Alzheimer's disease (
AD), also called
Alzheimer disease,
Senile Dementia of the Alzheimer Type (
SDAT) or simply
Alzheimer's, is the most common form of
dementiaDementia is a serious cognitive disorder. It may be static, the result of a unique global brain injury or progressive, resulting in long-term decline in cognitive function due to damage or disease in the body beyond what might be expected from normal aging...
. This incurable,
degenerativeA degenerative 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
terminal diseaseTerminal illness is a medical term popularized in the 20th century to describe an active and malignant disease that cannot be cured or adequately treated and that is reasonably expected to result in the death of the patient. This term is more commonly used for progressive diseases such as cancer...
was first described by
GermanGermany , officially the Federal Republic of Germany , is a country in Central Europe. It is bordered to the north by the North Sea, Denmark, and the Baltic Sea; to the east by Poland and the Czech Republic; to the south by Austria and Switzerland; and to the west by France, Luxembourg, Belgium,...
psychiatrist and neuropathologist
Alois AlzheimerAloysius "Alois" Alzheimer, was a German psychiatrist and neuropathologist and a colleague of Emil Kraepelin...
in 1906 and was named after him. Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. As of September 2009, this number is reported to be 35 million-plus worldwide. The prevalence of Alzheimer's is thought to reach approximately 107 million people by 2050.
Although the course of Alzheimer's disease is unique for every individual, there are many common symptoms. The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most commonly recognised symptom is
memory lossMemory loss can have many causes:*Alzheimer's disease is an illness which can cause mild to severe memory loss.*Parkinson's disease is a genetic defect which may result in memory loss....
, such as difficulty in remembering recently learned facts. When a doctor or physician has been notified, and AD is suspected, the diagnosis is usually confirmed with behavioural assessments and cognitive tests, often followed by a
brain scanNeuroimaging 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 include
confusionConfusion of a pathological degree, usually refers to loss of orientation and often memory...
, irritability and aggression,
mood swingA mood swing is an extreme or rapid change in mood. They are commonly associated with mood disorders, of which the classic example is bipolar disorder and also a major factor in hyperactive or hyperactive/inattentive such as ADHD...
s, language breakdown,
long-term memoryLong-term memory is memory that can last as little as a few days or as long as decades. It differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around...
loss, and the general withdrawal of the sufferer as their senses decline. Gradually, bodily functions are lost, ultimately leading to death. Individual
prognosisPrognosis is a medical term to describe the likely outcome of an illness. When applied to large 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 previous...
is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean 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
plaquesSenile 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
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
. Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available. As of 2008, more than 500 clinical trials have been conducted for identification of a possible treatment for AD, but it is unknown if any of the tested intervention strategies will show promising results. A number of non-invasive, life-style habits have been suggested for the
preventionPreventive medicine or preventive care refers to measures taken to prevent diseases, rather than curing them. It can be contrasted not only with curative medicine, but also with public health methods .-Levels:This takes place at primary, secondary and tertiary prevention levels.#Primary...
of Alzheimer's disease, but there is a lack of adequate evidence for a link between these recommendations and reduced degeneration.
Mental stimulationMental exercise is to perform an intellectual stimulating task such as solving a puzzle or engaging in a game of chess. Learning a new language is also a mental exercise...
, exercise, and a balanced diet are suggested, as both a possible prevention and a sensible way of managing the disease.
Because AD cannot be cured and is degenerative, management of patients is essential. The role of the main
caregiverCaregiver 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* An assisted living situation* A nursing home...
is often taken by the spouse or a close relative. Alzheimer's disease is known for
placing a great burden on caregiversAs 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 countriesThe term developed country is used to describe countries that have a high level of development according to some criteria. Which criteria, and which countries are classified as being developed, is a contentious issue and there is fierce debate about this. Economic criteria have tended to dominate...
, 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
functionalGenerally, functional refers to something able to fulfill its purpose or function.* Functional form and functionalism apply to architectural design....
impairmentImpairment may refer to:* A disability* In accounting, a downward revaluation of fixed assets* In physical therapy it is any loss or abnormality of physiological, psychological, or anatomical structure of function, whether permanent or temporary....
s.
Pre-dementia
The first symptoms are often mistaken as related to aging or stress. Detailed
neuropsychologicalNeuropsychology is the basic scientific discipline that studies the structure and function of the brain related to specific psychological processes and overt behaviors. The term neuropsychology has been applied to lesion studies in humans and animals...
testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for
diagnosisDiagnosis is the identification of the nature of anything, either by process of elimination or other analytical methods...
of AD. These early symptoms can affect the most complex
daily living activitiesActivities of daily living is a term used in medicine and nursing, especially in the care of the elderly. are "the things we normally do in daily living, including any daily activity we perform for self-care , work, homemaking, and leisure." A number of national surveys collect data on the ADL...
. 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 functionsThe executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is also referred to as the executive function, executive functions, supervisory attentional system, or cognitive control.The concept is used by psychologists and...
of
attentivenessAttention is the cognitive process of selectively concentrating on one aspect of the environment while ignoring other things. Attention has also been referred to as the allocation of processing resources...
,
planningPlanning 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...
,
flexibilityFlexibility may refer to:*Flexibility , the range of motion of a joint, which may be increased by stretching...
, and
abstract thinkingAbstraction is the process or result of generalization by reducing the information content of a concept or an observable phenomenon, typically to retain only information which is relevant for a particular purpose. For example, abstracting a leather soccer ball to a ball retains only the information...
, or impairments in
semantic memorySemantic 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, 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.
ApathyImage:Challenge_vs_skill.jpg|250px|Apathy in terms of challenge level and skill level. Clickable.|thumbpoly 66 7 211 9 285 189 254 234 67 152 Anxietypoly 221 7 428 7 351 188 296 187 294 188 Arousalpoly 439 7 583 7 584 149 388 236 360 194 Flow...
can be observed at this stage, and remains the most persistent
neuropsychiatricNeuropsychiatry 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 . However, neurology and psychiatry subsequently...
symptom throughout the course of the disease. The preclinical stage of the disease has also been termed
mild cognitive impairmentMild cognitive impairment is a diagnosis given to individuals who have cognitive impairments beyond that expected for their age and education, but that do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and...
