Alzheimer's disease

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For patient information click here Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Peter Pressman, M.D. [2], Northwestern Memorial Hospital, Department of Neurology

Dr. Pressman has nothing to disclose.

Overview

Alzheimer's disease is the most common cause of dementia among older people. Dementia is a loss of thinking, remembering, and reasoning skills that interferes with a person's daily life and activities. Other causes of dementia include blood-vessel disease in the brain (called vascular dementia), Parkinson's disease, frontotemporal dementia, and Lewy body disease.

Background

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 dementia. German psychiatrist Alois Alzheimer first described this incurable, degenerative, and terminal disease in 1906. Generally it is diagnosed in people over 65 years of age,[1] although the less-prevalent early-onset Alzheimer's can occur much earlier. An estimated 35 million people worldwide have Alzheimer's disease.

Although each sufferer experiences Alzheimer's in a unique way, there are many common symptoms.[2] The earliest observable symptoms are often mistakenly thought to be 'age-related' changes, or manifestations of stress.[3] The most commonly recognized symptom of early Alzheimer's disease is memory loss, usually the forgetting of recently learned facts. As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline.[3][4] Gradually, bodily functions are lost, ultimately leading to death.[5] When a doctor or physician has been notified, and AD is suspected, the diagnosis is usually further supported by behavioral assessments and cognitive tests, often followed by a brain scan if available.[6] Individual prognosis 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.[7] Fewer than three percent of individuals live more than fourteen years after diagnosis.[8]

The cause of Alzheimer's disease is poorly understood. Research indicates that the disease is associated with plaques and tangles in the brain.[9] Currently-used treatments offer a small symptomatic benefit. No treatments to halt the progression of the disease are yet available. As of 2010, more than 700 clinical trials were investigating possible treatments for AD, but it is unknown if any of them will prove successful.[10] Many measures have been suggested for the prevention of Alzheimer's disease, but the value of these measures is unproven in slowing the course and reducing the severity of the disease. Mental stimulation, exercise, and a balanced diet are often recommended as both a possible prevention and a sensible way of managing the disease.[11]

Because AD cannot be cured, management of patients is essential as the disease progresses. The role of the main caregiver is often taken by a spouse or a close relative.[12] Alzheimer's disease is known for placing a great burden on caregivers; the pressures can be wide-ranging, affecting social, psychological, physical, and economic components of the caregiver's life.[13][14][15] In developed countries, AD is one of the most economically costly diseases to society.[16][17]

History

Auguste D, first described patient with AD

Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,[18] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.[19] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[18] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[20]

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 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 of different etiologies. This eventually led to the use of Alzheimer's disease independently of onset age of the disease.[21][22] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[23]


Epidemiology

AD incidence rates
after 65 years of age[24]
Age Incidence
(new affected)
per thousand
person–years
65–69  3
70–74  6
75–79  9
80–84 23
85–89 40
90–   69

Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for the disease. [25] [26]

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at a given time.

Regarding incidence, cohort 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,[24][27] 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.[24][27] There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.[27][28]

Prevalence of AD in populations is dependent upon different factors including incidence and survival. Since the incidence of AD increases with age, it is particularly important to include the mean age of the population of interest. In the United States, Alzheimer prevalence was estimated to be 1.6% in 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.[29] Prevalence rates in less developed regions are lower.[30] The World Health Organization 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.[31] Other studies have reached similar conclusions.[30] 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.[32]

Characteristics

The disease course is divided into four stages, with a progressive decline in cognition and functional capabilities.

Predementia

The first symptoms are commonly misattributed to normal ageing or stress.[3] Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person meets the clinical criteria for diagnosis of AD.[33] These early symptoms can affect the most complex daily living activities.[34] The most noticeable early deficit is memory loss. The patient has difficulty remembering recently learned facts and acquiring new information.[35][36] Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and conceptual relationships), can also be symptomatic of the early stages of AD.[37][38] Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease.[39][40][41] The preclinical stage of the disease has also been termed mild cognitive impairment,[42] but there is still debate on whether this term corresponds to a different and separate diagnostic entity or is just a first step of Alzheimer's disease.[43]

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, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.[44] AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are less affected than new facts or memories.[45][46] Language problems include a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of adequately communicating basic ideas.[47][48][49] Sufferers may appear clumsy when performing fine motor tasks such as writing, drawing or dressing, as their brain has more difficulty with planning and coordinating certain movements (apraxia).[50] As the disease progresses, people with AD often continue to perform many tasks independently, but may need assistance or supervision with cognitively demanding activities.[44]

In 1994 United States ex-president R. Reagan informed the country of his AD diagnosis via a hand-written letter.

