Alzheimer's Disease: Maximizing Cognition and Function

Background

As adults age, mild changes in memory and rate of information processing may occur. Dementia, an irreversible, progressive decline leading to impaired daily functioning is not a normal part of the aging process, however. Alzheimer’s disease (AD) is the most common type, accounting for 60% of all dementias^.1

The various types of dementias differ in their pathophysiology and presentation (Table 1). The morbidity associated with AD poses a significant burden not only on the individuals affected, but also on caregivers and society at large.2 AD is the sixth leading cause of death, and the estimated cost of care is approximately $200 billion per year.¹

Pathophysiology and Risk Factors

AD pathology is characterized by abnormal deposits of amyloid plaques and neurofibrillary tangles. Age is the greatest risk factor, and although only 1 in 8 adults 65 years and older is diagnosed, this number increases to almost half of adults 85 years and older.¹ There is a strong genetic association and several markers have been identified. Vascular and metabolic diseases, including heart disease, stroke, hypertension, and diabetes, are also recognized risk factors.^1-3 Women, Hispanics, and African Americans are at higher risk.¹ Statins have been recently implicated for causing cognitive impairment; however, literature has shown that this rarely occurs and is not the same as AD.⁴

Clinical Presentation, Assessment, and Diagnosis

Patients present initially with memory complaints, but impairment in language, judgment, and visual-spatial skills, as well as behavior disturbances, can also be seen. As the disease progresses, the impairment worsens. Patients first lose the ability to perform complex executive functions such as managing bills and cooking. More severe stages are associated with an inability to complete simple activities independently, including eating, dressing, and toileting. Up to half of patients will have neuropsychiatric symptoms, such as depression and apathy. Delusions and hallucinations are present in approximately 20% of patients, and the agitation/aggression expressed by about 80% of patients is the leading cause of nursing home admission.³

There are several tools to assess cognitive and functional status. The most commonly used in clinical practice include the Mini Mental State Exam, Montreal Cognitive Assessment, Mini-Cog, Functional Assessment Staging Scale, Clock Draw, Trails B, and word naming.^3,5,6

Medical causes of cognitive decline, such as lab abnormalities (complete blood count, thyroid-stimulating hormone, B12, folate, chemistries), infectious diseases, uncontrolled pain, and use of illicit drugs should be assessed. Genetic testing is not currently recommended.^3,5,6

Definitive diagnosis can only be made at autopsy. Diagnosis is often made from clinical symptoms, caregiver input, and use of assessment tools. The score from each tool is used to categorize the patient as having either mild cognitive impairment or mild, moderate, or severe dementia.^3,5,6

Treatment

There are no treatments that slow or stop the progression of AD. Primary treatment goals are to maximize retention of cognition and function. The plan should include optimizing management of other comorbidities, avoiding medications that impair cognitive function, and encouraging a healthy lifestyle. Nonpharmacologic interventions include behavior redirecting, scheduled activities, and positive reinforcements.^3,5,6

Current FDA-approved medications for AD are cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine, and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine (Table 2). These agents target the cholinergic and glutamateric neurotransmission abnormalities associated with AD. In addition to cognition, medications have been shown to improve function and behavior and delay nursing home admission.⁷

ChEIs increase acetylcholine levels by preventing degradation in the synapse and are indicated for mild to severe AD. The most common side effects are nausea, vomiting, weight loss, diarrhea, vivid dreams, and muscle cramps, and are often transient. Bradycardia and syncope can also occur. The efficacy of ChEIs is similar and product selection should be based on adverse effects, dosing convenience, cost, and clinical experience. Rivastigmine is associated with higher gastrointestinal (GI) side effects, but can be reduced by using the patch formulation. ⁸ Donepezil is associated with the fewest GI side effects, but may cause more vivid dreams. High-dose donepezil (23 mg) is not routinely used in practice as its benefit in cognition is not clinically superior to standard dose, but does increase risk for GI side effects.⁹

NMDA receptor antagonists are thought to be neuroprotective by preventing excessive glutamate activation of NMDA receptors. Memantine is approved for moderate to severe AD as monotherapy or in combination with a ChEI. Common side effects include dizziness, headache, confusion, and constipation, and are usually transient.^10,11

The decision to start treatment should be made after extensive education of the progressive nature of the disease, limitations of treatment, and perceived risk versus benefit. The agents provide only clinically marginal improvements, and patient response can vary greatly. A majority may see little to no benefit while a small group may see dramatic differences.¹² There are no clear guidelines on when to stop these agents. Therefore, it is important to discuss with patients and caregivers about their desired therapeutic goals to help determine when to discontinue therapy. The decision to stop treatment should be made if the patient is experiencing intolerable adverse effects or experiences a rapid decline in disease despite therapy.¹³

Caregiver Support

Demands of caring for a patient with AD can be draining on caregivers. More than 50% will develop depression, and burnout is very common.

¹³

Caregiver respite is important. Adult day care for patients, respite services, and other support services are available.