, but whether this term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.
Early dementia
In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small proportion of them, difficulties with language, executive functions,
perceptionIn philosophy, psychology, and the cognitive sciences, perception is the process of attaining awareness or understanding of sensory information. It is a task far more complex than was imagined in the 1950s and 1960s, when it was predicted that building perceiving machines would take about a decade,...
(
agnosiaAgnosia 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 (
apraxiaApraxia is a neurological disorder 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 memoriesLong-term memory is memory that can last as little as a few days or as long as decades. It differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around...
of the person's life (
episodic memoryEpisodic 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 memorySemantic 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, generally thought to be independent of context and personal relevance...
), and
implicit memoryImplicit 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 problemsSemantic 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, generally thought to be independent of context and personal relevance...
are mainly characterised by a shrinking
vocabularyA person's vocabulary is the set of words they are familiar with in a language. A vocabulary usually grows and evolves with age, and serves as a useful and fundamental tool for communication and acquiring knowledge.- Knowing and using a word :...
and decreased word
fluencyFluency 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 languageA 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 tasksFine motor skills can be defined as coordination of small muscle movements which occur e.g., in the fingers, usually in coordination with the eyes...
such as writing, drawing or dressing, certain movement coordination and planning difficulties (
apraxiaApraxia is a neurological disorder 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 dementia
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 (
paraphasiaParaphasia is a notable 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. 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 memoryLong-term memory is memory that can last as little as a few days or as long as decades. It differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around...
, which was previously intact, becomes impaired. Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are
wanderingWandering, in persons with dementia, is a common behavior that causes great risk for the person and concern for caregivers. It is estimated to be the most common type of disruptive behavior in institutionalized persons with dementia. Although it occurs in several types of dementia, wandering is...
,
irritabilityIrritability 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....
and
labile affectLabile affect or pseudobulbar affect refers to the pathological expression of laughter, crying, or smiling. It is also known as emotional lability, pathological laughter and crying, emotional incontinence, or, more recently, involuntary emotional expression disorder...
, leading to crying, outbursts of unpremeditated
aggressionIn psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause pain or harm. Predatory or defensive behavior between members of different species is not normally considered "aggression." Aggression takes a...
, or resistance to caregiving.
SundowningIn 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...
can also appear. Approximately 30% of patients develop
illusionary misidentificationsDelusional misidentification syndrome is an umbrella term 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
delusionA delusion, in everyday language, is a fixed belief that is either false, fanciful, or derived from deception. Psychiatry defines the term more specifically as a belief that is pathological...
al symptoms. Subjects also lose insight of their disease process and limitations (
AnosognosiaAnosognosia is a condition in which a person who suffers disability seems unaware of or denies the existence of his or her disability. This may include unawareness of quite dramatic impairments, such as blindness or paralysis...
).
Urinary incontinenceUrinary 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...
can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from
home careHome care, , is health care or supportive care provided in the patient's home by healthcare professionals or by family and friends Home care, (commonly referred to as domiciliary care), is health care or supportive care provided in the patient's home by healthcare professionals (often referred to...
to other
long-term care facilitiesA nursing home, convalescent home, Skilled Nursing Unit , care home or rest 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. Residents include the elderly and younger...
.
Advanced dementia
During this last stage of AD, the patient 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, patients can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results.
Patients will ultimately not be able to perform even the most simple 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 ulcersBedsores, 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
pneumoniaPneumonia is an inflammatory illness of the lung. Frequently, it is described as lung parenchyma/alveolar inflammation and abnormal alveolar filling with fluid ....
, not by the disease itself.
Causes
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the
cholinergicA receptor is cholinergic if it uses acetylcholine as its neurotransmitter.Cholinergic means related to the neurotransmitter acetylcholine, and is typically used in a neurological perspective. The parasympathetic nervous system is entirely cholinergic...
hypothesis, which proposes that AD is caused by reduced synthesis of the
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
acetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division...
. 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
amyloidAmyloid beta is a peptide of 39–43 amino acids that appear to be the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating...
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 proteinAmyloid 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 and neural plasticity...
(APP) on chromosome 21, together with the fact that people with trisomy 21 (
Down SyndromeDown syndrome , Down's syndrome , trisomy 21, or trisomy G is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British doctor who described the syndrome in 1866...
) who thus have an extra
gene copyGene 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
transgenicA 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. In 2009, it was found that oligomeric Aβ exerts a deleterious effect on brain physiology by binding to a specific receptor on neurons. The identity of this receptor is the prion protein that has been linked to mad cow disease and the related human condition, Creutzfeldt-Jakob disease, 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
TNFRSF21Tumor 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 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 proteinTau proteins are microtubule-associated proteins that are abundant in neurons in the central nervous system and are less common elsewhere. They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University ...
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
apoEApolipoprotein 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.
Neuropathology
Alzheimer's disease is characterised by loss of
neuronA neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
s and synapses in the
cerebral cortexThe cerebral cortex is a structure within the brain that plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It constitutes the outermost layer of the cerebrum. In preserved brains, it has a grey color, hence the name "grey matter"...
and certain subcortical regions. This loss results in gross
atrophyAtrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include 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 lobeThe temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both the left and right hemispheres of the brain....
and
parietal lobeThe parietal lobe is a lobe in the brain. It is positioned above the occipital lobe and behind the frontal lobe....
, and parts of the frontal cortex and
cingulate gyrusCingulate gyrus is a gyrus in the medial part of the brain. It partially wraps around the corpus callosum and is limited above by the cingulate sulcus.The cortical part of the cingulate gyrus is referred to as cingulate cortex....