Moderate dementia

Progressive deterioration eventually hinders independence.[44] Speech difficulties become more evident, with an inability to recall vocabulary leading to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost.[47][51] Complex motor sequences become less coordinated as time passes, reducing the ability to perform most normal daily activities.[52] During this phase, memory problems worsen, and the person may fail to recognize close relatives.[53] Long-term memory, which was previously intact, becomes impaired,[54] and behavioural changes become more prevalent. Common neuropsychiatric manifestations are wandering, sundowning,[55] irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Approximately 30% of patients also develop illusionary misidentifications and other delusional symptoms.[39][56] Urinary incontinence can develop.[57] These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to a long-term care facility.[44][58]

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.[47] Despite the loss of verbal language abilities, patients can often understand and return emotional signals.[59] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.[44] Patients will ultimately not be able to perform even the most simple tasks without assistance. Muscle mass and mobility deteriorate to the point where the patient is bedridden,[60] and they lose the ability to feed themselves.[61] When death comes, it is usually directly caused by some external factor such as pressure ulcers or pneumonia, rather than the disease itself.[62][63]

Pathophysiology

MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.

At a macroscopic level, AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[64] Three major hypotheses exist to explain the cause of the disease, though other possible explanations also exist. The oldest major hypothesis is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. Most currently available drug therapies in Alzheimer's are based on this theory, however, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.[65] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,[66] leading to generalised neuroinflammation.[64] In 1991 the amyloid hypothesis was proposed,[67] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[68] Othr changes, including congophilic amyloid angiopathy, oxidative changes, neuronal loss and inflammation are also associated with Alzheimer's Disease.

Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.

Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.[69] The amyloid hypothesis postulates that amyloid beta (Aβ) deposits are the fundamental cause of the disease.[67][68] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.[70][71] In AD, APP is divided by enzymes such as gamma-secretase and BACE-1 through a mechanism called proteolysis.[72] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.[73][9] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age.[74][75] It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[76] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).[77] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.[78] If damage from Aβ is the primary initiating cause of AD, the exact mechanism has not been elucidated. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils.[79] The most neurotoxic form of amyloid are the soluble oligomers and intermeidate amyloids; the severity of cognitive defect in AD correlates with oligomeric level in brain tissue. It is also known that Aβ selectively builds up in the mitochondria of samples from the brains of humans with AD, and in mitochondria from transgenic mice with APP genes, and in both cases inhibits certain mitochondrial enzyme functions, and a similar decrease in glucose utilization in neurons to the one which is a known characteristic of AD. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis. Mechanisms which involve direct damage from Aβ before it forms fibrils and plaques also address the issue that neuronal damage is not correlated as well with plaques, since in this model it is not the plaques themselves which cause the major damage, but rather the precursor Aβ protein directly, via another mechanism.[80] Again, deposition of amyloid plaques does not correlate well with neuron loss.[81]

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein

This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade.[68] AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, makes the microtubules stable through a process named phosphorylation and is therefore called a microtubule-associated protein.[82] In AD, tau is changed chemically, becoming hyperphosphorylated.

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

In the tau hypothesis, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.[83] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.[84] Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[9] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.[85]

Recent research supports the previously obscure theory that Herpes simplex virus type 1 plays a role as a possible cause of AD in people carrying the susceptible versions of the apoE gene.[86] As HSV-1 is not a new virus, some additional factor is needed to explain the increase [3] in the age adjusted incidence of AD. Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.[87] Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid,[66] leading to generalised neuroinflammation.[64]

Diagnosis

Dementia is a clinical condition rather than an exact diagnosis. Alzheimer's disease is usually diagnosed clinically, using the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[88][89] Advanced medical imaging with CT or MRI, and with SPECT or PET may also be used to help to diagnose the subtype of dementia and exclude other cerebral pathology.[90] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[3] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed on autopsy when brain material is available and can be examined histologically and histochemically.[91]

Diagnostic criteria

The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) are among the most commonly used criteria for diagnosing AD.[92] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD, while they require histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.[93] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association are similar to the NINCDS-ADRDA Alzheimer's Criteria.[94][95]

Diagnostic tools

Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.

