Alzheimers Disease

Key Points

• Alzheimer's disease is the most common type of dementia and the fifth leading cause of death for Americans over age 65.

• Alzheimer's disease is classified as late-onset AD (much more common) and early-onset AD (less common but stronger genetic basis).

• Age is the strongest risk factor for AD.

• Course of AD is one of slow but relentless progression.

• Life expectancy from diagnosis is 4 to 6 years, although some patients live much longer. Clinical indicators of short life expectancy include eating problems and nonremediable weight loss, repeated bouts of pneumonia, and frequent febrile episodes.

• Family medicine's commitment to continuity, a biopsychosocial approach, and recognition of the family as a unit of care allow the family physician to be particularly effective when helping caregivers.

Alzheimer's disease is the most common type of dementia. The exact cause or causes of AD are unknown, but age is the most important risk factor. Given the increasing life expectancy in the United States (and worldwide), and that

Box 48-6 Diagnostic Considerations for Evaluating Patient with Suspected Dementia

D—Drugs and toxins (alcohol, neuroleptics, hypnotics, anticonvulsants, analgesics, many others)

E—Environmental deprivation (poor vision and hearing, lack of assistive devices); electrolyte disorders (sodium, calcium, magnesium) M—Metabolic and endocrine disorders (hypothyroidism, hyperammonemia); movement disorders (dementia with Lewy bodies, Parkinson's disease)

E—Emotional disorders (depression, delirium) N—Nutritional deficiencies (vitamin B12, thiamine, niacin) T—Tumors and trauma (subdural hematoma, normal-pressure hydro-cephalus, brain tumors)

I—Infections (human immunodeficiency virus, syphilis, CreutzfeldtJakob disease)

A—Alzheimer's disease, vascular dementia

"baby boomers" (those born between1946 and 1966) have begun turning 65, family physicians can expect more and more patients and families seeking treatment for AD. Currently, about 5.3 million Americans have AD. Unless new discoveries facilitate prevention, delay the onset, or slow the progression of AD, it is estimated there will be 11 to 16 million persons with AD in 2050.

Most cases of AD develop in people older than 60 years. Genetics appears to have little influence in late-onset AD, although there is great research interest in the apo E E4 allele, located on chromosome 19. Patients not expressing the apo E E4 allele have the least risk for AD, heterozygous patients are at intermediate risk, and homozygous patients are at greatest risk. Apolipoprotein E is involved in lipid transport. It is a risk factor for AD, as well as LBD and VaD. The clinical relevance of this observation is unclear.

Early-onset AD patients often have changes in chromosomes 21, 14, or 1. Persons with Down syndrome (trisomy 21) often develop the symptoms and histologic findings of AD in their 40s and 50s. Other risk factors for AD include head injury with loss of consciousness and lower educational level. Various risk factors for atherosclerosis (diabetes, hypertension) have also been shown to increase the risk of AD, as well as VaD.

Histopathologic markers of AD include extracellular senile plaques (aggregations of abnormal amyloid protein), intraneuronal neurofibrillary tangles (hyperphosphorylated tau protein), and brain cell death. Neurofibrillary tangles are preferentially distributed in the medial temporal lobe, hippocampus, and amygdala, whereas senile plaques are widely scattered throughout the cerebral cortex (Clark and Karlawish, 2003). The AD patient's brain displays shrinking gyri, widening of the sulci (particularly in the frontotemporal region), and enlargement of the ventricular system in proportion to the atrophy of the cortex. Caution should be taken in using these features exclusively for the diagnosis because normal aging occurs in much the same manner, although with more diffuse atrophy and slower progression if serial studies are performed. Decreases in hippocampal volume correlate well with deteriorating clinical status (Jack et al., 2000).

Many neurotransmitters, including norepinephrine, serotonin, somatostatin, and various neuropeptides, show alterations in AD patients. The most prominent neurochemical defect appears to be a deficiency in the enzyme choline O-acetyltransferase, resulting in a deficit of acetylcholine. This is most evident in the nucleus basalis of Meynert and the hippocampus. In the absence of cholinergic stimulation from these lower centers of the brain, there is secondary atrophy in the cerebral cortex, leading to memory problems and other deficits in cognitive function. Neurochemical alterations probably contribute to the associated psychiatric symptoms of AD (depression, anxiety, agitation, psychosis). Early in the course of AD, impaired memory is the predominant finding. Changes in mood and personality can also be seen. Later, memory impairment becomes more dramatic, and word-finding difficulty (anomia) appears. These changes can be subtle, and family, co-workers, and physicians might unconsciously adapt to the person's impairment. This is helpful to the patient, but it contributes to delay in diagnosing AD. Eventually, functional performance is affected, with deterioration in skills of driving, handling finances, meal planning, and hygiene. There is further deterioration in language with disordered syntax. Executive functions, manifesting with impaired judgment, sequencing, and problem solving, become more problematic. Memory loss becomes profound, with loss of recognition of previously familiar persons or things, as illustrated in Figure 48-2.