. Studies using
MRIMagnetic Resonance Imaging , or nuclear magnetic resonance imaging , is primarily a medical imaging technique most commonly used in radiology to visualize the internal structure and function of the body...
and
positron emission tomographyPositron emission tomography is a nuclear medicine imaging technique which 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 patients 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 tangleNeurofibrillary tangles are pathological protein aggregates found within neurons in cases of Alzheimer's disease. They were first described by Alois Alzheimer in one of his patients suffering from the disorder...
s are clearly visible by
microscopyMicroscopy is the technical field of using microscopes to view samples or objects. There are three well-known branches of microscopy, optical, electron and scanning probe microscopy....
in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
and
cellularThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, 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 ageing, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe.
Lewy bodiesLewy bodies are abnormal aggregates of protein that develop inside nerve cells. They are identified under the microscope when histology is performed on the brain....
are not rare in AD patient's brains.
Biochemistry
Alzheimer's disease has been identified as a
protein misfoldingProtein folding is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
disease (
proteopathyIn 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
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
s, 39–43
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
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 proteinAmyloid 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 and neural plasticity...
(APP), a
transmembrane proteinA transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them can be also extracted using denaturing agents.-Types:There are two basic...
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
proteolysisProteolysis 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 plaquesSenile 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
tauopathyTauopathies are a class of neurodegenerative diseases resulting from the pathological aggregation of tau protein in so-called neurofibrillary tangles in the human brain.
Some examples of tauopathies are:* Frontotemporal dementia...
due to abnormal aggregation of the
tau proteinTau proteins are microtubule-associated proteins that are abundant in neurons in the central nervous system and are less common elsewhere. They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University ...
. Every neuron has a
cytoskeletonThe cytoskeleton is a cellular "scaffolding" or "skeleton" contained within the cytoplasm. The cytoskeleton is present in all cells; it was once thought this structure was 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
axonAn axon or nerve fiber is a long, slender projectionof a nerve cell, or neuron, that conducts electrical impulsesaway from the neuron's cell body or soma....
and back. A protein called
tau stabilises the microtubules when
phosphorylatedPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation turns many protein enzymes on and off, causing or preventing the mechanisms of diseases such as cancer and diabetes....
, and is therefore called a
microtubule-associated proteinIn cell biology, microtubule-associated proteins are proteins that interact with the microtubules of the cellular cytoskeleton.-Function:...
. In AD, tau undergoes chemical changes, becoming
hyperphosphorylatedHyperphosphorylation 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
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
s as the central event triggering neuron degeneration. Accumulation of aggregated amyloid
fibrilFibril 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
calciumCalcium 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 grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
ionAn ion is an atom or molecule where the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge...
homeostasisHomeostasis is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition...
, induces
programmed cell deathProgrammed cell-death is death of a cell in any form, mediated by an intracellular program. In contrast to necrosis, which is a form of cell-death that results from acute tissue injury and provokes an inflammatory response, PCD is carried out in a regulated process which generally confers...
(
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
). It is also known that Aβ selectively builds up in the
mitochondriaIn cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5–10 micrometers in diameter...
in the cells of Alzheimer's-affected brains, and it also inhibits certain
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
functions and the utilisation of
glucoseGlucose , a monosaccharide also known as - grape sugar, blood sugar, or corn sugar, is a very important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate...
by neurons.
Various inflammatory processes and
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
s may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue 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-dominant inheritance, which usually have an onset before age 65.
Most of autosomal dominant familial AD can be attributed to mutations in one of three genes:
amyloid precursor proteinAmyloid 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 and neural plasticity...
(APP) and
presenilinPresenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase protease complex. Vertebrates have two presenilin genes, called PSEN1 that encodes presenilin 1 and PSEN2 that codes for presenilin 2...
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 plaquesSenile 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 size 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 factorsA 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
alleleAn allele is one of a series of different forms of a gene. The word is a short form of allelomorph , which was used in the early days of genetics to describe variant forms of a gene detected as different phenotypes...
of the
apolipoprotein EApolipoprotein 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 patients with AD possess at least one apoE4 allele. The APOE4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. 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. 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
neurologicalNeurology 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
neuropsychologicalNeuropsychology is the basic scientific discipline that studies the structure and function of the brain related to specific psychological processes and overt behaviors. The term neuropsychology has been applied to lesion studies in humans and animals...
features and the
absence of alternative conditionsThe term diagnosis of exclusion refers to a medical condition whose presence cannot be established with complete confidence from examination or testing...
. Advanced
medical imagingMedical imaging refers to the techniques and processes used to create images of the human body for clinical purposes or medical science .As a discipline and in its widest sense, it is part of biological imaging and incorporates...
with
computed tomographyComputed tomography is a medical imaging method employing tomography created by computer processing. Digital geometry processing is used to generate a three-dimensional image of the inside of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation.CT...
(CT) or
magnetic resonance imagingMagnetic Resonance Imaging , or nuclear magnetic resonance imaging , is primarily a medical imaging technique most commonly used in radiology to visualize the internal structure and function of the body...
(MRI), and with
single photon emission computed tomographySingle 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 tomographyPositron emission tomography is a nuclear medicine imaging technique which 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.
Assessment of intellectual functioningNeuropsychological 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-mortemAn autopsy–also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction–is a medical 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
histologicallyHistology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining a thin slice of tissue under a light microscope or electron microscope...
.
Diagnostic 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 AssociationThe 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 CriteriaThe 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 impairmentDevelopmental disability is a term used to describe life-long, disabilities attributable to mental and/or physical or combination of mental and physical impairments, manifested prior to age 18...
