Alzheimer's disease

The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.

Phases

The first symptoms are often mistaken as related to ageing or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD. These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships), can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. The preclinical stage of the disease has also been termed mild cognitive impairment, but there is still debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.

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. 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 affected to a lesser degree than new facts or memories. Language problems are mainly characterised by 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. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present, making sufferers appear clumsy. 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 dementiaProgressive deterioration eventually hinders independence. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes, reducing the ability to perform most normal daily living activities. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired, and behavioural changes become more prevalent. Common neuropsychiatric manifestations are wandering, sundowning, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Approximately % of patients also develop illusionary misidentifications and other delusional symptoms. Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.Advanced dementiaDuring 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. Finally comes death, usually caused directly by some external factor such as pressure ulcers or pneumonia, not by the disease itself.

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. They continue to grow into insoluble twisted fibres within the nerve cell, often called tangles. 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.BiochemistryEnzymes 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 (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, – amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques. In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.Disease mechanismExactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD has not been elucidated. The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.Various inflammatory processes and cytokines 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.GeneticsWhile the rare, early-onset form of Alzheimer's disease is mainly explained by mutations in three genes, the most common form has yet to be explained by a purely genetic model. The APOE gene is the strongest genetic risk factor for Alzheimer's discovered so far, but its presence is far from explaining all occurrences of the disease.Less than % of AD cases occurring before years of age are due to autosomal dominant (familial) mutations, which therefore represent less than .% of all cases. These mutations have been discovered in three different genes: amyloid precursor protein (APP) and presenilins and . Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta, which is the main component of senile plaques.Most cases of Alzheimer's disease do not exhibit familial inheritance, but genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε allele of the apolipoprotein E (APOE). This gene is implicated in up to % of late-onset sporadic Alzheimer's cases. 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 genes have been tested for association with late-onset sporadic AD. One example is a variant of the reelin gene that may contribute to Alzheimer's risk in women.

Causes

Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau proteinThree major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. 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.The amyloid hypothesis, currently the most popular, was proposed in . Here amyloid beta (Aβ) deposits are postulated to be the fundamental cause of the disease. It is a compelling theory because the gene for the amyloid beta precursor (APP) is located on chromosome , and people with trisomy (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD by years of age. Also APOE, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology. An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.Deposition of amyloid plaques does not correlate well with neuron loss. This observation supports the tau hypothesis, the idea that tau protein 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.

Diagnosis

PET scan of the brain of a person with AD showing a loss of function in the temporal lobeAlzheimer's disease is usually diagnosed clinically from 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. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Assessment of intellectual functioning 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. Sometimes the diagnosis can be confirmed or made at post-mortem when brain material is available and can be examined histologically.Diagnostic criteriaThe National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) established the most commonly used diagnostic criteria for Alzheimer's disease. 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. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation. Eight cognitive domains are most commonly impaired in AD—memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.Diagnostic toolsNeuropsychological 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. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Neurological examination 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 diagnosis of AD and other diseases. Interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function. A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits. 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 tests can identify other causes for dementia than AD—causes which may, in rare cases, be reversible. Psychological tests for depression are employed, since depression can either be concurrent with AD or be the cause of cognitive impairment.When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination. The ability of SPECT to differentiate Alzheimer's disease from other possible causes in somebody already known to be suffering from dementia, appears to be superior to attempts to diagnose by mental testing and history. A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a tracer that binds selectively to the Abeta deposits. Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins. Both advances have led to the proposal of new diagnostic criteria.PreventionIntellectual 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.Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. At present, there appears to be no definitive evidence to support the belief that any particular measure is effective in preventing AD. 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, in fact, these factors can help to prevent AD.The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Several vitamins such as B, B, C or folic acid have been found in some studies to be related to a reduced risk of AD but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects. Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models. The prevalence of AD among the elderly in India has been reported to be about one quarter of that in the U.S., and curry intake has been reported to correlate positively with cognitive function in elderly Asians.Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals. Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia, and a systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment.Intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction may also delay the onset or reduce the severity of Alzheimer's disease. Bilingualism is also related to a later onset of Alzheimer's.Some studies have shown an increased risk of developing AD with occupational exposure to magnetic fields, intake of metals, particularly aluminium, or exposure to solvents. 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.

