Lara Heflin, PhD

San Francisco, California

UCSF Memory & Aging Center

Neuropsychology

Alzheimer's Disease

By Bruce Miller, MD; Lara Heflin, PhD

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease—or a disease that causes progressive damage to brain cells leading to slow but relentless mental decline. The most common early symptoms with AD are difficulty learning and remembering new information, problems navigating familiar routes, difficulty with finding words, and deficits in multi-tasking (doing several things at once). As AD progresses, memory and spatial problems worsen and new cognitive problems arise, including deficits in understanding and expressing ideas, loss of the ability to calculate, read and write, and severe difficulties with problem-solving. Usually patients maintain their social graces but as the illness progresses behavioral symptoms including apathy, agitation, anxiety, and delusions (false beliefs) emerge. Eventually, the cognitive and behavioral problems associated with AD cause “dementia,” defined as cognitive impairment severe enough to interfere with daily life activities such as work, social interactions, hobbies, or self-care. There are many diseases that cause dementia, although AD is the most common cause of dementia in older adults.

Key facts about AD

• Current U.S. prevalence: >5 million people [1]
• U.S. age-related incidence of moderate AD: [2]
• Age 65-69: 1.6%
• Age 70-74: 3.5%
• Age 75-79: 7.8%
• Age 80-84: 14.8%
• Age 85-89: 26.0%
• Common Symptoms: [1, 3]
• Memory problems
• Trouble knowing the date or time
• Misplacing things
• Getting lost or disoriented, or wandering
• Difficulty with calculation
• Suspicious or paranoid beliefs, often about items or money being stolen
• Word finding problems (e.g., pausing while speaking to try to find the right word, or substituting “thing” or “it” for more specific words)
• Risk factors: [3, 4]
• Older age
• e4 allele of apolipoprotein gene
• Family history of dementia
• Family history of Parkinson’s disease
• Down’s syndrome
• Head injury with loss of consciousness
• Very low education (< 6 years)
• Female gender (mildly increases the risk)
• Diabetes

Causes/Risk Factors

The direct changes that are seen microscopically in the AD brain are described in the section, “Neurobiology and Pathology” below. But what are the factors that cause people to develop those neurobiological changes? Without a doubt, the most important risk is aging. Incidence, or new cases of AD, approximately double every five years after the age of 65 years [2]. In the very old, (above 90), the number of people who manifest AD-like changes is extremely high, leading some to believe that if we all lived long enough we would all get AD. How aging leads to these changes remains unknown.

For some, genetic factors contribute to, or even cause development of the disease. This risk is greatest for those with a strong family history of AD, and for individuals whose family members were diagnosed with AD before age 65. Familial AD, which is inherited in an autosomal dominant pattern, is caused by mutations in the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 gene on chromosome 14, or the presenilin 2 gene on chromosome 1 [5]. These mutations all lead to excessive production of a protein called beta amyloid (Aβ). With this genetic form of AD, if the gene is carried there is near 100% likelihood that the person will develop AD if they live beyond 60 years. Less than 5% of AD cases are transmitted in this fashion. A more common genetic risk is associated with the apolipoprotein gene on chromosome 19 [6]. This gene has three common variants or alleles, called APOE-e2, APOE-e3, and APOE-e4. Individuals with 1 or 2 copies of the APOE-e4 allele have a substantially increased risk for AD, whereas individuals with 1 or 2 copies of the APOE-e2 allele have decreased risk. Unlike the familial genes that cause AD, having APOE-e4 does not guarantee that you will get AD, but increases your risk substantially [5]. In addition, having Down’s syndrome, or a family history of other dementias or Parkinson’s disease, also appears to increase risk [4].

The remaining risks for developing AD appears to come from environmental factors, although the precise mechanisms by which these risk factors contribute to AD is not entirely known. Head injury is one of the most preventable environmental risk factors. Typically, head injuries are only considered risks when there is a loss of consciousness, which indicates brain trauma. Other potentially modifiable environmental risk factors include high blood pressure, high cholesterol, and diabetes, which can be reduced through diet and exercise. Diets rich in antioxidants, Vitamin E, and omega-3 fatty acids may reduce risk for AD, while diets high in fat and calories increase risk. In addition, exercise may reduce risk for AD by improving cerebrovascular health and promoting the growth of new neurons in brain regions responsible for memory[7].

Education is commonly considered to be a preventive factor, but the relationship between education level and AD is complex. Individuals with very high levels of education are typically diagnosed with AD less frequently and at older ages than similar individuals with less education. However, autopsy examinations show greater brain shrinkage in individuals with high education levels, which is an indication of greater progression of AD. Many researchers now believe that education and the associated intellectual strengths that come with it cannot prevent AD, but delay the diagnosis through what is referred to as “cognitive reserve,” or a cognitive cushion that buffers one against showing symptoms of AD [8].