, and a suspected dementia syndrome, be confirmed by
neuropsychological testingNeuropsychological 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
microscopicMicroscopic or Micro is a term 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 reliabilityIn statistics, reliability is the consistency of a set of measurements or measuring instrument, often used to describe a test. This can either be whether the measurements of the same instrument give or are likely to give the same measurement , or in the case of more subjective instruments, such as...
and
validityIn psychology, validity has two distinct fields of application. The first involves test validity, a concept that has evolved with the field of psychometrics: "Validity refers to the degree to which evidence and theory support the interpretations of test scores entailed by proposed uses of tests"....
have been shown between the diagnostic criteria and definitive histopathological confirmation. Eight cognitive domains are most commonly impaired in AD—
memoryIn psychology, memory is an organism's mental ability to store, retain, and recall information. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing the memory....
,
languageA language is a system for encoding and decoding information. In its most common use, the term refers to so-called "natural languages" — the forms of communication considered peculiar to humankind. In linguistics the term is extended to refer to the human cognitive facility of creating and using...
,
perceptual skillsIn philosophy, psychology, and the cognitive sciences, perception is the process of attaining awareness or understanding of sensory information. It is a task far more complex than was imagined in the 1950s and 1960s, when it was predicted that building perceiving machines would take about a decade,...
,
attentionAttention is the cognitive process of selectively concentrating on one aspect of the environment while ignoring other things. Attention has also been referred to as the allocation of processing resources...
, constructive abilities,
orientationOrientation 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 solvingProblem 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 DisordersThe Diagnostic and Statistical Manual of Mental Disorders is published by the American Psychiatric Association and provides diagnostic criteria for mental disorders...
(DSM-IV-TR) published by the
American Psychiatric AssociationThe 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...
.
Diagnostic tools
Neuropsychological testNeuropsychological tests are specifically designed tasks used to measure a psychological function known to be linked to a particular brain structure or pathway. They usually involve the systematic administration of clearly defined procedures in a formal environment...
s such as the
mini-mental state examinationThe 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 examinationA 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 standard dementia.
Further neurological examinations are crucial in the
differential diagnosisA differential diagnosis is a systematic method used to identify unknowns. This method, essentially a process of elimination, is used by taxonomists to identify living organisms, and by physicians or other clinicians to diagnose the specific disease in a patient.Not all medical diagnoses are...
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 functionMental process, 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...
. A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own
deficitsAnosognosia is a condition in which a person who suffers disability seems unaware of or denies the existence of his or her disability. This may include unawareness of quite dramatic impairments, such as blindness or paralysis...
. Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.
Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses.
Blood testA 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.
Psychological testsPsychological testing is a field characterized by the use of samples of behavior in order to infer generalizations about a given individual. The technical term for the science behind psychological testing is psychometrics...
for
depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities...
are employed, since depression can either be concurrent with AD (see
Depression of Alzheimer diseaseDepression 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.
When available as a diagnostic tool, SPECT and PET
neuroimagingFunctional 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...
are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving
mental status examinationThe mental status examination 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 historyThe 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. Another recent objective marker of the disease is the analysis of
cerebrospinal fluidCerebrospinal fluid , Liquor cerebrospinalis, is a clear bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain. In essence, the brain "floats" in it....
for amyloid beta or tau proteins. Both advances have led to the proposal of new diagnostic criteria. A new technique known as
PiB PETPittsburgh 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 vivoIn vivo refers to 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
tracerA radioactive tracer, also called a radioactive label, is a substance containing a radioisotope. Tracers can be 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 a tissue...
that
bindsMolecular 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 Abeta deposits. 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. Volumetric
MRIMagnetic Resonance Imaging , or nuclear magnetic resonance imaging , is primarily a medical imaging technique most commonly used in radiology to visualize the internal structure and function of the body...
, which can detect changes in the size of brain regions that atrophy during the progress of Alzheimer's disease, is also showing promise as a diagnostic method. It may prove less expensive than other imaging methods currently under study.
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
hypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be secondary to many diseases and can contribute to many forms of disease, most notably cardiovascular disease...
,
hypertensionHypertension is a chronic medical condition in which the blood pressure is elevated. It is also referred to as high blood pressure or shortened to HT, HTN or HPN. The word "hypertension", by itself, normally refers to systemic, arterial hypertension.Hypertension can be classified as either...
, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are
cholesterolCholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...
lowering drugs, have not been effective in preventing or improving the course of the disease. The components of a
Mediterranean dietThe modern incarnation of the Mediterranean diet is based upon the traditional dietary patterns of the countries of the Mediterranean Basin. Thus, our understanding of the Mediterranean diet is really a composite of several foods commonly consumed in the countries surrounded or bordered by the...
, which include fruit and vegetables,
breadBread is a staple food prepared by cooking a dough of flour and water and possibly more ingredients. Doughs are usually baked in the Western world , but in some cuisines breads are steamed, fried, or baked on a hot skillet. It may be leavened or unleavened...
,
wheatWheat is a worldwide cultivated grass from the Fertile Crescent region of the Near East. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
and other
cerealCereals, grains or cereal grains, {as a collective} are grasses cultivated for the edible components of their fruit seeds - the endocarp, germ and bran...
s,
olive oilOlive oil is a fruit oil obtained from the olive , a traditional tree crop of the Mediterranean Basin. The wild olive tree originated in Asia Minor and spread from there as far as southern Africa, Australia, Japan and China. It is commonly used in cooking, cosmetics, pharmaceuticals, and soaps and...
,
fishA fish is any aquatic vertebrate animal that is typically ectothermic , covered with scales, and equipped with two sets of paired fins and several unpaired fins...
, 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
vitaminA vitamin is an organic compound required as a nutrient in tiny amounts by an organism. The term 'vitamin' first became popular in the early 1800's as a contraction of the words 'vital' and 'mineral', though the actual meaning of the word has developed somewhat since that time...
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.
Long-term usage of
non-steroidal anti-inflammatory drugNon-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic, antipyretic and, in higher doses, with anti-inflammatory effects...
