Alzheimer’s Disease

What is Alzheimer’s disease?

Alzheimer’s disease bears the name of the German physician, Alois Alzheimer, who first described it in 1906. Alzheimer’s disease is the most common neurodegenerative disease worldwide and is the most common cause of dementia in people age 65 and older. It afflicts an estimated 5.3 million Americans and is the seventh leading cause of death.

Alzheimer’s disease is associated with characteristic pathological changes in the brain that involve deposition of the proteins amyloid and tau. Amyloid is deposited in brain tissue in plaque-like formations in the spaces between neurons (nerve cells), while the filaments of tau form neurofibillary tangles inside of the neurons. These pathological changes become more prominent, involving larger regions of the brain, as the disease progresses. Researchers have not yet determined what causes these proteins to be abnormally formed, and the exact relationship between these pathological changes and the clinical symptoms of the disease has not been entirely determined.

Cognitive decline associated with Alzheimer’s disease begins slowly and is gradually progressive. The average survival with Alzheimer’s disease is about 10.3 years, but survival can range from less than 3 years to more than 20.

Most of what we know about Alzheimer’s disease has been discovered in the past 15 years, and our understanding of the disease continues to progress.

What are the symptoms of Alzheimer’s disease?

Early symptoms of Alzheimer’s disease typically involve impairment of short-term memory. This may manifest as a tendency to repeat questions or to repeat oneself in conversation, or as an increased tendency to misplace objects around the house. Memory difficulties may contribute to increased confusion and difficulty managing personal finances or keeping track of appointments. The onset of these symptoms is typically gradual and insidious, and some of the earliest changes noted may be indecisiveness, as the individual increasingly looks to a spouse or family member for help making decisions, or subtle changes in personality. Some people may become more socially withdrawn because of minor depression symptoms or to self-consciousness about being forgetful in social situations.

Increased difficulty finding words may occur early in Alzheimer’s disease. A person may talk around the word that he or she cannot think of or rely on the listener to provide specific words during conversation. The melody and rhythm of speech are typically normal, but the content of spoken language may lack specific nouns, impairing the amount of content conveyed to the listener. Importantly, subtle changes in the brain’s ability to process visuospatial information may also occur. This can involve difficulties with the brain’s ability to process the entirety of a visual scene, difficulty locating objects in the environment with the eyes or misinterpretation of visual information (misrecognizing people or mistaking an object for something different). A familiar place may no longer be quite as easily recognized. Visuospatial difficulties and memory impairment combine to contribute to an increased risk of becoming lost or disoriented in a familiar location.

As Alzheimer’s disease progresses, short-term memory deficits become more severe and interfere more with the maintenance of daily activities. Confusion often increases, with people having difficulty comprehending temporal (time) relationships first, then later having increased geographical orientation difficulties. Language deficits may increase, and speech becomes more “empty” because of an increased reliance on general pronouns. This leads to decreased factual content in spoken language. An example might be, “I put the thing over on the porch for her on that day.” What thing? For whom? When? This type of communication can be frustrating for caregivers or spouses if it is not recognized as a feature of the disease.

A person with Alzheimer’s disease may or may not recognize the extent of cognitive impairment, and may deny having any difficulties with memory or thinking altogether.

A variety of different clinical staging techniques have been proposed. We generally divide staging of Alzheimer’s disease into early, moderate and severe.

In early Alzheimer’s disease, changes in thinking and memory may interfere with an individual’s ability to perform his or her more complex daily activities. Social graces and interactions are generally retained, and while a person may require some assistance as a result of memory and cognitive symptoms, people are generally able to function in a social environment. For example, if we were having lunch at a restaurant with a guest who has Alzheimer’s, our luncheon group might appear entirely normal, but our conversation might not be. The person with early Alzheimer’s disease might repeat questions or not recall exactly what we had been talking about a few minutes earlier, but other patrons in the restaurant would not notice anything amiss at our table.

In moderate Alzheimer’s disease, individuals typically require more assistance with daily activities, and as the disease progresses may even require assistance with essential daily activities, such as preparing a meal or requiring reminders to attend to hygiene. As discussed above, language and visuospatial symptoms often progress, leading to increased difficulties with communication and orientation. Neuropsychiatric symptoms, such as depression, anxiety or agitation, become more common during the moderate stage of Alzheimer’s disease. These can lead to increased difficulties in managing symptoms at home and may raise concerns related to the safety of the patient or spouse. If we were to have lunch in a restaurant with an individual in the moderate stage of Alzheimer’s disease, it is likely that other patrons would notice that something was not quite right at our table.

In severe Alzheimer’s disease, individuals are almost entirely dependent on others to ensure adequate hygiene and proper nutrition, and they may require prompts or assistance for common functions such as using the toilet. Patients with severe Alzheimer’s disease may develop more prominent behavioral difficulties and may even refuse others’ attempts to help with feeding or bathing.

