Alzheimer’s disease

Alzheimer’s disease (AD) is a devastating illness characterized by progressive memory loss, impaired thinking, neuropsychiatric symptoms (eg, hallucinations, delusions), and inability to perform routine tasks of daily living. AD affects about 5.3 million older Americans and kills about 100,000 each year, making it the fourth leading cause of death among adults, and the sixth leading cause overall. The annual cost of AD and other dementias—about $172 billion—is exceeded only by the costs of heart disease and cancer. Major pathologic findings are cerebral atrophy, degeneration of cholinergic neurons, and the presence of neuritic plaques and neurofibrillary tangles—all of which begin to develop years before clinical symptoms appear. This neuronal damage is irreversible, and hence AD cannot be cured. Drugs in current use do little to relieve symptoms or prevent neuronal loss. Furthermore, there is no solid proof that any intervention can delay the onset of AD or cognitive decline.

Neurofibrillary tangles and tau

Like neuritic plaques, neurofibrillary tangles are a prominent feature of AD. These tangles, which form inside of neurons, result when the orderly arrangement of microtubules becomes disrupted (Fig. 22–1). The underlying cause is production of an abnormal form of tau, a protein that, in healthy neurons, forms cross-bridges between microtubules, and thereby keeps their configuration stable. In patients with AD, tau twists into paired helical filaments. As a result, the orderly arrangement of microtubules transforms into neurofibrillary tangles.

Figure 22–1 Histologic changes in Alzheimer’s disease.
A, Healthy neuron. B, Neuron affected by Alzheimer’s disease, showing characteristic intracellular neurofibrillary tangles. Note also extracellular neuritic plaques.

Apolipoprotein E4

Apolipoprotein E (apoE), long known for its role in cholesterol transport, may also contribute to AD. Like some other proteins, apoE has more than one form. In fact, it has three forms, named apoE2, apoE3, and apoE4. (Don’t ask what happened to apoE1.) Only one form—apoE4—is associated with AD. Genetic research has shown that individuals with one or two copies of the gene that codes for apoE4 are at increased risk for AD. In contrast, apoE2 seems protective.

What does apoE4 do? One possibility is that it promotes formation of neuritic plaques. ApoE4 binds quickly and tightly to beta-amyloid, causing this normally soluble substance to become insoluble, which could promote deposition of beta-amyloid in plaque.

It is important to note that apoE4 is neither necessary nor sufficient to cause AD. There are many people with AD who do not have the gene for apoE4. Conversely, in one study involving people who were 90 years old and homozygous for apoE4, 50% had not developed AD.

Endoplasmic reticulum–associated binding protein

The discovery of endoplasmic reticulum–associated binding protein (ERAB) adds another piece to the AD puzzle. Involvement of ERAB in AD is supported by several observations: ERAB is present in high concentration in the brains of patients with AD; ERAB is found in association with beta-amyloid, a compound with neurotoxic effects; high concentrations of ERAB enhance the neurotoxic effects of beta-amyloid; and the neurotoxic effects of beta-amyloid can be blocked by blocking the actions of ERAB.

Homocysteine

Elevated plasma levels of homocysteine are associated with an increased risk of AD. (Homocysteine is an amino acid formed from dietary methionine.) An elevation of 5 mmol/L appears to increase the risk by 40%; an elevation of 14 mmol/L appears to double the risk. How might homocysteine promote AD? One possibility is reduced blood flow secondary to blockage of cerebral blood vessels. Another possibility is direct injury to nerve cells. Fortunately, even if homocysteine really does promote AD, the risk can be easily reduced: Levels of homocysteine can be lowered by eating foods rich in folic acid and vitamins B₆ and B₁₂, or by taking dietary supplements that contain these compounds.

Risk factors, symptoms, biomarkers, and diagnosis

Risk factors

The major known risk factor for AD is advancing age. In 90% of patients, the age of onset is 65 years or older. After age 65, the risk of AD increases exponentially, doubling every 10 years until age 85 to 90, after which the risk of getting AD levels off or declines. The only other known risk factor is a family history of AD. Being female may be a risk factor. However, the higher incidence of AD in women may occur simply because women live longer than men. Other possible risk factors include head injury, low educational level, production of apoE4, high levels of homocysteine, low levels of folic acid, estrogen/progestin therapy, sedentary lifestyle, and nicotine in cigarette smoke.

Alzheimer’s is a disease in which symptoms progress relentlessly from mild to moderate to severe (Table 22–1). Symptoms typically begin after age 65, but may appear in people as young as 40. Early in the disease, patients begin to experience memory loss and confusion. They may be disoriented and get lost in familiar surroundings. Judgment becomes impaired and personality may change. As the disease progresses, patients have increasing difficulty with self-care. Between 70% and 90% eventually develop behavior problems (wandering, pacing, agitation, screaming). Symptoms may intensify in the evening, a phenomenon known as “sundowning.” In the final stages of AD, the patient is unable to recognize close family members or communicate in any way. All sense of identity is lost and the individual is completely dependent on others for survival. The time from onset of symptoms to death may be 20 years or longer, but is usually 4 to 8 years. Although there is no clearly effective therapy for core symptoms, other symptoms (eg, incontinence, depression) can be treated. In addition, resources are available to help families cope with AD and prepare for future caregiving needs.

