Update on Diagnosis and Treatment of Alzheimer Disease

Alzheimer disease (AD) affects between 6% and 8% of Americans older than 65 years. As the population of older adults increases, the number of persons with AD is expected to rise from 4.5 million in 2000 to 13.2 million by 2050.1 This disease is important not only because of the number of patients affected but also because it leads to significant physical and emotional burdens on families and caregivers.

The cause of AD remains unclear, although progress continues to be made in understanding the pathobiology of the disease and its associated risk factors. Current therapies work mainly to delay further loss of function rather than to restore cognitive abilities. Delaying functional loss, however, may postpone the time to placement in nursing homes and reduce the burden on caregivers.

In this article, we summarize the risk factors for and pathophysiology of AD, outline an approach to making the diagnosis, and review pharmacologic therapies.

RISK FACTORS

Genetics Late-onset AD is the most common form of the disorder and accounts for more than 90% of cases.² Although early-onset AD has strong genetic links, many cases of late-onset AD are seen in persons who have no clear genetic predisposition.

A common polymorphism in the apolipoprotein E e (APOE) gene is the major determinant of risk in persons with late-onset AD.² Of the 3 common allelic forms (APOE2, APOE3, and APOE4), APOE4 is associated with a 2- to 4-fold increased risk of AD among persons who have at least one APOE4 allele.^2,3 However, the APOE4 genotype is neither necessary nor sufficient for the development of AD.

Recent estimates from 2 studies suggest that nearly 50% of cases of late-onset AD may be related to these and other unidentified genetic factors.⁴ Epidemiologic research continues to focus on environmental risks that may play a role in the remaining cases. Routine genetic testing for late-onset AD is not currently recommended.

Age This is the strongest risk factor for the development of late-onset AD. At 65 years, the incidence of AD approaches 3% per 1000 person-years; it climbs to 56% in persons older than 90 years.⁵ The greatest increase in incidence occurs among persons in their late 70s to early 80s, with a 3.5-fold rise in the number of cases.⁵ As this age group continues to increase, the prevalence of AD will grow dramatically.

Ethnicity AD affects persons from a wide variety of ethnic backgrounds. Study findings have been inconsistent about whether the incidence of AD varies by ethnicity.^5-9 These discrepancies in the relationship between AD and ethnicity may reflect inadequate sample sizes, lack of control for educational level or other environmental factors, or the use of nonstandardized techniques to make the diagnosis.⁵ Because AD affects all ethnic groups, treatment must be managed in a culturally sensitive manner.

Sex Although AD was once thought to be more common in women, prospective population-based studies have found similar incidence rates in men and women.^5,6,10 Some of the inconsistencies in study findings probably reflect methodologic problems in controlling for age, because women tend to live longer and age is a risk factor for AD. Women may also be more likely to seek or be referred for medical care, which may affect prevalence estimates.²

Vascular risk factors Recently, attention has focused on the association between midlife vascular risk factors and the development of AD in later life. Hypercholesterolemia, hypertension, hyperhomocystinemia, obesity, and elevated levels of inflammatory markers have all been associated with AD.^11-19 Expression of the APOE4 allele is related to abnormal cholesterol metabolism, which suggests that AD risk may be partially mediated through dysregulation of cholesterol. It is unclear whether treating these modifiable vascular risk factors will affect the development or progression of AD, although some epidemiologic and clinical studies support a role for such targeted therapy in preventing or delaying cognitive decline.^20-23

Other proposed risk factors for AD include family history, Down syndrome, low education level, head trauma with loss of consciousness, and cardiovascular disease.²

PATHOPHYSIOLOGY

In postmortem evaluation of the brains of persons with AD, cortical atrophy is most often apparent in the frontotemporal and parietal lobes, but it may also be seen throughout the cerebral cortex.²⁴ Microscopic examination of brains affected by AD shows 2 characteristic lesions identified by Alois Alzheimer in 1906: neuritic plaques and neurofibrillary tangles. The average concentration of these lesions in the cortex and hippocampus is significantly greater in persons with AD than in healthy persons or those with other disorders.²⁴ Neuritic plaques are composed principally of extracellular fibrillar deposits of b-amyloid peptide; neurofibrillary tangles contain the abnormally phosphorylated protein tau.²⁵

These lesions have served as targets for research into therapeutic interventions for AD in an effort to interrupt the pathologic cascade leading to their development. Some investigators, however, question whether these lesions are true "culprit" lesions or by-products of other processes that facilitate disease progression.