Depression, and particularly depression that occurs first in older adulthood, has been suggested to be a risk factor. Whether or not late-life depression is a risk, or rather just an an early sign of AD is still unknown [9]. Having depression at younger ages does not appear to be a risk factor for AD.

Female gender is associated with a slightly increased risk of developing AD. It is unclear, however, whether that risk stems primarily from the tendency of women to live longer than men, which puts them at increased risk simply by virtue of their older age.

Progression

Alzheimer’s disease is known for its insidious onset and slow progression. It is preceded by a stage where cognitive functioning is diminished relative to peers of a similar age and education level, but which is not sufficiently severe to merit a diagnosis of AD. This stage is sometimes called mild cognitive impairment (MCI) or mild AD; however, not everyone diagnosed with MCI will go on to develop AD. Although there are no true distinctions between different stages of the disease, these stages are helpful in describing the disease progression. It typically takes years for a person with AD to progress from 1 stage to another, and because there are no clear demarcations between stages, there is often overlap.

On imaging, the medial temporal and parietal areas of the brain are typically the first areas to appear shrunken as neurons die. Shrinkage is particularly early and prominent in the hippocampi, structures that are needed for making new memories, and in the posterior parietal lobes, which are involved in spatial skills, navigation, and calculation. Later, nearly the entire brain appears shrunken, and the spaces within the brain, called ventricles, grow larger.

Memory and spatial problems are usually the first symptoms seen and are disproportionate to problems with attention, organizing, and multi-tasking. About half of people with AD have one or more psychiatric symptoms [10] such as depression, apathy, or insomnia in the early to moderate stages. Agitation and insomnia become more common in the moderate stages of the disease, while behavioral disturbances are most likely to emerge in the moderate to severe stages. Of note, although people with AD have pronounced cognitive problems, they typically retain social skills until they are in the moderate to severe stages. These characteristics can help differentiate between AD and other types of dementia.

Image: coronal slices (planes parallel to the face) of the brain. The left slice shows a brain with a normal hippocampus traced in yellow, and the right slice shows a brain with a shrunken AD hippocampus traced in yellow. Images courtesy of Dr. Howard Rosen.

Impairments in activities of daily living, or basic living skills such as bathing and dressing one’s self, frequently do not occur until the moderate to severe stages of the disease. Difficulties with bathing and dressing may be the first observed difficulties that occur in the moderate stage, while difficulties eating and toileting occurring more frequently in the severe stage [10]. In addition, memory and judgment problems can impair safe self-care in the moderate to severe stages of the disease. Because AD tends to spare the motor systems until the latest stages of the disease, people with AD typically do not need wheelchairs or other movement aids as a result of the disease, although, of course, other medical problems common to aging may necessitate such devices.

In the last stage of the disease, which is sometimes called the terminal stage, people are frequently cared for in institutions due to increased care demands. At this stage, people may have difficulty swallowing whole foods and thin liquids, and consequently may need to drink thickened liquids for nutrition [11]. Tube feeding is sometimes implemented in institutions if a patient has difficulty swallowing even thickened liquids or refuses nutrition. However, tube feeding tends to be very uncomfortable and may not improve survival or reduce the risk of aspiration pneumonia [11], and so its use should be carefully considered. Reduced mobility, often leading patients to be bed-bound, increases risk for infections and bedsores. Because people with terminal stage AD have very reduced ability to make decisions and communicate, family members should be actively involved in making treatment decisions and ensuring care that is consistent with the patient’s desires and values.

Neurobiology & Pathology

Naturally occurring proteins in the brain called beta amyloid (Aβ) and tau are believed to cause the symptoms of AD by preventing brain cells from functioning normally. The amyloid hypothesis suggests that the symptoms and neuropathological changes of AD stem primarily from an overabundance of Aβ [12]. Aβ is a peptide, or protein segment, formed from the amyloid precursor protein (APP). Enzymes called β-secretase and γ-secretase cause APP to be cut in different places, creating Aβ [13]. Aβ then aggregates into small clusters, called oligomers, and eventually into larger aggregates called neuritic plaques (shown in A & C of figure below). These oligomers in particular appear to disrupt communication between neurons. In addition, Aβ oligomers are neurotoxic and when their concentration becomes sufficiently high they cause neuronal death [13].

