Encyclopedia
Alzheimer's disease is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. It is the most common cause of dementia.
The most striking early symptom is short term memory loss , which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive impairment extends to the domains of language , skilled movements , recognition , and those functions closely related to the frontal and temporal lobes of the brain as they become disconnected from the
limbic system, reflecting extension of the underlying pathological process.
This pathological process consists principally of
neuronal loss or atrophy, principally in the temporoparietal cortex, but also in the frontal cortex, together with an inflammatory response to the deposition of amyloid plaques and neurofibrillary tangles.
The ultimate cause of the disease is unknown. Genetic factors are known to be important, and autosomal dominant mutations in three different genes have been identified that account for a small number of cases of familial, early-onset AD. For late onset AD , only one susceptibility gene has so far been identified: the epsilon 4 allele of the apolipoprotein E gene. Age of onset itself has a heritability of around 50%.
History
The symptoms of the disease as a distinct entity were first identified by
Emil Kraepelin. The characteristic neuropathology was first observed by
Alois Alzheimer, a German psychiatrist, after whom the disease is named, in 1906. In this sense, the disease was co-discovered by Kraepelin and Alzheimer, who worked in Kraepelin's laboratory. Because of the overwhelming importance Kraepelin attached to finding the neuropathological basis of psychiatric disorders, Kraepelin made the generous decision that the disease would bear Alzheimer's name.
For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45–65 who developed symptoms of
presenile dementia due to the histopathologic process discovered by Dr. Alzheimer . During this time
senile dementia itself was considered to be a more or less normal outcome of the aging process, and thought to be due to age-related brain arterial "hardening." In the 1970s and early 1980s, because the symptoms and brain pathology were identical for Alzheimer victims older and younger than age 65, the name "Alzheimer's disease" began to be used, within and outside the medical profession, equally for afflicted individuals of all ages, although in this period the term
senile dementia of the Alzheimer type was often used to distinguish those over 65 who did not fit the classical age criterion. Eventually, the term Alzheimer's disease was adopted formally in the psychiatric and neurological nomenclature to describe individuals of all ages with the characteristic common symptom pattern, disease course, and neuropathology. The term
Alzheimer disease also continues to be used commonly in the literature.
Clinical features
The usual first symptom noticed is short term memory loss which progresses from seemingly simple and often fluctuating forgetfulness to a more pervasive loss of short-term memory, then of familiar and well-known skills or objects or persons. Aphasia, disorientation and disinhibition often accompany the loss of memory. Alzheimer's disease may also include behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior. In the later stages, deterioration of musculature and mobility, leading to bedfastness, inability to feed oneself, and incontinence, will be seen if death from some external cause does not intervene. Average duration of the disease is approximately 7–10 years, although cases are known where reaching the final stage occurs within 4–5 years, or up to 15 years.
Stages and symptoms
- Mild — At the early stage of the disease, patients have a tendency to become less energetic or spontaneous, though changes in their behaviour often goes unnoticed even by the patients' immediate family.
- Moderate — As the disease progresses to the middle stage, the patient might still be able to perform tasks independently, but may need assistance with more complicated activities.
- Severe — As the disease progresses from the middle to late stage, the patient will undoubtedly not be able to perform even the simplest of tasks on their own and will need constant supervision.
Diagnosis
The diagnosis is made primarily on the basis of history, clinical observation and tests of memory and intellectual functioning over a series of weeks or months, with various physical tests being performed to rule out alternative diagnoses. No medical tests are available to diagnose Alzheimer's disease conclusively pre-mortem. Expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85–90%, but a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue, generally at
autopsy. Functional neuroimaging studies such as PET and SPECT scans can provide a supporting role where dementia is clearly present, but the type of dementia is questioned. Recent studies suggest that SPECT neuroimaging approaches clinical exam in diagnostic accuracy and may outperform exam at differentiating types of dementia . However, Alzheimer's disease remains a primarily clinical diagnosis based on the presence of characteristic neurological features and the absence of alternative diagnoses, with neuroimaging providing a supporting role where dementia is clearly present, but the type of dementia is questioned.
Interviews with family members and/or caregivers are extremely important in the initial assessment, as the sufferer him/herself may tend to minimize his symptomatology or may undergo evaluation at a time when his/her symptoms are less apparent, as quotidian fluctuations are a fairly common feature. Such interviews also provide important information on the affected individual's functional abilities, which are a key indicator of the significance of the symptoms and the stage of dementia.