DIAGNOSIS

Diagnosing AD involves a determination of whether a patient's memory complaint represents normal aging, mild cognitive impairment (MCI), delirium, depression, or a true dementia such as AD. Although normal cognitive aging, MCI, and AD may be seen as part of a continuum, differentiating among these conditions may help identify which patients will undergo more rapid cognitive decline and, thus, potentially benefit from therapeutic intervention. An approach to patients with memory complaints is outlined in the algorithm (A Diagnostic Approach to AD).

Differential diagnosisNormal aging is associated with a decline in mental processing speed and difficulty in learning new material, but not with changes in day-to-day functioning. Memory loss that leads to a change in functional status is not a feature of normal aging and warrants further evaluation.

About 12% to 15% of persons per year with MCI progress to AD or other forms of dementia.²⁶ Patients with MCI have memory complaints and abnormal memory performance for their age but no functional impairment. Delirium, an acute or subacute onset of cognitive dysfunction, is a fluctuating mental state that can result from a wide variety of medical conditions and medications. In patients with delirium, a careful history taking frequently can tease out the temporal relationship between the onset of potentially reversible cognitive symptoms and medical prob- lems or medications. Depression may cause "pseudodementia" by leading to impaired concentration and attention, thus affecting performance on cognitive testing.

Dementia differs from these conditions in that it is a progressive, irreversible process that causes impairment in 2 or more cognitive domains (such as memory, language, and orientation) that affect social or occupational performance.²⁷ These deficits represent a decline from a previous level of functioning and cannot be attributed to delirium or depression. Once dementia is suspected, it is important to determine which type might be involved, whether it is multifactorial, and whether there is a reversible component to the cognitive loss that can be addressed.

Making the diagnosis of AD This entity is the most common form of dementia in the United States and accounts for 50% to 90% of cases.² Other forms include vascular dementia, dementia with Lewy bodies, and frontotemporal dementia (Table 1). Differentiating AD from other causes of memory loss can help in choosing effective therapies, anticipating behavioral changes and other potential complications, and educating patients and caregivers.

The diagnosis of AD is made clinically; it can be confirmed only on autopsy. The most widely used diagnostic criteria for the disorder are the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria²⁸ and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria.²⁷ In many cases, a clinical diagnosis of AD can be made in a primary care office setting after a careful history taking, a focused physical examination, and the use of appropriate laboratory data and cognitive screening tools (Table 2).

History The history should include collaborative information from the patient, family, caregivers, and friends. An estimate of a patient's baseline level of functioning may be based on educational background as well as on occupational history, including detailed information on the highest-level tasks associated with his or her vocation. For persons who have not worked outside the home, questions about hobbies, household management, and volunteer activities may provide important information about the patient's previous level of functioning. Changes in the patient's ability to perform these tasks should be ascertained, and the degree to which these impairments affect daily functioning should be documented. Questions about changes in instrumental activities of daily living (such as using the telephone, grocery shopping, managing finances, doing laundry, and driving) can help identify areas in which there is functional decline.

It is important to ascertain the period during which the memory symptoms have developed, because AD is characterized by a gradually progressive decline that occurs over years. Frequently, an inciting event that disrupts coping skills--such as a hospitalization or the death of a spouse--draws the attention of family members to a person's memory problems. The family may describe an acute onset of memory impairment that follows the inciting event, but careful questioning frequently elucidates memory problems that predate that time and indicate a gradually progressive course.

Obtain comprehensive information about the patient's safety, including incidents involving car accidents, getting lost, wandering, medication management, kitchen fires, unwitting victimization in financial scams, and hunting or other use of firearms. Include questions on depression, tremors, rigidity, falls, dysphagia, urinary incontinence, symptoms of stroke or transient ischemic attack, waxing and waning level of consciousness, and visual hallucinations.

A history of cardiovascular disease or associated risk factors, coronary artery bypass surgery, head injury, seizures, depression, Parkinson disease, or alcohol abuse may help clarify the underlying cause of memory loss. Obtain a careful substance use and medication history, and ask specific questions regarding use of alcohol and common over-the-counter anticholinergic medications that can increase confusion, such as products containing diphenhydramine.

Physical examination This includes an assessment of general appearance, including level of attention and cooperation, affect, hygiene, and speech pattern. The patient's insight may be evaluated by a few questions that probe his understanding of the effects of memory loss on his daily functioning. Judgment may be assessed by a simple question, such as "What would you do if you found the kitchen engulfed in flames?" An answer such as "I would shout for help" not only suggests impaired judgment but also may increase family members' awareness of the dangers of leaving persons with dementia by themselves.

Comprehension can be tested by using multistep commands. During the neurologic examination, screen for focal deficits that suggest stroke and increased muscle tone, cogwheeling, rigidity, or tremors that might indicate parkinsonism. Cardiac arrhythmias, carotid bruits, or abdominal or femoral bruits suggest a predisposition to vascular disease and may support a diagnosis of vascular dementia.

