Alzheimer's disease

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Editor(s)-in-Chief: C. Michael Gibson, M.S.,M.D. [1] Phone:617-632-7753; Peter Pressman, M.D. [2], Northwestern Memorial Hospital, Department of Neurology

Dr. Pressman has nothing to disclose.

Synonyms and keywords: AD; Alzheimer disease; senile dementia of the Alzheimer type; SDAT; Alzheimer's

Overview

Historical Perspective

Classification

Pathophysiology

Epidemiology and Demographics

Natural History, Complications and Prognosis

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.

Although each sufferer experiences Alzheimer's in a unique way, there are many common symptoms.[1] The earliest observable symptoms are often mistakenly thought to be 'age-related' changes, or manifestations of stress.[2] 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.[2][3] Gradually, bodily functions are lost, ultimately leading to death.[4] 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.[5] 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.[6] Fewer than three percent of individuals live more than fourteen years after diagnosis.[7]

The cause of Alzheimer's disease is poorly understood. Research indicates that the disease is associated with plaques and tangles in the brain.[8] 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.[9] 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.[10]

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.[11] 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.[12][13][14] In developed countries, AD is one of the most economically costly diseases to society.[15][16]

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.[17][18] 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.[19] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[2] 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.[20]

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.[21] 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.[22] 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.[23][24]

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.[25][26] 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.[2] 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. [27] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[28] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[29] 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,[2] which may even be reversible.[30] 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.[31][32]

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.[33] 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.[34] 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.[35][36][37] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[38] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[21][2]

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.[39] 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.[40]

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,[41] [42] but it is still considered premature to make dietary recommendations on this basis.[43][44] Vitamins E, B, and C, or folic acid have appeared to be related to a reduced risk of AD,[45] 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.[46] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.[47]

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[48][49] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[50][51] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[52][53][54]

Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[55][56] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[57]

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.[58][59] Bilingualism is also related to a later onset of Alzheimer's disease.[60]

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,[61] 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.[62] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[63] galantamine (Razadyne),[64] and rivastigmine (branded as Exelon,[65] and Exelon Patch[66]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[67] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[68] The use of these drugs in mild cognitive impairment has not shown any effect in delaying the onset of AD.[69] 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.[70][71][72][73]

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.[74] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[75] 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.[74] 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.[76] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[77] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[78]

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.[79][80][81]

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.[82]

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,[83] but can help to reduce some specific problem behaviors, such as incontinence.[84] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[85][86]

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.[82] 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.[87] 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.[88][89] 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.[90][91]

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,[92][93] although in some works these effects were transient. Negative effects, such as frustration, have also been reported.[82]

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.[82]

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.[94] Many family members choose to look after their relative,[95] but two-thirds of nursing home residents have dementias.[96]

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.[97][98] 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.[99]

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.[100] 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.[101] An example of such a vaccine under investigation is ACC-001.[102][103] Similar agents are bapineuzumab, an antibody designed as identical to the naturally-induced anti-amyloid antibody,[104] and MPC-7869, a selective amyloid beta-42 lowering agent.[105] Other approaches are neuroprotective agents, such as AL-108,[106] metal-protein interaction attenuation agents, such as PBT2,[107] or tumor necrosis factor-alpha receptor fusion proteins, such as etanercept.[108][109][110] 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.

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.[111]

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,[112] Alzheimer's disease is known for effecting a high burden on caregivers.[95]

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.[95]

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.[113]


References

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  39. ↑ Prevention recommendations not supported:
    • Kawas CH (2006). "Medications and diet: protective factors for AD?". Alzheimer Dis Assoc Disord. 20 (3 Suppl 2): S89–96. PMID 16917203.
    • 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.
    • Luchsinger JA, Noble JM, Scarmeas N (2007). "Diet and Alzheimer's disease". Curr Neurol Neurosci Rep. 7 (5): 366–72. doi:10.1007/s11910-007-0057-8. PMID 17764625.
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  41. ↑ Alcohol:
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  45. ↑ Vitamins:
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    • Alzheimer's Association. "Vitamin E".
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