The second of the commonly identified culprits is a neuronal protein called tau [14]. When functioning normally, tau helps to give the neuron its unique shape and transports oxygen and vital proteins and sugars along the neuron. In AD, enzymes attach phosphates to the tau protein until the sites that can receive phosphates are completely saturated, which is called hyperphosphorylation. Hyperphosphorylation causes the tau protein to form tangles (also known as neurofibrillary tangles; shown in B & D of figure below), which prevent microtubules from performing their typical functions of distributing nutrients throughout the cell. This is one mechanism by which hyperphosphorylated tau leads to neuronal death. These neurofibrillary tangles first emerge in the medial temporal lobe [15], in regions heavily involved in verbal and visual memory formation, and are believed to contribute to the memory problems characteristic of AD.

As the disease progresses, neuritic plaques and neurofibrillary tangles spread across the brain in wider regions, disrupting additional cognitive abilities. While the medial temporal and parietal lobes are usually affected early in AD, the frontal lobes are affected later in the disease, with the basic sensory and motor areas of the brain typically unaffected until very last stages of the disease. The spread of AD into the brain’s “lower centers,” which are involved with movement and swallowing, eventually leads to death.

In addition to accumulation of Aβ plaques and oligomers and tau tangles, AD is associated with changes in the brain’s neurotransmitters—the chemicals that allow neurons to communicate. In particular, the neurotransmitter acetylcholine is severely depleted in people with AD, and it is believed to contribute to the learning and memory problems that are so characteristic of the disease [17]. This deficiency, only one of many neurotransmitter deficiencies in AD, can be treated, but only partially alleviates symptoms.

Diagnosis

A thorough evaluation, which is the best way to distinguish between AD and other neurodegenerative disorders or normal aging, can be complex and ideally requires a multi-disciplinary team of physicians, nurses, neuropsychologists, and social workers. Such an evaluation often includes:

1. a careful history, including:
1. family history of neurological disease
2. current symptoms
3. the onset and course of symptoms
4. risk factors for AD and other neurological disorders
5. medical history
6. current medications
7. drug and alcohol use
8. sleep habits
9. education level and work history
2. a neurological exam, which examines:
1. cranial nerves
2. gait
3. balance and stability
4. motor function and motor sequences
5. sensory perception and discrimination
6. reflexes
3. cognitive or neuropsychological exam, which tests:
1. verbal and nonverbal learning and memory
2. visuospatial perception and copying/drawing ability
3. speech and language skills
4. attention
5. processing speed
6. executive functioning (higher-order cognitive tasks such as mentally manipulating information, mental flexibility, response inhibition, planning, problem solving, abstraction, and judgment)
7. motor speed
8. mood
4. blood work, which looks for signs of:
1. infection
2. kidney dysfunction
3. liver dysfunction
4. B12 or folic acid deficiency
5. thyroid dysfunction
6. autoimmune disorders
5. neuroimaging, using 1 or more of the following techniques:
1. CT or MRI – examines brain structure for places of atrophy characteristic of AD
2. PET or SPECT – examine brain function for places of hypometabolism or hypoperfusion characteristic of AD. This test is only recommended for patients in whom diagnosis is difficult.

After an evaluation, a person who is thought to have AD may be given a diagnosis of “probable AD,” “possible AD,” or “amnestic MCI.” MCI is an early stage where cognitive dysfunction is documented, but is not sufficiently severe to interfere with daily life. People with amnestic MCI show deficits primarily—or only—in the area of memory, and are at high risk of progressing to AD. Probable AD is diagnosed when a person has been established to have dementia by a clinical examination and neuropsychological testing, the dementia onset was between ages 40 and 90, the person shows deficits in 2 or more cognitive domains, has progressive memory loss and other cognitive deterioration, is not delirious, and does not have other disorders that could be responsible for causing the symptoms [19]. Possible AD is diagnosed when a person shows a slow progressive deterioration in only one cognitive area or has been diagnosed with another disorder that could produce dementia [19]. A definitive diagnosis of AD cannot be made until the brain has been directly examined for the characteristic pathological signs of AD, which typically occurs only at autopsy. However, due to the amount of research that has been conducted on AD, when pre-autopsy diagnoses are made after a thorough evaluation, diagnoses have a high degree of accuracy.

There are many causes for dementia that are not due to AD, including other degenerative conditions such as frontotemporal dementia, vascular dementia, Parkinsonian-dementia and medical conditions such as B12 deficiency [20]. Accurate diagnosis is the key to effective therapy.