Neuropsychological screening tests such as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive batteries are necessary for high reliability by this method, especially in the earliest stages of the disease.[96][97] The neurological examination in early AD is often normal independent of cognitive impairment, but is key for diagnosis of the other dementing disorders. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer's disease and other dementias.[3] In addition, 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 how the patient's mental function has changed over time. [98] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[99] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[100] Finally, supplemental testing may provide extra information on features of the disease, or may rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,[3] which may even be reversible.[101] psychological tests for depression are also important, as depression can both co-occur with AD or even be at the origin of the patient's cognitive impairment.[102][103]

The functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) may also be used in the diagnosis Alzheimer's.[104] In some cases, the ability of SPECT to differentiate Alzheimer's disease from other possible causes in a patient already known to be suffering from dementia may be superior to attempts to differentiate the cause of dementia cause by mental testing and history.[105] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.[106][107][108] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[109] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[92][3]

Prevention

Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.

Specific measures to delay or prevent the onset of AD are lacking. This is due to contradictory results in global studies, as well as a paucity of proven causal relationships between risk factors and the disease.[110] Modifiable factors such as diet, cardiovascular risks, pharmaceutical products, or intellectual activities have all been evaluated with epidemiological studies to see if they increase a population's risk of developing AD.[111]

The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may reduce the risk and course of Alzheimer's disease. There is evidence that frequent and moderate consumption of alcohol (beer, wine or distilled spirits) reduces the risk of the disease,[112] [113] but it is still considered premature to make dietary recommendations on this basis.[114][115] Vitamins E, B, and C, or folic acid have appeared to be related to a reduced risk of AD,[116] but other studies indicate that they do not have any significant effect on the onset or course of the disease, but may have important secondary effects in conjunction with other therapies.[117] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.[118]

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[119][120] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[121][122] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[123][124][125]

Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[126][127] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[128]

Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction may also delay the onset or reduce the severity of Alzheimer's disease.[129][130] Bilingualism is also related to a later onset of Alzheimer's disease.[131]

Management

There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.

Pharmaceutical

3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA)currently approve four medications to treat the cognitive manifestations of AD. Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug is currently able to delay or halt the progression of the disease.

Because reduction in cholinergic neuronal activity is well known in Alzheimer's disease,[132] acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down. This increases the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergic neurons.[133] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[134] galantamine (Razadyne),[135] and rivastigmine (branded as Exelon,[136] and Exelon Patch[137]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[138] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[139] The use of these drugs in mild cognitive impairment has not shown any effect in delaying the onset of AD.[140] The most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.[141][142][143][144]

Glutamate is an excitatory neurotransmitter of the nervous system. Excessive amounts of glutamate in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[145] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[146] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.[145] 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.[147] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[148] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[149]

Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline. These side effects do not permit the routine use of these medications.[150][151][152]

Psychosocial intervention

A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia

Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to Alzheimer's disease, focusing instead on dementia as a whole.[153]

Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,[154] but can help to reduce some specific problem behaviors, such as incontinence.[155] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[156][157]

Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. 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.[153] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, often with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.[158] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.[159][160] 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 senses. There is little evidence to support the usefulness of these therapies.[161][162]

The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists of the presentation of information about time, place or person in order to ease the the patient's understanding of their surroundings. On the other hand, cognitive retraining tries to improve impaired capacities by exercising mental abilities. Both have shown some efficacy improving cognitive capacities,[163][164] although in some works these effects were transient. Negative effects, such as frustration, have also been reported.[153]

Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, 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 improvement in the patient's daily life, as opposed to improving the underlying disease course.[153]

Caregiving

Further information: [[:Caregiving and dementia]]

Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[165] Many family members choose to look after their relative,[166] but two-thirds of nursing home residents have dementias.[167]

Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.[168][169] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[170]

Clinical research

Main article: Alzheimer's disease clinical research

As of 2008, the safety and efficacy of more than 400 pharmaceutical treatments are being investigated in clinical trials worldwide, and approximately one-fourth of these compounds are in Phase III trials, which is the last step prior to review by regulatory agencies.[171] It is unknown as to whether any of these trials will ultimately prove successful in treating the disease.