Initial suspicion of dementia may be strengthened by performing the
mini mental state examination, after excluding
clinical depression. Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, visuospatial abilities, and other cognitive functions. Results of psychological tests may not readily distinguish Alzheimer's disease from other types of dementia, but can be helpful in establishing the presence of and severity of dementia. They can also be useful in distinguishing true dementia from temporary cognitive impairment due to depression or psychosis, which has sometimes been termed "pseudodementia".
Pathology
Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease due to the accumulation of abnormally folded
amyloid beta protein in the brains of AD patients. Amyloid beta, also written Aß, is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein
amyloid precursor protein , whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.
Amyloid beta monomers are soluble and contain short regions of
beta sheet and
polyproline II helix secondary structures in solution, though they are largely
alpha helical in membranes; however, at sufficiently high concentration, they undergo a dramatic conformational change to form a
beta sheet-rich tertiary structure that aggregates to form amyloid fibrils. These fibrils deposit within neurons as
senile plaques or
neuritic plaques, outside neurons as
diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.
AD is also considered a tauopathy due to abnormal aggregation of the
tau protein, a
microtubule-associated protein expressed in neurons that normally acts to stabilize
microtubules in the cell
cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulated as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as
neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques. Although little is known about the process of filament assembly, it has recently been shown that a depletion of a prolyl isomerase protein in the parvulin family accelerates the accumulation of abnormal tau.
Neuropathology
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains. At an anatomical level, AD is characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes 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. Levels of the neurotransmitter
acetylcholine are reduced. Levels of the neurotransmitters
serotonin,
norepinephrine, and somatostatin are also often reduced.
Glutamate levels are usually elevated.
Disease mechanism
Three major competing hypotheses exist to explain the cause of the disease.
The oldest hypothesis is the "cholinergic hypothesis". It states that Alzheimer's begins as a deficiency in the production of
acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting
acetylcholinesterases . These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical. More recently, cholinergic effects have been proposed as a potential causative agent for the formation of plaques and tangles leading to generalized neuroinflammation., insulin-degrading enzyme , endothelin-converting enzymes , and inflammatory 5-lipoxygenase gene .
Genetic linkage
Alzheimer's disease is definitely linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not, as yet, confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.
Epidemiology and prevention
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 Alzheimer's. Among people aged 65, 2-3% show signs of the disease, while 25 - 50% of people aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. Every five years after the age of 65, the probability of having the disease doubles. The proportion of people with Alzheimer's begins to decrease after age 85 because of the increased mortality due to the disease, and relatively few people over the age of 100 have the disease.
The evidence relating certain behaviors, dietary intakes, environmental exposures, and diseases to the likelihood of developing Alzhemier's varies in quality and its acceptance by the medical community. It is important to understand that interventions that reduce the risk of developing disease in the first place may not alter disease progression after symptoms become apparent. Due to their observational design, studies examining disease risk factors are often at risk from confounding variables. Several recent large, randomized controlled trials—in particular the Women's Health Initiative—have called into question preventive mesasures based on cross-sectional studies. Some proposed preventive measures are even based on studies conducted solely in animals.
Risk reducers
- Intellectual stimulation
- Regular physical exercise
- Regular social interaction
- A generally healthy diet low in saturated fat, supplemented in particular with:
- B vitamins
- Omega-3 fatty acids, especially DHA
- Fruit and vegetable juice
- High doses of the antioxidant Vitamin E seem to reduce Alzheimer's risk in cross sectional studies but not in a randomized trial and so are not currently a recommended preventive measure because of observed increases in overall mortality
- Cholesterol-lowering drugs reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials
- Hormone replacement therapy is no longer thought to prevent dementia based on data from the Women's Health Initiative
- Regular use of non-steroidal anti-inflammatory drugs like ibuprofen and aspirin reduces the chance of dementia but the risks appear to outweigh the drugs' benefit as a method of primary prevention
Risk factors
- Advancing age
- ApoE epsilon 4 genotype
- Head injury
- Poor cardiovascular health
- Exposure to heavy metals, including aluminum and copper, is a proposed but not widely-accepted risk factor
Treatment
There is currently no cure for Alzheimer's disease. Currently available medications offer relatively small symptomatic benefit for some patients but do not slow disease progression. The American Association for Geriatric Psychiatry published a consensus statement on Alzheimer's treatment in 2006.
Acetylcholinesterase inhibitors
Acetylcholinesterase inhibition was thought to be important because there is a reduction in activity of the cholinergic neurons. AChE-inhibitors reduce the rate at which acetylcholine is broken down and hence increase the concentration of ACh in the brain . Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms but do not prevent disease progression including cell death.