Influenced somewhat by premorbid personality, psychiatric syndromes can develop at any point in the course of the illness. Paranoia, agitation, frustration, irritability, anxiety or restlessness, socially inappropriate behavior, delusions, and hallucinations are all common. Food preferences may change. In later stages, apraxia and probable decrease in the pleasurable, endorphin-mediated response to eating lead to a decrease in nutritional intake without suffering. Finally, near-coma deteriorates to coma. Seizures and myoclonic jerks are often observed in AD and other dementias (Scar-meas et al., 2009). Life expectancy of AD patients is generally 4 to 6 years after diagnosis (Larson et al., 2004), although some patients live for 10 years and longer. Box 48-7 summarizes diagnostic criteria for dementia and AD.

Pharmacotherapy

Early recognition of AD offers the greatest opportunity for modification of the course of the illness. Pharmacotherapy should be considered only as part of a comprehensive treatment plan that addresses comorbid medical and psychiatric conditions, behavioral management, social interventions, and support and education of caregivers. Goals of pharmacotherapy include improving memory and cognition (or at least slowing cognitive decline), alleviating behavioral disturbances, decreasing caregiver burden, and delaying need for institutionalization.

Two classes of pharmacotherapeutic agents have recognized indications for the treatment of AD, comprising four cholinesterase inhibitors and one N-methyl-D- aspartate (NMDA) receptor agonist. The first cholinesterase inhibitor developed, tacrine, has little current use because of inconvenient dosing and need for laboratory monitoring for liver toxicity. The other three, donepezil, galantamine, and riv-astigmine, have shown consistent, modest beneficial effects in the domains of cognition and global assessment. Diarrhea, nausea, and vomiting, consistent with expected effects of cholinesterase inhibitors, were the most common side effects. Memantine, the NMDA receptor agonist, improves cognition and global assessment, but effect sizes were small. Other studies suggest improvement in quality of life. Common side effects include nausea, diarrhea, dizziness, and headache (Raina et al., 2008). No clinically important differences among the drugs have been demonstrated. Alternative delivery systems (rapidly dissolving tablets, liquid formulations, transdermal patches) are available.

Based on an exhaustive and comprehensive reviewed of these five FDA-approved dementia treatments, the Joint American College of Physicians/American Academy of Family Physicians Panel on dementia concluded that a decision to start therapy should be based on individual assessment, noting that all the drugs are associated with known adverse events and have shown only modest or even, in some studies, no benefit. The panel also stated treatment with meman-tine or a cholinesterase inhibitor is not appropriate when the goals of care no longer include slowing decline, a circumstance frequently seen when AD is advanced (Qaseem et al., 2008).

Dear son Dennis,

I am proud that ^ou have vfour Doctorate. I am Kind of Lost mother. I am at good Samaritan Luther Manor and want to call a Ta*i to 90 home. I need >{ou. Your mother is confused. I Know too man>( people with the same name. I am hoping to be home ty 3pm tonight. I placed the organ tonight and we had fun.

Love,

Figure 48-2 A note, transcribed by a nursing home volunteer, from an Alzheimer's disease patient to her son.

Box 48-7 Diagnostic Criteria for Dementia and Probable Alzheimer's Disease

KEY TREATMENT

Dementia

Loss of memory, documented by MMSE or similar testing and

Evidence of at least one additional impairment including: Aphasia Apraxia Agnosia

Impairment of executive function and

Resulting impairment sufficient to interfere with usual social or occupational functioning

Probable Alzheimer's Disease

Typical history, including: Insidious onset Gradual progression Documented cognitive loss

Absence, documented by physical exam, laboratory testing, and neu-roimaging of other diseases that could cause dementia.

Based on DSM-IV-TR and National Institute of Neurologic and Communicative Disorders and Stroke, Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

MMSE, Mini-Mental State Examination.