A critical area of clinical research is focused on treating the underlying disease pathology. Reduction of amyloid beta levels is a common target of compounds under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study. Unlike vaccines which seek to prevent disease, this therapy would be used to treat diagnosed patients, and is based upon the concept of training the immune system to recognize, attack, and reverse deposition of amyloid, thereby altering the course of the disease.[172] An example of such a vaccine under investigation is ACC-001.[173][174] Similar agents are bapineuzumab, an antibody designed as identical to the naturally-induced anti-amyloid antibody,[175] and MPC-7869, a selective amyloid beta-42 lowering agent.[176] Other approaches are neuroprotective agents, such as AL-108,[177] metal-protein interaction attenuation agents, such as PBT2,[178] or tumor necrosis factor-alpha receptor fusion proteins, such as etanercept.[179][180][181] There are also many basic investigations attempting to increase the knowledge on the origin and mechanisms of the disease that may lead to new treatments.

Prognosis

The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises everyday activities, although the person may still be living independently. People with Alzheimer's disease progress from mild cognitive problems, such as memory loss, through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living.[44]

Life expectancy of the population with the disease is reduced.[7][182][183] The mean life expectancy following diagnosis is approximately seven years.[7] Fewer than 3% of patients live more than fourteen years.[8] Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival.[182][184][185] 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.[183] Men have a less favourable survival prognosis than women.[8][186] Pneumonia and dehydration are the most frequent immediate causes of death, while cancer is a less frequent cause of death than in the general population.[7][186]

Society and culture

Social costs

Because the median age of the industrialised world's population is gradually increasing, Alzheimer's is a major public health challenge. Much of the concern about the solvency of governmental social safety nets is founded on estimates of the costs of caring for baby boomers, assuming that they develop Alzheimer's in the same proportions as earlier generations. For this reason, money spent informing the public of available effective prevention methods may yield disproportionate benefits.[187]

Caregiving burden

Further information: [[:Caregiving and dementia]]

The role of family caregivers has become more prominent in both reducing the social cost of care and improving the quality of life of the patient. Home-based care also can have economic, emotional, and psychological costs to the patient's family. Although family members in particular often express the desire to care for the sufferer to the end,[188] Alzheimer's disease is known for effecting a high burden on caregivers.[166]

Alzheimer's disease can incur a variety of stresses on the caregivers: typical complaints are stress, depression, and an inability to cope. Reasons for these complaints can include: high-demands on the caregiver's concentration, as Alzheimer's sufferers have a decreasing regard for their own safety (and can wander when unattended, for example); the lack of gratitude received when the sufferer is unaware of the help being given; and the lack of satisfaction when the sufferer's condition does not abate. Alzheimer's sufferers can be verbally and physically aggressive, and can stubbornly refuse to be helped. Aggression in particular can lead to a temptation to retaliate, which can put both the sufferer and carer at risk. It is additionally stressful for caregivers who are friends and family to witness a sufferer lose his or her identity, and eventually be unable to recognise them.[166]

Family caregivers often give up time from work and forego pay to spend 47 hours per week on average with the person with AD. From a 2006 survey of US patients with long term care insurance, direct and indirect costs of caring for an Alzheimer's patient average $77,500 per year.[189]