Treatment

Once a diagnosis of AD has been made, treatment of the disease should be considered. Treatment has many components and should focus around the following:

• Symptomatic therapy with medications
• Treatment of difficult behaviors with medications
• Treatment of difficult behaviors with changes in the environment
• Organizing finances, legal issues, advanced directives
• Making sure that the caregiver maintains his or her health

Symptomatic therapy with medications: Currently there are two types of medications approved for the treatment of AD, cholinesterase inhibitors and NMDA antagonists. Cholinesterase inhibitors work by increasing the brain’s level of acetylcholine, and they are the mainstay of AD treatment. The three cholinesterase inhibitors used in medical practice are Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne). When these medications work they typically lead to mild improvements in attention, thinking, and memory. Generally, patients on these medications do better than patients not taking them. Donepezil, Rivastigmine and Galantamine are all approved for treatment of mild to moderate AD, while Donepezil is also approved for treatment of severe disease. The side effects of these medications are low, with gastrointestinal upset and sleep disturbance the major concerns. When AD is diagnosed the patient should be started on one of the cholinesterase inhibitors. Memantine (Namenda) is approved for the treatment of moderate to severe AD and it works by blocking areas in the brain that are overexcited by a neurotransmitter called glutamate. Memantine can be added to a cholinesterase inhibitor, or used alone, and has few side effects. None of these medications leads to miraculous improvements, but even subtle changes in patients can be a big positive for caregivers. New medications designed to slow the aggregation of Aβ are under active study and may have more impressive effects than the current generation of compounds [21].

Treatment of Difficult Behaviors with Medications or Environmental Changes: Treating agitated or unwanted behaviors is extremely difficult and should always begin by thinking about why the behavior has emerged. AD patients may not be able to explain how they feel. Pain associated with a urinary infection, tooth decay, or back problems can manifest as agitation or confusion. Similarly, depressed mood can trigger difficult behaviors. Therefore, a careful medical evaluation is important if behavior has changed. Additionally, review of possible environment triggers is needed. Sleep in the daytime will often mean that the patient stays awake at night. Lack of exercise will increase the likelihood that the patient will become irritable or agitated. Overstimulation and big changes in the environment often precipitate difficult behaviors.

Medications for these behaviors have limited value and often make things worse rather than better. Sometimes antidepressant compounds will smooth out difficult periods. Antipsychotic and anxiolytic medications have significant toxicities and are typically most effective when they are used in low doses for limited periods of time.

Organizing finances, legal issues, advanced directives: Thinking ahead is a key to effective caregiving. AD is a continually changing illness and what works at one stage may not work later on. Eventually patients lose their ability to make good decisions and the family will need to consider wills, financial decision-making, and advanced directives for health care at the earliest possible stage. Included in this planning is the designation of a health care proxy – a person who is chosen to make medical decisions once the patient is unable to participate in these him or herself.

Making sure that the caregiver maintains his or her health: Caregiving is one of the most difficult tasks that we will ever face. Maintaining good health and good spirits is essential. Exercise programs, time alone, daycare, sitters, respite programs, and support groups can make caregiving less difficult and should be considered at all stages of the illness. The Alzheimer’s Association can aid families in accessing health support.

Practical tips for living with AD

People may feel overwhelmed after being diagnosed with AD. Some find it helpful to read about the disease, so that they understand their diagnosis and know better what to expect as the disease progresses. Understanding the disease and prognosis can help you plan for your future and make important decisions, such as creating an advance health care directive, and making decisions about how and where you want to live. It is also helpful to have a trusted friend or family member with you at your medical appointments. This person can help you in a number of ways. He or she can ask your doctor important questions, help you remember the information your doctor provides you, help plan future appointments or make other relevant plans, provide emotional support, and help you get to and from your appointments.

In addition, AD affects more people than those diagnosed with it—it affects family members and other loved ones. Behavioral problems are typically more difficult for caregivers and other loved ones than are memory problems. Here are several behavioral issues that frequently arise with AD, and ways that may help deal with them.