(NSAIDs) is associated with a reduced likelihood of developing AD. Human postmortem studies, in
animal modelAn 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 vitroA procedure performed in vitro is performed not in a living organism but in a controlled environment, such as in a test tube or Petri dish...
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.
CurcuminCurcumin 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 polyphenols and are responsible for the yellow color of turmeric. Curcumin can...
from the
curryCurry is a generic description used throughout European and American culture to describe a general variety of spiced dishes, best known in Asian cuisines, especially South Asian cuisine...
spice
turmericTurmeric 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 damageBrain damage, or acquired brain injury, is the destruction or degeneration of brain cells.-Causes:Brain damage may occur due to a wide range of conditions, illnesses, injuries, and as a result of iatrogenesis...
in mouse models due to its anti-inflammatory properties.
Hormone replacement therapyHormone replacement therapy may refer to:*Hormone replacement therapy *Hormone replacement therapy *Hormone replacement therapy *Androgen replacement therapy -See also:...
, 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 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 instrumentA musical instrument is an object constructed or used for the purpose of making the sounds of music. In principle, anything that produces sound can serve as a musical instrument. The history of musical instruments dates back to the beginnings of human culture...
s, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the
cognitive reserveThe 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. Physical activity is also associated with a reduced risk of AD.
Some studies have shown an increased risk of developing AD with
environmental factorIn epidemiology, environmental factors are those determinants of disease that are not transmitted genetically. Apart from the true monogenic genetic disorders, environmental factors may determine the development of disease in those genetically predisposed to a particular condition...
s such the intake of
metalA metal is a chemical element that is a good conductor of both electricity and heat, forms cations and ionic bonds with non-metals. In chemistry, a metal is an element, compound, or alloy characterized by high electrical conductivity. In a metal, atoms readily lose electrons to form positive ions...
s, particularly
aluminiumAluminium or aluminum is a silvery white and ductile member of the boron group of chemical elements. It has the symbol Al; its atomic number is 13. It is not soluble in water under normal circumstances....
, or exposure to
solventA solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution.The most common solvent in everyday life is water. Most other commonly-used solvents are organic chemicals. These are called organic solvents...
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.
Electromagnetic fieldThe electromagnetic field is a physical field produced by electrically charged objects. It affects the behavior of charged objects in the vicinity of the field. Light is the electromagnetic field in a certain frequency range...
s (EMF) have also been proposed to be related to AD by some experts,
but not others. Regarding extremely low frequency EMFs, while a metanalysis found that exposed people had more than two-fold probabilities of having the disease, reviews do not agree on whether studies point towards a relationship, or not. Doubts on how to interpret the statistically significant results of the metaanalysis have been raised.
Management
There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but remain
palliativePalliative care is any form of medical care or treatment that concentrates on reducing the severity of disease symptoms, rather than striving to halt, delay, or reverse progression of the disease itself or provide a cure. The goal is to prevent and relieve suffering and to improve quality of life...
in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.
Pharmaceutical
Four medications are currently approved by regulatory agencies such as the U.S.
Food and Drug AdministrationThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
(FDA) and the
European Medicines AgencyThe European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as The European Agency for the Evaluation of Medicinal Products....
(EMEA) to treat the cognitive manifestations of AD: three are
acetylcholinesterase inhibitorAn 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 and the other is
memantineMemantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors...
, an
NMDA receptor antagonistNMDA 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
cholinergicA receptor is cholinergic if it uses acetylcholine as its neurotransmitter.Cholinergic means related to the neurotransmitter acetylcholine, and is typically used in a neurological perspective. The parasympathetic nervous system is entirely cholinergic...
neurons is a well-known feature of Alzheimer's disease.
Acetylcholinesterase inhibitorAn 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
acetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division...
(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. As of 2008, the cholinesterase inhibitors approved for the management of AD symptoms are
donepezilDonepezil , 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 treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. Its binding to the...
(brand name
Aricept),
galantamineGalantamine or galanthamine is a chemical used for the treatment of mild to moderate Alzheimer’s disease and various memory impairments...
(
Razadyne), and
rivastigmineRivastigmine 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 impairmentMild cognitive impairment is a diagnosis given to individuals who have cognitive impairments beyond that expected for their age and education, but that do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and...
has not shown any effect in a delay of the onset of AD. The most common
side effectAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dose. The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial...
s are
nauseaNausea is the sensation of unease and discomfort in the stomach with an urge to vomit.-Causes:...
and
vomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Undesired vomiting may result from many causes, ranging from gastritis or poisoning to brain tumors, or elevated intracranial pressure...
, 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 rateHeart rate is determined by the number of heartbeats per unit of time, typically expressed as beats per minute , it can vary with as the body's need for oxygen changes, such as during exercise or sleep. The measurement of heart rate is used by medical professionals to assist in the diagnosis and...
(
bradycardiaBradycardia , as applied to adult medicine, is defined as a resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min....
), decreased
appetiteThe 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 acidGastric acid is a secretion produced in the stomach. It is one of the main ditotonic solutions secreted, together with several enzymes and intrinsic factors...
production.
Glutamate is a useful excitatory
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
of the
nervous systemThe nervous system is a network of specialized cells that communicate information about an organism's surroundings and itself. It processes this information and causes reactions in other parts of the body. It is composed of neurons and other specialized cells called glial cells that aid in the...
, although excessive amounts in the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
can lead to
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, 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
excitotoxicityExcitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated...
which consists of the overstimulation of glutamate
receptorsIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as
Parkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions....
and
multiple sclerosisMultiple sclerosis is an idiopathic disease of suspected autoimmune cause, in which the body's immune response attacks a person's central nervous system , leading to demyelination. Disease onset usually occurs in young adults, and it is more common in females...
.
MemantineMemantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors...
