Alzheimer's Disease

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Images courtesy of the National Institute on Aging/National Institutes of Health.

What is Alzheimer’s disease?

Alzheimer’s disease (AD) is a progressive, degenerative brain disease that slowly erodes memory and thinking skills, and eventually even the ability to carry out simple tasks. It is the most common cause of dementia. It is the most common cause of dementia, accounting for approximately 50-70% of all cases of dementia. The incidence of AD rises exponentially with advancing age. Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimer’s. The greatest risk for Alzheimer’s disease is advancing age, with the risk increasing as we get older.

The major underlying mechanism of AD is the accumulation of proteins called beta-amyloid and tau within the brain. Although we still don’t know what starts the disease process, it can go on for many years without symptoms. This is called the preclinical or presymptomatic stage of the disease. As more and more beta-amyloid plaques and neurofibrillary tangles (aggregates of tau) form in particular brain areas, healthy neurons begin to work less efficiently, then lose their ability to function and communicate with each other, and eventually die. This process seems to begin in the parts of the brain responsible for forming new memories, in particular, the hippocampus and entorhinal cortex. The early symptomatic stage of AD is called mild cognitive impairment (MCI). As more neurons die, affected brain regions begin to shrink, leading to the functional problems, which are the signs and symptoms of Alzheimer's. By the final stage, damage is widespread and brain tissue has shrunk significantly.

The major underlying mechanism of Alzheimer’s is the accumulation of a protein called beta-amyloid in neurons. Although we still don’t know what starts the disease process, we do know that damage to the brain begins as many as 10 to 20 years before any problems are evident. As more and more beta-amyloid plaques and neurofibrillary tangles form in particular brain areas, healthy neurons begin to work less efficiently, then lose their ability to function and communicate with each other, and eventually die. This process spreads to the hippocampus, which is essential in forming new memories. As more neurons die, affected brain regions begin to shrink, leading to the functional problems, which are the signs and symptoms of Alzheimer's. By the final stage, damage is widespread and brain tissue has shrunk significantly.

Genetics of Alzheimer’s disease

Less than 5% of AD is caused by dominant genes that are transmitted through families. In these families, people usually show symptoms well before the age of 65 and symptoms sometimes begin in the 30s. This form of AD is called early-onset familial Alzheimer’s disease (EOFAD). Additionally, there are other genes that increase or decrease susceptibility to AD but do not cause the disease.

Three predisposition genes have been associated with EOFAD. They are presenilin 1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1, and the amyloid precursor protein gene (APP) on chromosome 21. All of these genes affect the processing of the amyloid precursor protein and increase the generation of toxic beta-amyloid (Abeta 42), which creates the plaques in AD. All three of these genes are inherited as autosomal dominant genes, which means that carriers of the genes have a 50% risk of passing the gene to their offspring. Likewise, other first-degree relatives (parents and siblings) have a 50% chance of carrying the gene. Clinical testing is available for the PS1 gene, but because of the small number of families with mutations in PS2 and APP, testing for these genes is currently only done through research labs.

Up to 20% of presenile AD seems to be due to the presence of certain susceptibility genes that cause the disease to occur earlier in life than it would without the gene. Of these genes, the APOE gene has the clearest and strongest association. APOE is found in three different forms: APOE 2, APOE 3 or APOE 4. Like all other genes, each cell contains two copies (alleles) of the APOE gene. These alleles can be the same form or different forms of APOE. APOE 3 is the most common form of the gene and is found in approximately 75% of the population. APOE 4 has been associated with an increased risk for developing Alzheimer’s. People with two copies of APOE 4 have a significant increased risk (16-fold) over the general population, and people with one copy have about a 3-fold increased risk. Unlike the predisposition genes, however, APOE is a susceptibility gene. Not everybody with APOE 4 develops AD. Similarly, people without APOE 4 can develop AD. Other genetic and environmental factors also influence susceptibility. Therefore, until preventative treatment is available, presymptomatic testing for APOE is not recommended.

Signs & symptoms of Alzheimer’s disease

Usually appearing after the age of 60, the first symptom of AD is impaired memory formation, especially for recent events or newly learned information. Memory lapses may be very subtle at first, thus leading many people to discount the symptoms as a sign of getting old. A person may ask the same question or say the same thing repeatedly within a short period of time but without remembering the prior conversation. Important objects such as checkbooks or wallets may be misplaced and lost. In the kitchen, pots can be left on the stove resulting in burnt food or small fires.

As AD progresses, details or even the occurrence of recent events may be forgotten. Implicit (or memory for overlearned activities like riding a bike) and semantic memory (fact memory), as well as long-term memory, remain relatively intact early, but decline in these forms of memory eventually develops.

While memory is a key feature, AD is also defined by a decline in visuospatial skills, language, abstraction, planning and organization. Visuospatial problems may cause a person to become disoriented or lost in familiar environments. Accidents or becoming lost while driving can occur. Inability to recognize familiar individuals may also develop. Language problems such as word-finding difficulty occurs early but impaired comprehension or decreased speech output may occur in the later stages. Declines in planning and organization often result in missed bill payments and difficulty handling finances.