• Suspicion or paranoia: People with AD sometimes become suspicious of others. If you are the subject of that suspicion, it can be hurtful and confusing. It is helpful to understand that people with AD frequently become suspicious because they cannot keep track of things as well as they used to; when they move something, they often cannot remember that they have done so. It therefore seems to them that their environment, and the valuable things in it, changes inexplicably, and so they make sense of these changes by thinking that other people must be stealing from them. This thought typically has nothing to do with how trustworthy a loved one has been, and it is usually the person or people closest to the AD patient who is blamed. Rather than defending yourself, or getting emotional if this happens, you can help the person look for whatever has been misplaced. Or, if possible, you can replace it.
• Forgotten bills: People with AD can have a difficult time paying bills, keeping track of their finances, and otherwise managing their money. They can also be at risk for elder financial abuse. Caregivers often find their lives improve dramatically when they take over handling the finances, and no longer have to worry about whether or not the bills are being paid. Being involved with finances also can help prevent elder financial abuse, or enable any scams or fraud to be quickly recognized and remedied.
• Personality changes: Although personality change is typically not as striking in AD as it is in some other types of dementias, it is not uncommon. People with AD can become agitated, confused, depressed, anxious, stubborn, or needy. Some personality or emotional changes, such as depression, can be treated pharmacologically. Sometimes, it is helpful to recognize that personality changes can be the result of poorer cognitive skills—that when people cannot communicate their thoughts and feelings well verbally, they communicate through actions. Identifying “triggers,” or the preceding events or circumstances, of unwanted behavior can help you understand what may be distressing to the person. Once you understand this, you can modify the environment appropriately. In addition, blame the disease for the distressing behavior or personality changes, rather than blaming the person.
• Fluctuating symptoms: One of the most confusing things to many caregivers is that a loved one with AD can sometimes seem to remember things, or be able to perform certain tasks, and other times cannot. This is normal, and it is part of the disease process. Although it may seem that a person is “faking” when their symptoms are worse, or that they should be able to do something all the time if they can do it some of the time, neither of these ideas are true. People with AD truly do have fluctuating abilities. Blaming the disease for these frustrating and confusing moments, rather than blaming the person with AD for not always being able to do things, is very helpful. It is also helpful to simply recognize that symptoms, including cognitive abilities, fluctuate over the course of the day and change over time.
• Wandering: Individuals with AD often leave their home to take a walk or with the intention of going somewhere, but become disoriented or lost. It’s not unusual for caregivers to become panicked when they realize that the person with AD is gone. To prevent wandering, you can affix a bell to the door, so that you are alerted when the person with AD is trying to leave, or post a sign on the door that says, “Do not open” [22]. There are also steps you can take to help find the person who has wandered. First, you can have the person wear an ID bracelet with the person’s name and your phone number. Second, you can enroll the person in the Alzheimer’s Association’s Safe Return program, which provides an ID bracelet or pendant, a “community support network to help reunite the lost person with his or her caregiver,” and 24-hour wandering or medical emergency response services [23]. Third, you can call the police. Try not to be angry or overly emotional when you find your loved one after he or she has wandered—this will only be upsetting, and not helpful. In addition to these steps, it may be helpful to take walks with the person during the daytime, to enable him or her to get exercise while giving yourself the security of knowing where he or she is.

Q & A

• Q:Is there a blood test to diagnose Alzheimer’s disease?
• A: There is no blood test currently available that can diagnose AD, although researchers are working to create a test that would make diagnosis more fast and accurate. Doctors frequently order blood tests during a dementia evaluation, in order to rule out other causes of cognitive impairment such as problems with liver or kidney functioning.
• Q: Is there any way to vaccinate against, or otherwise prevent, AD?
• A: Not yet, although scientists are exploring methods to reduce amyloid and tau deposition in the brain, and these promising new methods could yield vaccine-like treatments in the future (20). Until those treatments arrive, exercise may be the best way to prevent AD--research has shown that exercise may help prevent or minimize the symptoms. Similarly, a diet rich in antioxidants and Vitamin E may help reduce risk. In general, it appears that what is good for your heart is good for your brain.
• Q: My loved one was recently diagnosed with AD. Is it fatal?
• A: Yes. Alzheimer’s disease is the seventh leading cause of death in the US (1). Individuals live an average of 8 years after being diagnosed with AD.
• Q: Is it okay to drive after being diagnosed with AD?
• A: People are discouraged from driving after being diagnosed with AD or other dementias due to increased risk of accidents. Even in familiar environments, driving is a complex task that requires fast reaction speed, accurate perception and understanding of your environment, concentration, the ability to multi-task, and physical coordination. These abilities can be impaired in people with AD. In addition, if you have been diagnosed with AD and get into an accident, you are likely to be held liable for the accident. In some states, doctors are required by law to report to the DMV when an individual has been diagnosed with dementia. Although losing the ability to drive can represent a loss of independence, there are resources to help ensure that people with AD have access to transportation.
• Q: What are the benefits of participating in research about AD?
• A: The specific benefits of participating in research depend upon the research protocol. Often, research involves brain imaging and neuropsychological testing, and participants can sometimes receive feedback about the structure and function of the brain and the way that they change over time. This information can help individuals and family members understand the severity of their cognitive problems, and this information can help in planning for the future. Research also benefits millions of other people; by volunteering for research, participants can help scientists understand the disease better, and ultimately develop and test treatments. The knowledge generated through research benefits future generations of people who may be affected by AD.

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