(brand names
Akatinol,
Axura,
Ebixa/
Abixa,
Memox and
Namenda), is a noncompetitive
NMDA receptor antagonistNMDA 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-
influenzaInfluenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals. The name influenza is Italian and means "influence"...
agent. It acts on the glutamatergic system by blocking
NMDA receptorThe 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
hallucinationA hallucination, in the broadest sense, 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, substantial, and...
s,
confusionConFusion 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...
,
dizzinessDizziness refers to an impairment in spatial perception and stability. It is considered imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or for a non-specific feeling such as giddiness or foolishness....
,
headacheIn medicine a headache or cephalalgia is a symptom of a number of different conditions of the head. Some of the causes are benign while others are medical emergencies.There are a number of different classification systems for headaches...
and fatigue. The combination of memantine and donepezil has been shown to be "of
statistically significantIn 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".
AntipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
drugs are modestly useful in reducing
aggressionIn psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause pain or harm. Predatory or defensive behavior between members of different species is not normally considered "aggression." Aggression takes a...
and
psychosisPsychosis literally 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 patients 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.
Psychosocial intervention
PsychosocialThe term psychosocial refers to one in psychological development in and interaction with a social environment. The individual is not necessarily fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of social development...
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 interventionsBehavior modification is the use of empirically demonstrated behavior change techniques to improve behavior, such as altering an individual's behaviors and reactions to stimuli through positive and negative reinforcement of adaptive behavior and/or the reduction of maladaptive behavior through...
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
incontinenceUrinary 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...
. 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 therapyReminiscence 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 therapyValidation 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
psychotherapyPsychotherapy or personal counseling with a psychotherapist, is an intentional interpersonal relationship used by trained psychotherapists to aid a client or patient in problems of living.It aims to increase the individual's sense of their own well-being...
,
sensory integrationSensory 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
snoezelenSnoezelen or controlled multisensory stimulation is used for people with mental disabilities, and involves exposing them to a soothing and stimulating environment, the "snoezelen room". These rooms are specially designed to deliver stimuli to various senses, using lighting effects, color, sounds,...
, and
simulated presence therapySimulated 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 patients 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
cognitionCognition is the scientific term for "the process of thought". Usage of the term varies in different disciplines; for example in psychology and cognitive science, it usually refers to an information processing view of an individual's psychological functions...
and
moodA mood is a relatively long lasting emotional state. Moods differ from simple 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 theoriesAttachment theory is a psychological, evolutionary and ethological theory concerning relationships between humans. The most important tenet of attachment theory is that a young child needs to develop a relationship with at least one primary caregiver for normal social and emotional development...
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 behaviourChallenging behaviouris 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 facilities"...
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
senseSenses are the physiological methods of 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 retrainingRehabilitation 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 deficitCognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance. The term may describe deficits in global intellectual performance, such as mental retardation, it may describe specific deficits in cognitive abilities , or it may describe...
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
artArt therapy is a form of expressive therapy that uses art materials, such as paints, chalk and markers. Art therapy combines traditional psychotherapeutic theories and techniques with an understanding of the psychological aspects of the creative process, especially the affective properties of the...
,
musicMusic therapy is 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 health...
and
petAnimal-assisted therapy is a type of therapy that involves an animal with specific characteristics becoming a fundamental part of a person's treatment. Animal-assisted therapy is designed to improve the physical, social, emotional, and/or cognitive functioning of the patient, as well as provide...
therapies,
exercisePhysical therapy is a health care profession which provides services to individuals in order to develop, maintain and restore maximum movement and functional ability throughout life...
, and any other kind of
recreational activitiesRecreation therapy, also referred to as recreational therapy and therapeutic recreation, contributes to the broad spectrum of health care through treatment, education, and the provision of adapted recreational opportunities — all of which aid in improving and maintaining physical, cognitive,...
. 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 safetyPatient safety is a new healthcare discipline that emphasizes the reporting, analysis, and prevention of medical error that often lead 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 difficultiesDysphagia 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 tubeA 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 enteral feeding or tube feeding. Placement may be temporary for the treatment of acute conditions or lifelong in the case of chronic...
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-External links:*...
,
pressure ulcersBedsores, 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...
,
malnutritionMalnutrition is the insufficient, excessive or imbalanced consumption of nutrients.A number of different nutrition disorders may arise, depending on which nutrients are under or overabundant in the diet....
,
hygieneHygiene, refers to the set of practices associated with the preservation of health and healthy living. Hygiene is a concept related to medicine, as well as to personal and professional care practices related to most aspects of living, although it is most often associated with cleanliness and...
problems, or
respiratoryThe respiratory systems function is to allow gas exchange to all parts of the body. The space between the alveoli & the capillaries, the anatomy or structure of the exchange system, and the precise physiological uses of the exchanged gases vary depending on the organism...
,
skinThe skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system made up of multiple layers of mesodermal tissue, and guards the underlying muscles, bones, ligaments and internal organs. Skin of a different nature exists in amphibians, reptiles, birds...
, or
eyeEyes are organs that detect light, and send electrical impulses along the optic nerve to the visual and other areas of the brain. Complex optical systems with resolving power have come in ten fundamentally different forms, and 96% of animal species possess a complex optical system...
infectionAn infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host's resources to multiply, usually at the expense of the host. The infecting organism, or pathogen, interferes with the normal functioning of the...
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.
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. He 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 expectancyLife expectancy is the expected number of years of life remaining at a given age. It is denoted by e
x, 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 patients 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 problemsHeart disease or cardiopathy is an umbrella term for a variety for different diseases affecting the heart. As of 2007, it is the leading cause of death in the United States, England, Canada and Wales, killing one person every 34 seconds in the United States alone.-Coronary heart disease:Coronary...
,
diabetesDiabetes mellitus —often referred to simply as diabetes—is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy...
or history of
alcohol abuseAlcohol abuse, as described in the DSM-IV, is a psychiatric diagnosis describing the recurring use of alcoholic beverages despite negative consequences. It is differentiated from alcohol dependence by the lack of symptoms such as tolerance and withdrawal. Alcohol abuse is sometimes referred to by...