References

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    • Luchsinger JA, Mayeux R (2004). "Dietary factors and Alzheimer's disease". Lancet Neurol. 3 (10): 579–87. doi:10.1016/S1474-4422(04)00878-6. PMID 15380154.
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  111. ↑ Szekely CA, Breitner JC, Zandi PP (2007). "Prevention of Alzheimer's disease". Int Rev Psychiatry. 19 (6): 693–706. doi:10.1080/09540260701797944. PMID 18092245.
  112. ↑ Alcohol:
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    • Ganguli M; et al. (2005). "Alcohol consumption and cognitive function in late life: A longitudinal community study". Neurology. 65: 1210–1217.
    • Huang W; et al. (2002). "Alcohol consumption and incidence of dementia in a community sample aged 75 years and older". Journal of Clinical Epidemiology. 55 (10): 959–964.
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  113. ↑ Mediterranean diet:
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    • Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB (2006). "Fruit and vegetable juices and Alzheimer's disease: the Kame Project". American Journal of Medicine. 119 (9): 751–759. doi:10.1016/j.amjmed.2006.03.045. PMID 16945610.
    • Savaskan E, Olivieri G, Meier F, Seifritz E, Wirz-Justice A, Müller-Spahn F (2003). "Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity". Gerontology. 49 (6): 380–383. doi:10.1159/000073766. PMID 14624067.
  114. ↑ Luchsinger JA, Mayeux R (2004 Oct). "Dietary factors and Alzheimer's disease". Lancet Neurology. 3 (10): 579–587. PMID 15380154. Available data do not permit definitive conclusions regarding diet and AD or specific recommendations on diet modification for the prevention of AD. Check date values in: |date= (help)
  115. ↑ Kawas CH (2006 Jul-Sep). "Medications and diet: protective factors for AD?". Alzheimer Dis Assoc Disord. 20 (3 Suppl 2): S89–96. PMID 16917203. Evidence regarding dietary and supplemental intake of vitamins E, C, and folate, and studies of alcohol and wine intake are also reviewed. At present, there is insufficient evidence to make public health recommendations, but these studies can provide potentially important clues and new avenues for clinical and laboratory research. Check date values in: |date= (help)
  116. ↑ Vitamins:
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    • Alzheimer's Association. "Vitamin E".
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  117. ↑ Vitamins only of secondary benefit:
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    • Sun Y, Lu CJ, Chien KL, Chen ST, Chen RC (2007). "Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomised, double-blind, placebo-controlled study in Taiwanese patients". Clin Ther. 29 (10): 2204–14. doi:10.1016/j.clinthera.2007.10.012. PMID 18042476.
    • Boothby LA, Doering PL (2005). "Vitamin C and vitamin E for Alzheimer's disease". Ann Pharmacother. 39 (12): 2073–80. doi:10.1345/aph.1E495. PMID 16227450.
    • Gray SL, Anderson ML, Crane PK, Breitner JC, McCormick W, Bowen JD, Teri L, Larson E (2008). "Antioxidant vitamin supplement use and risk of dementia or Alzheimer's disease in older adults". J Am Geriatr Soc. 56 (2): 291–295. doi:10.1111/j.1532-5415.2007.01531.x. PMID 18047492.
  118. ↑ Curcumin in diet:
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    • Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001). "The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse". Journal of Neuroscience. 21 (21): 8370–8377. PMID 11606625.
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  147. ↑ Areosa Sastre A, McShane R, Sherriff F (2004). "Memantine for dementia". Cochrane Database Syst Rev (4): CD003154. doi:10.1002/14651858.CD003154.pub2. PMID 15495043.
  148. ↑ "Namenda Prescribing Information" (PDF). Forest Pharmaceuticals. Retrieved 2008-02-19.
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  154. ↑ Bottino CM, Carvalho IA, Alvarez AM; et al. (2005). "Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study". Clin Rehabil. 19 (8): 861–869. doi:10.1191/0269215505cr911oa. PMID 16323385.
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  156. ↑ Hermans DG, Htay UH, McShane R (2007). "Non-pharmacological interventions for wandering of people with dementia in the domestic setting". Cochrane Database Syst Rev (1): CD005994. doi:10.1002/14651858.CD005994.pub2. PMID 17253573.
  157. ↑ Robinson L, Hutchings D, Dickinson HO; et al. (2007). "Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review". Int J Geriatr Psychiatry. 22 (1): 9–22. doi:10.1002/gps.1643. PMID 17096455.
  158. ↑ Woods B, Spector A, Jones C, Orrell M, Davies S (2005). "Reminiscence therapy for dementia". Cochrane Database Syst Rev (2): CD001120. doi:10.1002/14651858.CD001120.pub2. PMID 15846613.
  159. ↑ Peak JS, Cheston RI (2002). "Using simulated presence therapy with people with dementia". Aging Ment Health. 6 (1): 77–81. doi:10.1080/13607860120101095. PMID 11827626.
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