody designed as identical to the naturally induced anti-amyloid antibody. Other approaches are neuroprotective agents, such as AL-108, and metal-protein interaction attenuation agents, such as PBT2. A TNFα receptor fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...

, etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...

 has showed encouraging results.

In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride (trade name rember
Rember
Methylthioninium chloride is an investigational drug being developed by the University of Aberdeen and TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation. The drug is of potential interest for the treatment of patients with Alzheimer's...

), a drug that inhibits tau aggregation, and dimebon
Dimebon
Latrepirdine , is an antihistamine drug which has been used clinically in Russia since 1983....

, an antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...

.
The consecutive Phase-III trial of Dimebon failed to show positive effects in the primary and secondary endpoints.

The possibility that AD could be treated with antiviral
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...

 medication is suggested by a study showing colocation of herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...

 virus with amyloid plaques.

Preliminary research on the effects of meditation on retrieving memory and cognitive functions have been encouraging. Limitations of this research can be addressed in future studies with more detailed analyses.

An FDA panel voted unanimously to recommend approval of florbetapir (tradename: Amyvid), which is currently used in an investigational study. The agent can detect Alzheimer's brain plaques, but will require additional clinical research before it can be made available commercially.

External links