What are risk factors for Alzheimer’s disease?

Age is the most important risk factor for Alzheimer’s disease. Other risk factors include heredity, diabetes, hypertension, traumatic brain injury and poor nutrition.

Although numerous medical and genetic risk factors for Alzheimer’s disease have been investigated, age remains the most prominent and important risk factor for Alzheimer’s disease.

Heredity, as in most medical conditions, plays an important role in the development of Alzheimer’s disease. Very uncommonly, Alzheimer’s disease may be caused by a genetic mutation, such as mutations in presenilin 1 (PSEN1). People with Down syndrome (most often associated with having an extra copy of chromosome 21) typically develop Alzheimer’s disease in their late 30s or early 40s. While these observations may help us to better understand the pathological process of Alzheimer’s disease, they are different in important ways from the typical circumstances of late-onset Alzheimer’s disease.

How is Alzheimer’s disease diagnosed?

A diagnosis of probable Alzheimer’s disease is made after a careful clinical evaluation, which involves a review of laboratory and brain imaging studies and other diagnostic studies that may be ordered. In some cases, neurocognitive testing, functional brain imaging studies (such as FDG-PET), or electroencephalopgram (EEG) may be arranged to help to establish an accurate diagnosis and to exclude other conditions that may cause disorders of memory or thinking.  Although a diagnosis of definite Alzheimer’s disease can be confirmed only at autopsy, a diagnosis of probable Alzheimer’s disease established in a behavioral neurology clinic achieves an accuracy of approximately 90 percent.

What treatments exist?

The U.S. Food and Drug Administration has approved two types of medications for people who have Alzheimer’s disease: cholinesterase inhibitors (Aricept, Exelon, Razadyne, Cognex) and memantine (Namenda). These medications are used to treat symptoms of Alzheimer’s disease, including memory loss, confusion, and difficulty with reasoning.

Cholinesterase inhibitors
Cholinesterase inhibitors work by preventing the breakdown of acetylcholine (a-SEA-til-KOH-lean), a chemical that plays an important role in learning and memory. When acetylcholine breaks down, the ability of nerve cells (brain cells) to communicate is compromised.

Acetylcholine is a neurotransmitter used by many neurons in the surface (cortex) of the brain to communicate. Pathological studies in the 1970s demonstrated that levels of this neurotransmitter are reduced in people who are in the early phase of the disease, and that this reduction becomes more severe and widespread as the disease progresses. Colinesterase inhibitors partially block (inhibit) the action of the enzyme that breaks down acetylcholine (acetylcholinesterase), resulting in a greater likelihood that a neuron producing acetylcholine will successfully transmit the desired signal.

Three cholinesterase inhibitors commonly used – donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon). All are similar in terms of effectiveness and side effects. They have a demonstrated benefit in people with early, moderate and severe Alzheimer’s disease. The benefit from these medicines is modest, however, and does not appear to impact the underlying pathological changes that occur during the course of Alzheimer’s disease. Nonetheless, trials of cholinesterase inhibitors have demonstrated a slower progression of cognitive and other clinical symptoms when compared to patients taking placebo (an inactive pill).

The most commonly reported side effects of the cholinesterase inhibitors are gastrointestinal, including nausea, queasiness and loss of appetite. These side effects may be lessened by taking the medicine with food. In rare cases, taking the medicine before bed may cause vivid or unpleasant dreams.

The other medication approved for treatment of Alzheimer’s disease is memantine (Namneda), which regulates the activity of glutamate, a different messenger chemical plays a role in learning and memory. Scientific evidence has identified overactivation of the NMDA receptor, which detects a neurotransmitter called glutamate, in the brains of people with Alzheimer’s disease. This overactivation leads to an excessive influx of calcium into the neuron, and memantine helps to reduce this excessive calcium influx.

Clinical trials of have shown that memantine’s effectiveness is similar to that of the cholinesterase inhibitors, and a modest effect on the progression of cognitive and clinical symptoms has been demonstrated. Side effects, which affect a small percentage of patients, include headache, increased confusion or dizziness.

Clinical use
Many patients with Alzheimer’s disease are treated with a cholinesterase inhibitor, memantine or both medications. A recent, restrospective study suggests that using the two medications in combination may have an added benefit. Generally, the medications are well-tolerated, and most patients will be started on both medications as their disease progresses. Because the medications alleviate symptoms, it may be desirable to begin them earlier in the disease course in order to maximize and preserve quality of life.

Lifestyle modifications
Remaining physically and intellectually active, socially engaged and maintaining a healthy diet are associated with a slower clinical progression of Alzheimer’s disease in multiple epidemiologic studies. Learn more >>

Many compounds, including Ginkgo biloba, curcumin, and huperzine, are used by people with Alzheimer’s disease. Although some of these alternative medications are associated with interesting basic science, none has shown clear clinical benefit.