Cognitive testing can be readily performed in the primary care or clinic setting with use of the Mini-Mental State Examination,²⁹ the clock-drawing test,³⁰ and the animal fluency test.³¹ In adults with high baseline cognitive functioning, however, test results may be normal in the presence of obvious functional impairment; this will necessitate referral to a neuropsychologist for more detailed testing. In persons who are at lower educational levels, these screening tests may suggest impairment but the history may not indicate any changes in functional status. Thus, it is important to use historical information on baseline function to decide whether further neuropsychological testing is warranted or whether abnormal test results may actually represent the person's baseline status.

Screening for depression is a critical part of a memory assessment. Suspected mood disturbances can be evaluated with a screening tool such as the Geriatric Depression Scale.³² Many cognitive and affective screening tools can be easily administered by a nurse, social worker, or medical assistant, which facilitates their use in a busy practice.

Laboratory testing Recommended tests include a complete blood cell count and cholesterol panel, as well as measurement of serum vitamin B₁₂, thyroid-stimulating hormone, electrolyte, liver enzyme, homocysteine, and red blood cell folate levels. If symptoms are atypical or if there are specific risk factors, a serologic test for syphilis may be performed. An HIV test may be considered in those who are at risk for infection. A CT scan of the head without contrast is usually sufficient to rule out other causes of dementia and to determine whether significant cerebrovascular disease, brain tumor, subdural hematoma, or normal pressure hydrocephalus is present. MRI can provide more information if lacunar infarcts leading to vascular dementia are suspected. Functional MRI and positron emission tomography scans are often used in research settings; however, they are not recommended for routine use in clinical practice.

If a patient does not meet the criteria for AD but clinical suspicion remains, more detailed neuropsychological testing or repeated testing in 6 months may clarify the diagnosis as the symptoms progress. Patients with only an isolated memory deficit on cognitive testing and no apparent functional impairment based on history may have MCI. These patients should be reassessed annually. If the symptoms or course of the disease is atypical for AD; if the level of functional decline is out of proportion to neuropsychological testing results; or if there are significant behavioral problems, referral to a geriatrician, neurologist, or psychiatrist with expertise in dementia is appropriate.

MANAGEMENT

Management of AD involves a comprehensive, multidisciplinary team approach that includes presentation of the diagnosis, initiation of medical therapy, assessment and treatment of concomitant depression and/or behavioral problems, development of a social support network, education of patients and caregivers, provision of support for caregivers, and initiation of appropriate safety measures.

Presenting the diagnosis This is a difficult task because presenting the diagnosis may elicit significant emotional responses from the patient and his family and trigger fear of the future. Frequently, patients and their family members suspect the diagnosis before it is presented; how they respond to the news depends on personal coping mechanisms, cultural influences, family dynamics, and their understanding of the disease.

Clinicians may help patients and families adjust to the diagnosis by prefacing the news with comments about the high incidence of memory problems and conditions such as AD in older persons. Emphasize that one of the goals after diagnosing AD is to take steps to protect the patient's memory and delay disease progression. Mention that appropriate safety measures are important to maintain the patient's autonomy and good health, although sometimes that means giving up privileges such as driving or cooking.

It is best to use the term "Alzheimer disease" in presenting the diagnosis to the patient and family,³³ because it provides them with a starting point for education. Encouraging patients and caregivers to use resources such as local support groups and the Alzheimer's Association is an important part of the management plan.

Medical therapy Cholinesterase inhibitors are the mainstay of therapy for mild to moderate AD and, until recently, were the only medications approved in the United States for the treatment of this disorder. These agents increase the levels of acetylcholine in neuronal synapses, thereby enhancing cholinergic activity in the affected brain regions.

Although 18% to 48% of persons may experience improved cognition after taking these medications,³⁴ most patients do not improve noticeably but instead experience a plateau or slowing in their rate of cognitive decline. This lack of noticeable improvement has led to controversy about the benefits of cholinesterase inhibitors.³⁵ However, because of the chronic nature of AD, delaying the progression of cognitive decline may lead to improvements in quality of life, reduce the burden on caregivers, and postpone placement in nursing homes. Studies have shown that discontinuation of cholinesterase inhibitors leads to a sharp increase in the rate of decline to a level similar to that of those not taking medications.³⁴

The approved cholinesterase inhibitors are tacrine, donepezil, rivastigmine, and galantamine. Because of the risk of hepatic toxicity, tacrine is rarely used; the newer medications have a better safety and tolerability profile (Table 3).

