Alzheimer's disease (AD) is a progressive disease of the brain that is characterized by impairment of memory and a disturbance in at least one other thinking function (for example, language or perception of reality). Many scientists believe that AD results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) that leads to nerve cell death. Loss of nerve cells in strategic brain areas, in turn, causes deficits in the neurotransmitters, which are the brain's chemical messengers.
What is Alzheimer's disease?
Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception. Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.
The likelihood of having Alzheimer's disease increases substantially after the age of 70 and may affect around 50% of persons over the age of 85. Nonetheless, Alzheimer's disease is not a normal part of aging and is not something that inevitably happens in later life. For example, many people live to over 100 years of age and never develop Alzheimer's disease.
Who develops Alzheimer's disease?
The main risk factor for Alzheimer's disease is increased age. As a population ages, the frequency of Alzheimer's disease continues to increase. Ten percent of people over 65 years of age and 50% of those over 85 years of age have Alzheimer's disease. Unless new treatments are developed to decrease the likelihood of developing Alzheimer's disease, the number of individuals with Alzheimer's disease in the United States is expected to be 14 million by the year 2050.
There are also genetic risk factors for Alzheimer's disease. Most patients develop Alzheimer's disease after age 70. However, 2%-5% of patients develop the disease in the fourth or fifth decade of life (40s or 50s). At least half of these early onset patients have inherited gene mutations associated with their Alzheimer's disease. Moreover, the children of a patient with early onset Alzheimer's disease who has one of these gene mutations has a 50% risk of developing Alzheimer's disease.
There is also a genetic risk for late onset cases. A relatively common form of a gene located on chromosome 19 is associated with late onset Alzheimer's disease. In the majority of Alzheimer's disease cases, however, no specific genetic risks have yet been identified.
Other risk factors for Alzheimer's disease includehigh blood pressure (hypertension), coronary artery disease, diabetes, and possibly elevated blood cholesterol. Individuals who have completed less than eight years of education also have an increased risk for Alzheimer's disease. These factors increase the risk of Alzheimer's disease, but by no means do they mean that Alzheimer's disease is inevitable in persons with these factors.
All patients with Down syndrome will develop the brain changes of Alzheimer's disease by 40 years of age. This fact was also a clue to the "amyloid hypothesis of Alzheimer's disease"
Symptoms
The onset of Alzheimer's disease is usually gradual, and it is slowly progressive. Memory problems that family members initially dismiss as "a normal part of aging" are in retrospect noted by the family to be the first stages of Alzheimer's disease. When memory and other problems with thinking start to consistently affect the usual level of functioning; families begin to suspect that something more than "normal aging" is going on.
Problems of memory, particularly for recent events (short-term memory) are common early in the course of Alzheimer's disease. For example, the individual may, on repeated occasions, forget to turn off an iron or fail to recall which of the morning's medicines were taken. Mild personality changes, such as less spontaneity, apathy, and a tendency to withdraw from social interactions, may occur early in the illness.
As the disease progresses, problems in abstract thinking and in other intellectual functions develop. The person may begin to have trouble with figures when working on bills, with understanding what is being read, or with organizing the day's work. Further disturbances in behavior and appearance may also be seen at this point, such as agitation, irritability, quarrelsomeness, and a diminishing ability to dress appropriately.
Later in the course of the disorder, affected individuals may become confused or disoriented about what month or year it is, be unable to describe accurately where they live, or be unable to name a place being visited. Eventually, patients may wander, be unable to engage in conversation, erratic in mood, uncooperative, and lose bladder and bowel control. In late stages of the disease, persons may become totally incapable of caring for themselves. Death can then follow, perhaps from pnuemonia or some other problem that occurs in severely deteriorated states of health. Those who develop the disorder later in life more often die from other illnesses (such as heart disease) rather than as a consequence of Alzheimer's disease.
