Alzheimer's disease (AD), the most common cause of dementia, increases in prevalence exponentially with age, and the trend of growing incidence of the disease is likely to continue in the United States. Alzheimer's dementia is a common, acquired disorder that is manifested as slowly progressive memory loss with at least 1 cognitive dysfunction (ie, aphasia, apraxia, agnosia, or executive dysfunction) and resulting in impaired occupational and social performance. The deterioration in cognition from earlier levels must occur in the absence of delirium or other causes of dementia (eg, Parkinson's disease or vascular dementia).1,2
The National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association classifies AD as3,4:
- Definite—clinical diagnosis and histology confirmed
- Probable—clinical syndrome, no histology
- Possible—atypical presentation, no alternative diagnosis or histologic proof.
It is important to distinguish AD, which refers to the pathologic changes in the brain, from Alzheimer's dementia, which refers to the clinical manifestations. AD is more common than Alzheimer's with dementia; not everyone with AD, even AD that is proved at autopsy, necessarily manifests the clinical features of dementia.
There are currently more than 5 million Americans with AD, and the prevalence increases with age. The prevalence of AD is 4% among people younger than 65 years, which increases to more than 13% in the older than 65-year age-group, and up to 50% in the older than 85-year age-group.5 But these US trends are not universal. In Japan, vascular dementia is more common than Alzheimer's dementia.6 The US Alzheimer's Association predicts a surge in the incidence of AD in the baby boom era (Figure 1). AD is the fifth leading cause of death in people older than 65 years in the United States.7
Economic Burden of AD
With annual costs exceeding $100 billion, dementia in AD is the third most costly illness in the United States, following heart disease and cancer.8 The annual cost of caring for AD varies from $42,049 for institutionalized patients to $12,572 for patients living in the community.9
However, the tremendous mental and physical burden costs on the caregiver are hard to delineate. Delay in disease progression through early diagnosis and early initiation of therapy may cut costs. Direct costs are incurred for long-term care in nursing homes or by physicians; indirect costs include lost productivity of caregivers.10
Because a major AD epidemic is being forecast, health plans and the healthcare system must be prepared to fund the care of the many potential patients. Initiating early interventions in community-living patients with AD often is associated with lower overall costs compared with costs for institutional placement.10 Table 1 outlines the economic impact of AD and dementia on the healthcare system.11
Neuropathology
The core of AD pathology involves formation of amyloid neuritic plaques and neurofibrillary tangles (NFTs). Beta-amyloid (Aß) 42 is derived from proteolysis of amyloid precursor protein, which undergoes polymerization to form abnormal, insoluble, sticky amyloid plaques, resulting in inflammation and loss of neurons in areas of the brain involving memory and cognition (Figure 2). Hyperphosphorylation of tau protein leads to formation of insoluble intraneuronal NFTs and to neuronal destruction. Senile plaques and NFTs are markers of AD. In patients with AD, senile plaques are seen throughout the neocortex, whereas NFTs are seen in the amygdala, hippocampus, thalamus, association areas, and the cortical region. Although amyloid plaques and NFTs occur with normal aging, it is the distribution, density, and neuronal loss in the association areas and the cerebral cortex that characterize Alzheimer's dementia. Because these plaques and tangles are insoluble, future therapy should focus on prevention strategies.
Risk Factors
Of the different risk factors that have been linked to AD and dementia, aging is the most important factor. Data are inconsistent for most of the other risk factors, which include genetic factors, white race, female sex, low education level, poor physical status, a history of head trauma, depression or postoperative delirium, family history of dementia, elevated C-reactive protein, and lower household income.
Predisposition to dementia in general is linked to low thyroid-stimulating hormone, hypertension, folic acid or vitamin B12 deficiency, elevated homocysteine levels, hyperlipidemia, smoking, diabetes mellitus and metabolic syndrome, and cerebrovascular disease.