Behavioral symptoms are also common in AD. Apathy or decreased motivation causes affected individuals to appear lazy and indifferent. Depression is also common. In some cases, the onset of depression late in life may precede the cognitive symptoms of AD. Agitation including physical and verbal aggressiveness may develop, usually later in the illness. Delusions and hallucinations can appear at any stage of Alzheimer's, but usually occur a few years after AD is diagnosed. In rare instances, patients may believe that familiar people have been replaced with imposters.

Progression of Alzheimer’s disease

Memory problems are one of the first signs of AD. Some people with memory problems have a condition called amnestic mild cognitive impairment (MCI), which means they have more memory problems than normal for people their age, but their symptoms are not as severe as those with AD. More people with MCI, compared with those without MCI, go on to develop AD.

Mild Alzheimer’s disease

As Alzheimer’s disease progresses, memory loss continues and changes in other cognitive abilities appear. Problems can include getting lost, trouble handling money and paying bills, repeating questions, taking longer to complete normal daily tasks, poor judgment, and small mood and personality changes. People often are diagnosed in this stage.

Moderate Alzheimer’s disease

As Alzheimer's disease progresses, plaques and tangles spread throughout the brain, starting in the neocortex. By the final stage, damage is widespread and brain tissue has shrunk significantly. In this stage, damage occurs in areas of the brain that control language, reasoning, sensory processing and conscious thought. Memory loss and confusion increase, and people begin to have problems recognizing family and friends. They may be unable to learn new things, carry out tasks that involve multiple steps (such as getting dressed) or cope with new situations. They may have hallucinations, delusions and paranoia and may behave impulsively. Imaging of the brain often reveals atrophy of the parietal and medial temporal lobes.

Severe Alzheimer’s disease

By the final stage, plaques and tangles have spread throughout the brain, and brain tissue has shrunk significantly. People with severe Alzheimer’s cannot communicate and are completely dependent on others for their care. Near the end, the person may be in bed most or all of the time, as the body shuts down. Generalized cerebral atrophy with posterior predominance may be seen on imaging.

Treatment of Alzheimer’s disease

Cholinesterase inhibitors (donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Razadyne®/Reminyl®)) can help manage Alzheimer’s, but they do not cure or reverse the course of AD. In the Alzheimer-afflicted brain, the cells that transmit the chemical messenger acetylcholine are damaged or destroyed, resulting in lower levels of the messenger. A cholinesterase inhibitor is designed to stop the activity of acetylcholinesterase, thereby slowing the breakdown of acetylcholine. By maintaining higher levels of acetylcholine, the drug may help compensate for the loss of functioning brain cells. Some individuals may experience a mild, temporary improvement in cognition soon after starting the medication. However, the duration of improvement and stability is highly variable. It appears that all individuals with AD will progress over the long-term despite treatment. Generally, cholinesterase inhibitors are well tolerated. Symptoms such as nausea, vomiting, loss of appetite, and increased frequency of bowel movements may occur with any cholinesterase inhibitor. There is no evidence that combining the drugs would be any more beneficial than taking one alone and combining the drugs results in greater side effects. Patients taking acetylcholinesterase inhibitors should be monitored when they have physical conditions that might be worsened by cholinergic drugs such as some heart conditions, and when they are taking other cholinergic drugs. Nausea, dizziness and diarrhea are the most common side-effects, although some patients show worsening of dreams. Several herbals, Chinese club moss also known as huperzine A and galantamine in the herbal form, are found in over the counter “memory products” possess similar side effects as the Alzheimer’s prescription drugs. It is important to report all medications, including herbals, nutraceuticals, etc. to your physicians. In addition, medications with anticholinergic activity should be avoided where possible (examples: Benadryl, Cogentin, Tylenol PM, Ditropan). Ask your pharmacist which medications have significant anticholinergic activity.

Memantine (Namenda®) has been approved for the treatment of moderate-severe AD. As a NMDA antagonist, memantine reduces the excessive excitation of nerve cells by glutamate. Most patients will be prescribed a cholinesterase inhibitor and memantine together. Memantine appears to have few side effects and drug interactions. Memantine is useful for those individuals who cannot tolerate a cholinesterase inhibitor or in those patients with heart disease that affects the timing mechanism of the heart. Side effects are not common, but increased confusion, falls, and headaches may occur. Nausea and vomiting are not typically a problem. The dose of memantine may need to be adjusted downwards for individuals with significantly impaired kidney function.

A variety of medications are prescribed, with variable success, for psychiatric behavioral problems associated with AD and other dementia. Hallucinations, paranoia, delusions, severe agitation with aggressive/combative features and depression may require more potent (and toxic) psychotherapeutic agents, although their use should be considered with caution. Keeping a detailed diary of “problem behaviors” can greatly assist the health care provider in evaluating these behaviors and selecting an appropriate medication or non-pharmacological approaches to treating the behavior.

Non-pharmacological interventions can be beneficial for people with AD. A regular exercise regimen may increase energy levels, reduce apathy and improve the overall sense of well-being. Since lack of motivation can be significant in AD, a personal trainer may assist in compliance with the exercise program.

Medications to avoid

Ergoloid mesylates (Hydergine®), clyclandelate (Cyclospasmol®), papaverine (Pavabid®), niacin, lecithin and choline hydrochloride have been tried as agents to improve memory and reduce confusion. Although published research suggested many of these drugs should be effective in dementia patients, this was not generally observed in actual patient care. At this time, there appears to be little reason to prescribe any of these drugs for AD.

Resources for Alzheimer’s disease

February 3, 2014