Causes of Alzheimer's disease
The cause(s) of Alzheimer's disease is (are) not known. The "amyloid cascade hypothesis" is the most widely discussed and researched hypothesis about the cause of Alzheimer's disease. The strongest data supporting the amyloid cascade hypothesis comes from the study of early-onset inherited (genetic) Alzheimer's disease. Mutations associated with Alzheimer's disease have been found in about half of the patients with early-onset disease. In all of these patients, the mutation leads to excess production in the brain of a specific form of a small protein fragment called ABeta (Aβ). Many scientists believe that in the majority of sporadic (for example, non-inherited) cases of Alzheimer's disease (these make up the vast majority of all cases of Alzheimer's disease) there is too little removal of this Aβ protein rather than too much production. In any case, much of the research in finding ways to prevent or slow down Alzheimer's disease has focused on ways to decrease the amount of Aβ in the brain.
Risk factors for Alzheimer's disease
The biggest risk factor for Alzheimer's disease is increased age. The likelihood of developing Alzheimer's disease doubles every 5.5 years from 65 to 85 years of age. Whereas only 1%-2% of individuals 70 years of age have Alzheimer's disease, in some studies around 40% of individuals 85 years of age have Alzheimer's disease. Nonetheless, at least half of people who live past the 95 years of age do not have Alzheimer's disease.
Common forms of certain genes increase the risk of developing Alzheimer's disease, but do not invariably cause Alzheimer's disease. The best-studied "risk" gene is the one that encodes apolipoprotein E (apoE). The apoE gene has three different forms (alleles) -- apoE2, apoE3, and apoE4. The apoE4 form of the gene has been associated with increased risk of Alzheimer's disease in most (but not all) populations studied. The frequency of the apoE4 version of the gene in the general population varies, but is always less than 30% and frequently 8%-15%. Persons with one copy of the E4 gene usually have about a two to three fold increased risk of developing Alzheimer's disease. Persons with two copies of the E4 gene (usually around 1% of the population) have about a nine-fold increase in risk. Nonetheless, even persons with two copies of the E4 gene don't always get Alzheimer's disease. At least one copy of the E4 gene is found in 40% of patients with sporadic or late-onset Alzheimer's disease.
This means that in majority of patients with Alzheimer's disease, no genetic risk factor has yet been found. Most experts do not recommend that adult children of patients with Alzheimer's disease should have genetic testing for the apoE4 gene since there is no treatment for Alzheimer's disease. When medical treatments that prevent or decrease the risk of developing Alzheimer's disease become available, genetic testing may be recommended for adult children of patients with Alzheimer's disease so that they may be treated.
Many, but not all, studies have found that women have a higher risk for Alzheimer's disease than men. It is certainly true that women live longer than men, but age alone does not seem to explain the increased frequency in women. The apparent increased frequency of Alzheimer's disease in women has led to considerable research about the role of estrogen in Alzheimer's disease. Recent studies suggest that estrogen should not be prescribed to post-menopausal women for the purpose of decreasing the risk of Alzheimer's disease. Nonetheless, the role of estrogen in Alzheimer's disease remains an area of research focus.
Some studies have found that Alzheimer's disease occurs more often among people who suffered significant traumatic head injuries earlier in life, particularly among those with the apoE 4 gene.
In addition, many, but not all studies, have demonstrated that persons with limited formal education – usually less than eight years – are at increased risk for Alzheimer's disease. It is not known whether this reflects a decreased "cognitive reserve" or other factors associated with a lower educational level.
Treatment and management options are available for Alzheimer's disease
The management of Alzheimer's disease consists of medication based and non-medication based treatments. Two different classes of pharmaceuticals are approved by the FDA for treating Alzheimer's disease: cholinesterase inhibitors and partial glutamate antagonists. Neither class of drugs has been proven to slow the rate of progression of Alzheimer's disease. Nonetheless, many clinical trials suggest that these medications are superior to placebos (sugar pills) in relieving some symptoms.
Cholinesterase inhibitors
In patients with Alzheimer's disease there is a relative lack of a brain chemical neurotransmitter called acetylcholine. (Neurotransmitters are chemical messengers produced by nerves that the nerves use to communicate with each other in order to carry out their functions.) Substantial research has demonstrated that acetylcholine is important in the ability to form new memories. The cholinesterase inhibitors (ChEIs) block the breakdown of acetylcholine. As a result, more acetylcholine is available in the brain, and it may become easier to form new memories.