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 deathDeath is the termination of the biological functions that define a living organism. It refers to both a particular event and to the condition that results thereby. The true nature of the latter has for millennia been a central concern of the world's religious traditions and of philosophical...
in 70% of all cases.
PneumoniaPneumonia is an inflammatory illness of the lung. Frequently, it is described as lung parenchyma/alveolar inflammation and abnormal alveolar filling with fluid ....
and
dehydrationDehydration is defined as excessive loss of body water. It is literally the removal of water from an object. In physiological terms, it entails a relative deficiency of water molecules in relation to other dissolved solutes...
are the most frequent immediate causes of death, while
cancerCancer is a class of diseases in which a group of cells display uncontrolled growth , invasion , and sometimes metastasis...
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
epidemiologicalEpidemiology is the study of factors affecting the health and illness of populations, and serves as the foundation and logic of interventions made in the interest of public health and preventive medicine...
studies: incidence and prevalence.
IncidenceIncidence 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
prevalenceIn epidemiology, the prevalence of a disease in a statistical population is defined as the total number of cases of the disease 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. It is used as an estimate of how...
is the total number of cases of the disease in the population at a given time.
Regarding incidence,
cohortA cohort study or panel study is a form of longitudinal study used in medicine, social science and ecology. It is one type of study design and should be compared with a cross-sectional study....
longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10–15 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 StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
, Alzheimer prevalence was estimated to be 1.6% in the year 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 OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public 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 26.6 million, range 11.4–59.4 million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by the year 2050.
History
The
ancient Greek and RomanClassical 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
physicianA physician — also known as medical practitioner, doctor of medicine, medical doctor, or simply doctor — practices the ancient profession of medicine, which is concerned with maintaining or restoring human health through the study, diagnosis, and treatment of disease or injury...
s associated old age with increasing
dementiaDementia is a serious cognitive disorder. It may be static, the result of a unique global brain injury or progressive, resulting in long-term decline in cognitive function due to damage or disease in the body beyond what might be expected from normal aging...
. It was not until 1901 that German
psychiatristPsychiatry is a medical specialty officially devoted to the treatment and study of mental disorders. The term was first coined by the German physician Johann Christian Reil in 1808....
Alois Alzheimer identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called
Auguste DAuguste Deter was born in May 1850 in Kassel. Her maiden name is unknown: however, the D stands for Deter. She married Karl Deter in the 1880s or so 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...
. 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 literatureMedical 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 KraepelinEmil Kraepelin was a German psychiatrist. The Encyclopedia of Psychology by H. J. Eysenck identifies him as the founder of contemporary scientific psychiatry, as well as of psychopharmacology and psychiatric genetics. Kraepelin believed the chief origin of psychiatric disease to be biological...
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 dementiaDementia is a serious cognitive disorder. It may be static, the result of a unique global brain injury or progressive, resulting in long-term decline in cognitive function due to damage or disease in the body 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 in 1910 .
For most of the twentieth 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
nomenclatureNomenclature refers to either a list of names and/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
neuropathologyNeuropathology 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...
.
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
ArgentinaArgentina, officially the Argentine Republic , is the second largest country in South America, constituted as a federation of 23 provinces and an autonomous city, Buenos Aires. It is the eighth largest country in the world by land area and the largest among Spanish-speaking nations, though Mexico,...
, or
South KoreaSouth Korea, officially the Republic of Korea and often simply referred to as Korea, is a country in East Asia, located on the southern half of the Korean Peninsula. It is neighbored by China to the west, Japan to the east, and North Korea to the north. Its capital is Seoul, the second largest...
, is also high and rising. These costs will probably increase with the
ageingAgeing or aging is the accumulation of changes in an organism or object 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 problemSocial issues are matters which directly or indirectly affect many or all members of a society and are considered to be problems, controversies related to moral values, or both....
. AD-associated costs include direct medical costs such as
nursingNursing 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 birth to the end of life....
home careHome care, , is health care or supportive care provided in the patient's home by healthcare professionals or by family and friends Home care, (commonly referred to as domiciliary care), is health care or supportive care provided in the patient's home by healthcare professionals (often referred to...
, direct nonmedical costs such as in-home
day careDay care or child 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
productivityProductivity is a measure of output from a production process, per unit of input. For example, labor productivity is typically measured as a ratio of output per labor-hour, an input. Productivity may be conceived of as a metric of the technical or engineering efficiency of production. As such, the...
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 careLong-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 professionalsA health care provider or health professional is an organization or person who delivers proper health care in a systematic way professionally to any individual in need of health care services.- Hospital :...
and particularly
institutionalisationThe term institutionalisation is widely used in social theory to denote the process of making something become embedded within an organization, social system, or society as an established custom or norm within that system...
, which corresponds to 2/3 of the total costs for society.
The cost of livingThe Cost of Living E.P. is a 7" EP by The Clash released in 1979 in a gatefold sleeve. Produced by the band and Bill Price, it marked a transition in musical styles for the band, bridging the intensity of their earlier, punky albums with the broader, more American influenced rock and roll yet to...
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
caregiverAs 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 patients and 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.
DementiaDepression 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 isolationSocial isolation is the pervasive withdrawal or avoidance of social contact or communication. It can contribute toward many emotional, behavioural and physical disorders including anxiety, panic attacks, eating disorders, addictions, substance abuse, violent behaviour and overall disease.-Illness...
. 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 StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
, depending on the study.
Cognitive behavioural therapy and the teaching of
coping strategiesThe psychological definition of coping is the process of managing taxing circumstances, expending effort to solve personal and interpersonal problems, and seeking to master, minimize, reduce or tolerate stress or conflict....