³

Prevention

Many nutritional supplements, herbal preparations, and other medications have been studied to prevent AD, but none have proved to be effective.¹⁴ In a randomized control trial, vitamin E and selegiline, either as monotherapy or in combination, for moderate disease showed a difference only after adjustment of the statistics,¹⁵ and the conclusion of a meta-analysis suggested no justification for the use of selegiline in AD.¹⁶ A meta-analysis of estrogen showed that there may be a benefit with use in symptomatic postmenopausal women, but not asymptomatic women¹⁷; the risk of hormone replacement, however, outweighs the potential benefit.

Epidemiologic studies have suggested a decreased risk with nonsteroidal antiinflammatory drug use, but clinical trials have failed to show benefits.¹⁸ The evidence for ginkgo biloba is inconsistent, and a meta-analysis concluded the data were unconvincing.¹⁹ In addition, supplementation with B vitamins or omega- 3 fatty acids provides no advantage.^20,21

Future Agents

Several companies are investigating monoclonal antibodies to attack amyloid plaques. A study of bapineuzumab was recently stopped due to failure to demonstrate efficacy, but research on solenazumab and crenezumab is still in progress.^22,23 Resveratrol, a natural substance found in the skin of fruits, has demonstrated mixed results for improving cognition. Resveratrol’s mechanism of action is unknown, but it is thought to inhibit amyloid production or provide protection from toxins. Several studies are ongoing, including the Resveratrol in Alzheimer’s Disease study.²⁴ Another promising new agent for treatment of AD may be insulin nasal spray, and the clinical trial registry lists several ongoing studies evaluating its benefit.²⁵

Conclusion

AD has a significant clinical and financial impact for patients, caregivers, and society. The decision to initiate treatment should be made with specific patient and caregiver goals. Initial treatment includes use of a ChEI for mild to severe disease. For moderate to severe disease, memantine can be used alone or in combination with a ChEI. Several potential treatment options are currently being investigated in clinical trials.

Rachel L. Basinger, PharmD, BCPS, CPP, is a geriatric specialty pharmacy resident at the UNC Hospitals and Clinics in Chapel Hill, North Carolina.

References:

• Alzheimer’s Association. 2012 Alzheimer’s disease facts and figures. Alzheimers Dement. 2012;8:131-168.
• US Department of Health and Human Services, National Institutes of Health, National Institute of Aging, Alzheimer’s Disease Education and Referral Center. Alzheimer’s disease fact sheet (NIH Publication No. 11-6423). www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet. Published 2011. Accessed January 2013.
• Reuben D, Herr K, Pacala J, et al. Geriatrics at your fingertips. 13th ed. New York, NY: American Geriatrics Society; 2012.
• Rojas-Fernandez C, Cameron J. Is statin-associated cognitive impairment clinically relevant? a narrative review and clinical recommendations. Ann Pharmacother. 2012;46(4):549-557.
• American Geriatrics Society. A guide to dementia diagnosis and treatment. http://dementia.americangeriatrics.org/. New York, NY: American Geriatrics Society. Accessed January 2013.
• Qaseem A, Snow V, Cross T, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-378.
• Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148:379.
• Lanctôt K, Herrmann N, Yau K, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ. 2003;169:557.
• Farlow M, Salloway S, Tariot P, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard dose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: a 24 week, randomized, double-blind study. Clin Ther. 2010;32(7):1234-1251.
• McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006; CD003154.
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• Herrmann N, Li A, Lanctot K. Memantine in dementia: a review of the current evidence. Expert Opin Pharmacother. 2011;12(5):787-800.
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• Daviglus M, Bell C, Berrettini W, et al. NIH State-of-the-Science Conference Statement: preventing Alzheimer’s disease and cognitive decline. NIH Consens State Sci Statements. 2010;27(4).
• Sano M, Ernesto C, Thomas R, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. N Engl J Med. 1997;336:1216.
• Birks J, Flicker L. Selegiline for Alzheimer’s disease. Cochrane Database Syst Rev. 2000; CD000442.
• LeBlanc E, Janowsky J, Chan B, et al. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA. 2001;285:1489.
• Jaturapatporn D, Isaac M, McCleery J, et al. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev. 2012; 2:CD006378.
• Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2007; CD003120.
• Aisen P, Schneider L, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300:1774.
• Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63:1402.
• Johnson & Johnson announces discontinuation of phase 3 development of bapineuzumab intravenous (IV) in mild-to-moderate Alzheimer’s disease [press release]. www.jnj.com/connect/news/all/johnson-and-johnson-announces-discontinuation-of-phase-3-development-of-bapineuzumab-intravenous-iv-in-mild-to-moderate-alzheimers-disease. Johnson & Johnson; August 6, 2012. Accessed August 23, 2012.
• Aisen P, Vellas B. Editorial: passive immunotherapy for Alzheimer’s disease: what have we learned, and where are we headed? J Nutr Health Aging. 2013;17(1):49-50.
• Alzheimer’s Disease Cooperative Study: Resveratrol in Alzheimer’s Disease study. www.adcs.org/studies/RES.aspx. Accessed January 2013.
• Craft S, Baker L, Montine T. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29-38.