The most common adverse effects of cholinesterase inhibitors are nausea, anorexia, and diarrhea. GI effects may be alleviated by taking the medications with food. Sleep disturbances are also common; they may improve after a change in dosing schedule, such as administering the donepezil dose in the morning or the second galantamine or rivastigmine dose in the afternoon.³⁶

Memantine, an uncompetitive N-methyl d-aspartate receptor antagonist, was recently approved for use in moderate to severe AD, either alone or in combination with a cholinesterase inhibitor. At high concentrations, memantine can inhibit mechanisms involved in learning and memory, but at lower concentrations, it preserved or enhanced memory in animal models of AD.³⁷ Memantine may protect against the excitotoxic destruction of cholinergic neurons,³⁷ and it also may inhibit b-amyloid production.³⁸

In a 6-month trial of memantine versus placebo in persons with moderate to severe AD, memantine slowed the progression of cognitive decline.³⁹ Patients who took a combination of memantine and stable doses of donepezil showed modestly better outcomes on measures of cognition, activities of daily living, global outcome, and behavior; the combination was well tolerated.⁴⁰ Further studies are needed before memantine can be recommended for early AD.

Emphasize to patients and families that the primary end point of memantine therapy is to delay the progression of the disease and that the drug may not significantly improve cognition. Families may need to weigh the modest expected benefit against the cost of therapy. Some pharmaceutical companies have patient assistance programs to help ease the financial burden.

Behavioral managementAD is frequently associated with behavioral disturbances such as agitation, emotional or physical outbursts, sleep disorders, and sexual inappropriateness. These signs may be more distressing to families and caregivers than memory decline; also, they may be more challenging for the clinician. Such behaviors may be managed by nonpharmacologic and pharmacologic interventions. Nonpharmacologic therapies should be explored and exhausted before phar- macotherapy is initiated, unless the patient's agitation threatens his safety or living situation. For example, a woman with advanced AD who no longer recognizes her husband may become agitated when he assists her with bathing. Her agitation may be relieved by having a female caregiver help her with personal grooming.

Be sure that pain or other medical symptoms, as well as medication side effects that might be contributing to behavioral symptoms, are addressed before pharmacologic intervention is undertaken. Identifying and correcting physical or emotional stressors may alleviate agitation. Symptoms of wandering typically do not respond to pharmacologic therapy. Taking patients for a walk or giving them specific tasks may help reduce the incidence of wandering.

After nonpharmacologic measures have been tried, low-dose atypical antipsychotic medications, such as quetiapine, risperidone, olanzapine, and aripiprazole, should be considered; how- ever, these agents are all associated with potentially significant side effects. Selective serotonin reuptake inhibitors may reduce sexually inappropriate behaviors and concomitant depression or agitation. Referral to a multidisciplinary memory disorders clinic and a geriatric psychiatrist is appropriate for patients with significant behavioral problems.

Safety management A review of common safety concerns may help identify significant risks and provide an opportunity to educate family members and caregivers about which areas to monitor closely and what safety measures to take. Some patients may require further evaluation to assess driving safety; this can be done through occupational or physical therapy departments or local driving schools. Pillboxes or other medication planners may facilitate correct administration of medications. Other safety concerns, such as proper use of the stove, woodworking equipment, and firearms, should be discussed, and appropriate supervision arranged. In patients with concomitant depression, a careful assessment of suicide risk is warranted.

PREVENTION

Although identification of potentially modifiable risk factors--such as hypertension and elevated levels of serum cholesterol and plasma homocysteine--has raised interest in the treatment of these conditions in the hope of preventing AD, clinical trial evidence to support this role is lacking. However, given the numerous trials that support the beneficial cardiovascular effects of exercise; healthful weight maintenance; and treatment of hyperlipidemia, diabetes, and hypertension, such measures may be recommended for the prevention of cardiovascular events so that one day, they may prove to offer cognitive protection as well. *

A previous version of this article was published in the January 2005 issue of Consultant. It has been revised for Applied Neurology.

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Cynthia M. Carlsson, MD, is assistant professor of geriatrics and gerontology at the University of Wisconsin Medical School and Veterans Affairs-Geriatrics Research, Education, and Clinical Center in Madison.

Carey E. Gleason, PhD, is a neuropsychologist and assistant scientist in the section of geriatrics and gerontology at the same institution.

Sanjay Asthana, MD, is associate professor of medicine and head of the University of Wisconsin Medical School Section of Geriatrics and Gerontology, director of the Madison Veterans Affairs-Geriatrics Research, Education, and Clinical Center, and associate director of the Wisconsin Alzheimer's Institute, also in Madison.