Management

There is no 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.PharmaceuticalThree-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptomsMolecular structure of memantine, a medication approved for advanced AD symptomsFour medications are currently approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) to treat the cognitive manifestations of AD: three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (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 , the cholinesterase inhibitors approved for the management of AD symptoms are donepezil (brand name Aricept), galantamine (Razadyne), and rivastigmine (branded as Exelon and Exelon Patch). There is evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease, and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD. The most common side effects are 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 production. Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts 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. Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda), is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors 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 hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".Antipsychotic drugs are modestly useful in reducing aggression and psychosis 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.Psychosocial interventionA specifically designed room for sensory integration therapy, also called snoezelen; an emotion-oriented psychosocial intervention for people with dementiaPsychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general.Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning, but can help to reduce some specific problem behaviours, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called 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. Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT, it may be beneficial for cognition and mood. Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with Alzheimer's disease. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviours. 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.The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his or her place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities, although in some studies these effects were transient and negative effects, such as frustration, have also been reported.Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. 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 improvement in the person's daily life routines.CaregivingFurther information: Caregiving and dementiaSince Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving essentially is the treatment and must be carefully managed over the course of the disease.During the early and moderate stages, modifications to the living environment and lifestyle can increase patient safety and reduce caretaker burden. Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labelling of household items to cue the person with the disease or the use of modified daily life objects. The patient may also become incapable of feeding themselves, so they require food in smaller pieces or pureed. When swallowing difficulties arise, the use of feeding tubes 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, pressure ulcers, malnutrition, hygiene problems, or respiratory, skin, or eye infections. 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.PrognosisThe 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 expectancy of the population with the disease is reduced. The mean life expectancy following diagnosis is approximately seven years. Fewer than % 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 problems, diabetes or history of alcohol abuse are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.The disease is the underlying cause of death in % of all cases. 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.

Epidemiology

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 – per thousand person–years for all dementias and – 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 , the risk of acquiring the disease approximately doubles, increasing from to as much as 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 .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 .% in the year both overall and in the – age group, with the rate increasing to % in the – group and to % in the greater than group. Prevalence rates in less developed regions are lower. The World Health Organization estimated that in , .% of people worldwide had dementia, and that the prevalence would increase to .% in and to .% in . Other studies have reached similar conclusions. Another study estimated that in , .% of the world population (range .–.%; absolute number . million, range .–. million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by the year .HistoryAuguste D, first described patient with AD by Alois Alzheimer in The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alzheimer followed her until she died in , when he first reported the case publicly. During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by Emil Kraepelin, who included Alzheimer’s disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in .For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of and who developed symptoms of dementia. The terminology changed after 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 of different aetiologies. 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 , 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.

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in the developed countries, while their cost in developing countries such as Argentina, or Korea, is also high and rising. These costs will probably increase with the ageing of society, becoming an important social problem. AD associated costs include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver. Numbers vary between studies but dementia costs worldwide have been calculated around $ billion, while costs of Alzheimer in the United States may be $ billion each year.The greatest origin of costs for society is the long-term care by health care professionals and particularly institutionalisation, which corresponds to / of the total costs for society. The cost of living at home is also very high, specially 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.The role of the main caregiver 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.Dementia caregivers are subject to high rates of physical and mental disorders. Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviours of the cared person such as depression, behavioural disturbances, hallucinations, sleep problems or walking disruptions and social isolation. Regarding economic problems, family caregivers often give up time from work to spend 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 $, and $, per year in the United States, depending on the study.Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.Research directionsAs of , the safety and efficacy of more than 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.One 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 preventative vaccination, the putative therapy would be used to treat people already diagnosed. It is based upon the concept of training the immune system 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-, although the trials were suspended in . Similar agents are bapineuzumab, an antibody designed as identical to the naturally-induced anti-amyloid antibody, and MPC-, a selective amyloid beta- lowering agent. Other approaches are neuroprotective agents, such as AL-, and metal-protein interaction attenuation agents, such as PBT. A TNFα receptor fusion protein, etanercept has showed encouraging results.In , two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride (trade name rember), a drug that inhibits tau aggregation, and dimebon, an antihistamine.