Examples include:
There is significant doubt as to the effectiveness of cholinesterase inhibitors. A number of recent articles have criticzed the design of studies reporting benefit from these drugs, concluding that they have doubtful clinical utility, are costly, and confer many side effects. The pharmaceutical companies, but also some independent clinicians, dispute the conclusions of these articles. A transdermal patch is under development that may ease administration of rivastigmine.
NMDA antagonists
Recent evidence of the involvement of
glutamatergic neuronal excitotoxicity in the aetiology of Alzheimer's disease led to the development and introduction of memantine. Memantine is a novel NMDA receptor
antagonist, and has been shown to be moderately clinically efficacious.
Psychosocial interventions
Cognitive and behavioral interventions and rehabilitation strategies may be used as an adjunct to pharmacologic treatment, especially in the early to moderately advanced stages of disease. Treatment modalities include counseling, psychotherapy , reminiscent therapy, reality orientation therapy, and behavioral reinforcements as well as cognitive rehabilitation training.
Potential treatments
A large number of potential treatments for Alzheimer's disease are currently under investigation, including four compounds being studied in phase 3 clinical trials. Xaliproden had been shown to reduce neurodegeneration in animal studies. Tramiprosate is a GAG-mimetic molecule that is believed to act by binding to soluble amyloid beta to prevent the accumulation of the toxic plaques. R-flurbiprofen is a gamma secretase modulator sometimes called a selective amyloid beta 42 lowering agent. It is believed to reduce the production of the toxic amyloid beta in favor of shorter forms of the peptide.
Leuprolide is also being studied for Alzheimer’s. It is hypothesized to work by reducing leutenizing hormone levels which may be causing damage in the brain as one ages.
- Vaccines for Alzheimer's, unlike typical vaccines, would be used to treat diagnosed patients rather than for disease prevention. Ongoing efforts are based on the idea that, by training the immune system to recognize and attack beta-amyloid, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results using this approach in animals were promising. However, when the first vaccines were used in humans, a small fraction of participants developed encephalitis and the trials were stopped. Participants in the halted trials continued to be followed, and some showed possible benefit in the form of slower progression of the disease. Work is continuing on less toxic Aß vaccines, such as a DNA-based therapy that recently showed promise in mice.
- Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements. In general, research on the efficacy of these substances is either non-existent or far too weak to support therapeutic claims of improved memory or slowed disease progression.
In a 2006 review
Laboratory studies with cells and animals continually fuel the pipeline of potential treatments. Some currently approved drugs such as
statins and thiazolidinediones
have also been under investigation for the treatment and prevention of Alzheimer’s.
Recent clinical trials for Phase 2 and Phase 3 in this category have taken 12 to 18 months under study drug, plus addtional months for patient enrollment and analysis. Compounds that are just entering into human trials or are in pre-clinical trials would be at least 4 years from being available to the public and would be available only if they can demonstrate safety and efficacy in human trials.
Design for Alzheimer's patients
- According to a small Boston University study, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast, a condition often found among people with advanced AD. Study participants were found to increase by 25% or more the amount they ate and drank.
Social issues
Alzheimer's is considered to be a major public health challenge since the median age of the industrialized world's population is increasing gradually. Indeed, 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.
The role of family caregivers has also become more prominent, as 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. However, home-based care may entail tremendous economic, emotional, and even psychological costs as well. Family caregivers often give up time from work and foregoing pay to spend 47 hours per week on average with an affected loved one who frequently cannot be left alone. Direct and indirect costs of caring for an Alzheimer's patient average $77,500 per year.
Famous Alzheimer's disease sufferers have included President
Ronald Reagan,
Charlton Heston,
Ralph Waldo Emerson, and
Rita Hayworth.
See also
External links
- - The major Alzheimer's support and advocacy group in the United States provides excellent information on topics ranging from basics of diagnosis and caregiving to the disease's legal implications and ways to talk to children about the disease. Similar groups provide country-specific information in and .
- - A website intended to provide information to and foster collaboration among scientists and physicians conducting research on Alzheimer's. Features debates between and article annotations by many top Alzheimer's researchers
- - Substantial website by a division of the U.S. National Institutes of Health with links to information about ongoing clinical studies
- - Links to each of the NIH-funded centers of excellence for Alzheimer's disease located at academic medical centers scattered throughout the U.S.
- - Running, highly technical synopsis of research on Alzheimer's disease maintained by the NIH
- - Subscription required for full text
- - Well-organized article on Alzheimer's
References