Four ChEIs have been approved by the FDA, but onlydonepezil hydrochloride (Aricept), rivastigmine (Exelon), and galantamine (Razadyne - previously called Reminyl) are used by most physicians because the fourth drug, tacrine (Cognex) has more undesirable side effects than the other three. Most experts in Alzheimer's disease do not believe there is an important difference in the effectiveness of these three drugs. Several studies suggest that the progression of symptoms of patients on these drugs seems to plateau for six to 12 months, but inevitably progression then begins again.
Of the three widely used AchEs, rivastigmine and galantamine are only approved by the FDA for mild to moderate Alzheimer's disease, whereas donepezil is approved for mild, moderate, and severe Alzheimer's disease. It is not known whether rivastigmine and galantamine are also effective in severe Alzheimer's disease, although there does not appear to be any good reason why they shouldn't.
The principal side effects of ChEIs involve the gastrointestinal system and include nausea, vomiting, cramping, and diarrhea. Usually these side effects can be controlled with change in size or timing of the dose or administering the medications with a small amount of food. Between 75% and 90% of patients will tolerate therapeutic doses of ChEIs.
Partial glutamate antagonists
Glutamate is the major excitatory neurotransmitter in the brain. One theory suggests that too much glutamate may be bad for the brain and cause deterioration of nerve cells. Memantane (Namenda) works by partially decreasing the effect of glutamate to activate nerve cells. It has not been proven that memantine slows down the rate of progression of Alzheimer's disease. Studies have demonstrated that some patients on memantine can care for themselves better than patients on sugar pills (placebos). Memantine is approved for treatment of moderate and severe dementia, and studies did not show it was helpful in mild dementia. It is also possible to treat patients with both AchEs and memantine without loss of effectiveness of either medication or an increase in side effects.
Non-medication based treatments
Non-medication based treatments include maximizing patients' opportunities for social interaction and participating in activities such as walking, singing, dancing that they can still enjoy. Cognitive rehabilitation, (whereby a patient practices on a computer program for training memory), may or may not be of benefit. Further studies of this method are needed.
Treatment of psychiatric symptoms
Symptoms of Alzheimer's disease include agitation, depression, hallucinations, anxiety, and sleep disorders. Standard psychiatric drugs are widely used to treat these symptoms although none of these drugs have been specifically approved by the FDA for treating these symptoms in patients with Alzheimer's disease. If these behaviors are infrequent or mild, they often do not require treatment with medication. Non-pharmacologic measures can be very useful.
Nevertheless, frequently these symptoms are so severe that it becomes impossible for caregivers to take care of the patient, and treatment with medication to control these symptoms becomes necessary. Agitation is common, particularly in middle and later stages of Alzheimer's disease. Many different classes of agents have been tried to treat agitation including:
- antipsychotics,
- mood-stabilizing anticonvulsants,
- trzadone (Desyrel),
- anxiolytics,
Apathy and difficulty concentrating occur in most Alzheimer's disease patients and should not be treated with antidepressant medications. However, many Alzheimer's disease patients have other symptoms of depression including sustained feelings of unhappiness and/or inability to enjoy their usual activities. Such patients may benefit from a trial of antidepressant medication. Most physicians will try selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft), citalopram (Celexa), or fluoxetine (Prozac), as first-line agents for treating depression in Alzheimer's disease.
Anxiety is another symptom in Alzheimer's disease that occasionally requires treatment. Benzodiazepines such as diazepam (Valium) or lorazepam (Ativan) may be associated with increased confusion and memory impairment. Non-benzodiazepine anxiolytics, such as buspirone (Buspar) or SSRIs, are probably preferable.
Difficulty sleeping (insomnia) occurs in many patients with Alzheimer's disease at some point in the course of their disease. Many Alzheimer's disease specialists prefer the use of sedating atypical antidepressants such as trazodone (Desyrel). However, other specialists may recommend other classes of medications. Sleep improvement measures, such as sunlight, adequate treatment of pain, and limiting nighttime fluids to prevent the need for urination, should also be implemented.