Three cholinesterase inhibitors and one NMDA agonist are available for the treatment of AD (Raina et al., 2008). Comprehensive literature review shows modest efficacy and predictable non-life-threatening side effects (SOR: B).

Prevention

The absence of clearly effective active treatments has created considerable interest in efforts to prevent AD and other dementias. Numerous vitamins, nutraceuticals, and pharmacologic agents have been examined for use as preventive agents for AD-related memory loss. A double-blind placebo-controlled study of vitamin E and donepezil for the treatment of MCI was unable to demonstrate a benefit from vitamin E and showed only modest and short-term benefit from donepezil (Petersen et al., 2005). No medication, nutraceutical, or vitamin has been shown to prevent AD.

Ginkgo biloba is probably the best studied of the nutra-ceuticals promoted for the prevention of dementia. Initially encouraging studies have not been supported by subsequent RCTs. A National Institutes of Health (NIH)-funded study involving more than 3000 volunteers age 75 and older concluded that Ginkgo biloba "was not effective in reducing the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI" (DeKosky et al., 2008; Snitz et al., 2009).

Enthusiasm for a preventive role for estrogen and non-steroidal anti-inflammatory drugs (NSAIDs), based on epidemiologic correlations, have not been supported by follow-up studies. Neither is recommended.

A number of cohort studies suggest that educational and occupational attainment, cognitively stimulating activities such as reading, playing cards or board games, going to museums, playing musical instruments, and dancing are associated with reduced risk of developing AD. Controlled trials have not been done (and will be difficult or impossible to perform) to confirm these associations (Verghese et al., 2002; Wilson et al., 2002). Given the benign nature of the proposed interventions, it would seem prudent to encourage such activities when patients or family members raise questions about prevention.

Given the increasing awareness of the contribution of cerebrovascular pathology to disease burden of all types of dementia, aggressive management of hypertension and diabetes, as well as the management of vascular risk factors through diet, exercise, and preventive pharmacologic agents, is having the added benefit of lowering the risk of dementia (Middleton and Yaffe, 2009).

KEY TREATMENT

Cognitive, physical, and social activity; a diet rich in antioxidants and polyunsaturated fatty acids; and vascular risk factor control (particularly hypertension treatment) may have a role in the prevention of AD dementia (Middleton and Yaffe, 2009; Verghese et al., 2002; Wilson et al., 2002) (SOR: B).

Caregiver Education and Support

Family physicians are often in a particularly powerful position to address caregiver issues. In some cases the family physician is the doctor for both the dementia patient and the caregiver. Family medicine's commitment to continuity and a comprehensive biopsychosocial approach provides a useful framework for understanding and addressing the stresses that affect family members. A meta-analysis of psychosocial interventions for caregivers showed decreased levels of caregiver stress, improved knowledge, and improved patient mood, but no effect on caregiver burden. Involving both the caregiver and the patient in the intervention increased the benefit. At least four studies indicate that caregiver interventions delay nursing home admission (Brodaty et al., 2003).

Knowledge of and referral to community resources is critical to managing caregiver stress and preserving patient quality of life. Adult day care, respite care, medical and non-medical home care, and hospice programs all play a role in the care of the AD patient and family. Particularly helpful are the Alzheimer's Association and the National Institute of Aging's Alzheimer's Disease Education and Referral (ADEAR) Center. Bibliotherapy references include The 36-Hour Day (Mace et al., 2006) and Alzheimer's Disease: the Family Journey (Caron et al., 2000).

End-of-Life Care

Alzheimer's disease is a terminal illness. It is currently the fifth leading cause of death for persons age 65 and older (Heron et al., 2009). AD progresses slowly, making it difficult to recognize when a patient goes from the advanced to terminal phase of the illness. This in turn makes it difficult to determine when to initiate discussions with family about shifting to an exclusively palliative care approach and possible involvement of hospice. Potential clinical indicators for the shift include progressive nonremedi-able weight loss (White et al., 1998), eating problems, repeated episodes of pneumonia, and frequent febrile episodes (Mitchell et al., 2009). The Center for Medicare and Medicaid Services (CMS) has published guidelines to assist in the determination of terminal status in patients with dementia (Box 48-8). Once the terminal stage is recognized by the physician and acknowledged by the family and other caregivers, an appropriate end-of-life care plan can be instituted.

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