TABLE 22–1

Symptoms of Alzheimer’s Disease

Mild Symptoms

Confusion and memory loss
Disorientation; getting lost in familiar surroundings
Problems with routine tasks
Changes in personality and judgment

Moderate Symptoms

Difficulty with activities of daily living, such as feeding and bathing
Anxiety, suspiciousness, agitation
Sleep disturbances
Wandering, pacing
Difficulty recognizing family and friends

Severe Symptoms

Loss of speech
Loss of appetite; weight loss
Loss of bladder and bowel control
Total dependence on caregiver

Biomarkers

Biomarkers are biochemical, anatomic, or physiologic parameters—measured in vivo—that reflect a pathophysiologic process. The biomarkers of AD fall into two major groups: (1) biomarkers of beta-amyloid accumulation and (2) biomarkers of neuronal degeneration or injury.

To detect beta-amyloid accumulation, two tests are used most widely:

• Positron emission tomography (PET). The test uses a radiolabeled compound—–usually florbetapir or Pittsburgh Compound B—–that binds with beta-amyloid, and thereby renders beta-amyloid visible in the scan.

• Measurement of beta-amyloid₄₂ in cerebrospinal fluid (CSF). A low level of beta-amyloid₄₂ in CSF indicates a high level of beta-amyloid in the brain.

Because beta-amyloid accumulation begins early in the disease process, measurement of these biomarkers can detect possible disease onset years before symptoms appear.

To detect neuronal degeneration or injury, three principal tests are employed:

• Measurement of tau in CSF. A high level of tau suggests neuronal injury.

• PET scan showing fluorodeoxyglucose uptake. Synaptic dysfunction of AD is suggested by reduced fluorodeoxyglucose uptake at specific sites in the temporoparietal cortex.

• Structural magnetic resonance imaging (sMRI). Neuronal degeneration of AD is indicated by a specific pattern of atrophy involving the medial, basal, and lateral temporal lobes, as well as the medial and lateral parietal cortices.

Unlike the biomarkers for beta-amyloid accumulation, which can be detected very early in the disease process, biomarkers for neuronal degeneration don’t appear until just before symptom onset.

It is important to note that, at this time, biomarkers have only limited clinical utility. Why? Because interpreting test results can be difficult. It is true that, in many cases, test results will be clearly abnormal or clearly normal, and hence can help confirm or exclude a diagnosis of AD. However, in many other cases, results may be ambiguous, and hence will not allow a clear assessment of disease status. Furthermore, since tests for biomarkers are relatively new, universal standards for quantifying these tests have not been developed. Accordingly, although testing for biomarkers can be very helpful in a research setting (see below), testing is much less helpful for routine patient management.

Diagnosis

In 2011, the National Institute on Aging and the Alzheimer’s Association issued revised diagnostic criteria for AD. The new criteria update those issued in 1984 by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA), now the Alzheimer’s Association. Under the revised criteria, AD is divided into an asymptomatic preclinical phase and two symptomatic clinical phases: (1) mild cognitive impairment (MCI) due to AD, and (2) probable dementia due to AD. Diagnosis of the preclinical phase is based solely on biomarkers. For the two clinical phases, diagnosis is routinely based on the clinical evaluation. However, although biomarkers are not required for these diagnoses, biomarkers can be used to compliment the clinical evaluation. The new guidelines are available online at www.alz.org.

Preclinical AD.

The preclinical phase of AD begins years before patients develop any memory loss or problems with thinking. Because there are no symptoms at this stage, diagnosis is based entirely on the presence of biomarkers, indicating beta-amyloid accumulation and/or neuronal degeneration. If the diagnosis is correct, cognitive symptoms will develop long after the evidence for beta-amyloid accumulation was obtained. Similarly, biomarkers for neuronal degeneration should appear long after the biomarkers for beta-amyloid were first evident.

At this time, a diagnosis of preclinical AD is useful only for selecting subjects for research, not for routine patient care. For studies on drug development, application of these criteria will greatly increase the likelihood that subjects actually have AD, even though cognitive impairment is mild or completely absent. Without using biomarkers to diagnose preclinical AD, we couldn’t tell if minimal cognitive impairment was an early sign of AD, some other pathology, or no pathology at all—and hence study results would be difficult to interpret. What about clinical practice? At this time, we have no treatments that can alter the course of AD. Accordingly, even if we could establish a definitive early diagnosis, there’s not much we can do to help. In the future, when we do have drugs that can delay AD onset or slow disease progression, then a definitive early diagnosis will have great benefit, allowing us to implement effective therapy at the earliest possible time.

Probable dementia due to AD.

Diagnostic criteria for all-cause dementia and probable dementia of AD are summarized in Table 22–2. As indicated, dementia of any cause is defined by deficits in two or more cognitive areas—memory, decision making, language, personality, visuospatial function—that are severe enough to interfere with function at work or in usual daily activities. In addition, these deficits must represent a decline from a previous level of functioning, and they must not be due to delirium or a major psychiatric disorder.

TABLE 22–2