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 ReaganRonald Wilson Reagan was the 40th President of the United States and the 33rd Governor of California .Born in Tampico, Illinois, Reagan moved to Los Angeles, California in the 1930s...
and Irish writer
Iris MurdochDame Iris Murdoch DBE was an English author and philosopher, best known for her novels about sexual relationships, morality, and the power of the unconscious. Her first published novel, Under the Net, was selected in 2001 by the editorial board of the American Modern Library as one of the 100...
, both of whom were the subjects of scientific articles examining how their cognitive capacities deteriorated with the disease. Other notable cases include the retired
footballerA footballer is a person who plays in various games known as "football" – especially association football, although the term is also used to refer to participants in Australian rules football, Gaelic football, rugby league and rugby union in some regions....
Ferenc PuskasFerenc Puskás was a Hungarian footballer and manager and is regarded as one of the greatest footballers of all time. He scored a remarkable 84 goals in 85 international matches for Hungary, and 514 goals in 529 matches in the Hungarian and Spanish leagues...
, the former
Prime MinisterA prime minister is the most senior minister of cabinet in the executive branch of government in a parliamentary system. The position is usually held by, but need not always be held by, a politician. In many systems, the prime minister selects and can dismiss other members of the cabinet, and...
s
Harold WilsonJames Harold Wilson, Baron Wilson of Rievaulx, KG, OBE, FRS, PC was a British Labour Party politician; one of the most prominent British politicians of the latter half of the 20th century, he served two terms as Prime Minister of the United Kingdom, firstly from 1964 to 1970, and again from 1974...
(
United KingdomThe United Kingdom of Great Britain and Northern Ireland is a sovereign state located off the northwestern coast of continental Europe. It is an island country, spanning an archipelago including Great Britain, the northeastern part of Ireland, and many small islands...
) and
Adolfo SuárezDon Adolfo Suárez y González, 1st Duke of Suárez, Grandee of Spain, KOGF 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 Hipólito Suárez y … and...
(
SpainSpain , officially the Kingdom of Spain , is a country located in southwestern Europe on the Iberian Peninsula.
[The Spanish constitution does not establish any official denomination of the country, even though España , Estado español and Nación española are used interchangeably...]
), the actress
Rita HayworthRita Hayworth was an American film actress and dancer who attained fame during the 1940s not only as one of the era's top stars, but also as the era's greatest sex symbol, most notably in Gilda...
, the actor
Charlton HestonCharlton Heston was an American actor of film, theatre and television.Heston is known for having played heroic roles, such as Moses in The Ten Commandments, Colonel George Taylor in Planet of the Apes, Rodrigo Díaz de Vivar in El Cid, and Judah Ben-Hur in Ben-Hur, for which he won the Academy...
,, the novelist
Terry PratchettSir Terence David John Pratchett, OBE , more commonly known as Terry Pratchett, 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...
and the 2009 Nobel Prize in Physics recipient
Charles K. KaoProfessor Charles Kuen Kao CBE 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 BayleyProfessor John Bayley CBE, FBA, FRSL is a British literary critic and writer.-Biography:...
's memoir of his wife
Iris MurdochDame Iris Murdoch DBE was an English author and philosopher, best known for her novels about sexual relationships, morality, and the power of the unconscious. Her first published novel, Under the Net, was selected in 2001 by the editorial board of the American Modern Library as one of the 100...
;
The NotebookThe Notebook is a romantic drama 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 Noah and Allie, a young couple who fall in love during the early 1940s...
(2004), based on
Nicholas SparksNicholas Charles Sparks is an internationally bestselling American author, writing novels with themes that include Christianity, love, tragedy and fate. He has fifteen published novels, four of which have been turned into films, including The Notebook, Message in a Bottle, A Walk to Remember, and...
' 1996
novel of the same nameThe Notebook is a 1996 American romantic novel by American novelist Nicholas Sparks. The novel was later adapted into a popular romance film by the same name in 2004. However, the movie and the book have very different endings....
;
ThanmathraThanmathra is a Malayalam film directed by Blessy 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; and
Away from HerAway 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 MunroAlice Ann Munro is a Canadian short-story writer, winner of the 2009 Man Booker International Prize for her lifetime body of work, and three-time winner of Canada's Governor General's Award for fiction...
's
short storyA short story is a work of fiction that is usually written in prose, often in narrative format. This format or medium tends to be more pointed than longer works of fiction, such as novellas and novels or books...
"
The Bear Came over the MountainHateship, 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 PointonMalcolm 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
As of 2008, the safety and efficacy of more than 400 pharmaceutical treatments are being investigated in
clinical trialClinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices. These trials can only take place once satisfactory information has been gathered on the quality of the product and its non-clinical safety, and Health Authority/Ethics Committee approval is...
s worldwide, and approximately one-fourth of these compounds are in Phase III trials, which is 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 betaAmyloid beta is a peptide of 39–43 amino acids that appear to be the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating...
levels is a common target of compounds under investigation.
ImmunotherapyImmunotherapy is a medical term defined as "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....
or
vaccinationVaccination is the administration of antigenic material to produce immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by a pathogen. Vaccination is generally considered to be the most effective and cost-effective method of preventing infectious diseases...
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 systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour 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
bapineuzumabBapineuzumab 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 proteinFusion proteins, AKA 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...
,
etanerceptEtanercept is a drug that treats autoimmune diseases by interfering with the TNF receptor by acting as a TNF inhibitor.Etanercept is a fusion protein produced through expression of recombinant DNA...
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
remberRember is an investigational drug being developed by startup TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation. One active ingredient is methylthioninium chloride , a form of methylene blue. The drug is of potential interest for the...
), a drug that inhibits tau aggregation, and
dimebonDimebolin hydrochloride is an antihistamine drug which has been used clinically in Russia since 1983.Research is continuing in both Russia and western nations into potential applications as a neuroprotective and potential nootropic.-Uses:It is an orally active small molecule that has been shown to...
, an
antihistamineAn H
1 antagonist is a histamine antagonist of the H
1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
.
External links