Although no single risk factor is known to cause Alzheimer's dementia, it is tempting to speculate an interplay between aging and genetics, modified by environmental factors. The link between AD and genes is evident in early- and late-onset AD, but no single genetic etiology is known to cause AD. The neuropathology of AD mimics Down syndrome; patients with Down syndrome who live to age 40 manifest neuropathology identical to Alzheimer's dementia. In early-onset familial AD, genes PS1, APP, and PS2 are linked to chromosomes 1, 14, and 21; late-onset AD is linked to the APOE gene and to chromosome 19. The €4 allele of the APOE gene is implicated in increased risk of late-onset AD, whereas €2 allele appears protective, and €3 allele is neutral.
Clinical Features of Dementia in AD
The onset of dementia in AD is insidious, with a progressive decline in functioning level. Possibly the earliest stage is mild cognitive impairment (MCI), which is evident without impairment in social or occupational functioning. Cognitive impairment without dementia is more prevalent than dementia; the Aging, Demographics and Memory Study found that 22% of adults older than 71 years in the United States had cognitive impairment without dementia; 8% died and 11.7% advanced to dementia annually.12 The conversion rate is 1% to 2% annually.13 MCI is common and is considered a precursor to dementia, but not necessarily Alzheimer's dementia. A diagnosis at this early stage helps delay onset of dementia and nursing home placement.
The 3-stage classification categorizes Alzheimer's dementia into mild, moderate, and severe stages.14 A diagnosis is often missed by the first physician consulted, and "normal aging" is a common misdiagnosis.10
In mild dementia, patients have memory loss for recent events and are unable to learn new facts; welleducated patients may mask their difficulties. Subtle personality changes are evident. Behavioral and motor changes are not evident, and patients are independent for activities of daily living (ADLs).
In moderate dementia, worsening of recent, remote, and recall memory is more readily apparent, along with significant cognitive impairment and personality changes. Behavioral changes include agitation, aggressive behavior, anxiety and depression, with partial dependence for ADLs.
With severe or advanced Alzheimer's dementia, memory, language, and cognition are markedly impaired, requiring complete caregiver dependence. The patient is incontinent, unable to feed or swallow, resulting in poor nutrition, and speech deteriorates to a few words and can include echolalia and palilalia. Patients are lost in familiar environments; wandering, falls, and accidents are common. At this stage, nursing home placement and means for nutrition are at stake.
Cognitive Assessment
The Mini-Mental State Examination (MMSE) is a common screening instrument used to evaluate cognition, and is administered in less than 10 minutes. A score higher than 24 does not rule out dementia nor does a score below 24 confirm dementia; age and educational status influence the score. MMSE scores deteriorate at a rate of about 4 points annually in Alzheimer's dementia.
The Clock Drawing Test (CDT) is easily administered. The Mini-Cog test is a composite of the CDT combined with a "3-item recall"; its strengths are brevity and ease of administration. The Mini-Cog test takes no more than 5 minutes and appears more valid in better-educated individuals. The Functional Assessment Staging and Global Deterioration Scale help evaluate functional deterioration and dependency for assistance.
Evaluation
Most important in the evaluation of dementia in AD is the initial focused history (and physical examination), with the history obtained separately from the patient and from a family member or caregiver who truly knows the patient.
A diagnosis of Alzheimer's dementia can be made by the primary physician and is considered a diagnosis of inclusion rather than of exclusion.
Drug-Induced Memory Loss
Several medications can lead to memory impairment; a detailed review of over-the-counter drugs and supplements is indicated, especially products with anticholinergic activity that are known to worsen cognition. Decline in cognition results from the drugs blocking muscarinic receptors; the resulting worsening of working memory, speed of processing, and praxis predict overall performance and cognitive status, as well as its impairment.15
A recent study of 107 medications revealed moderate-to-severe anticholinergic activity with many frequently used medications (oxybutinin, tolterodine, diphenhydramine, amitriptyline, thioridazine, among others) warranting caution with their use in dementia.15 These drug-induced anticholinergic effects can cause cognitive deficits that resemble dementia and have the potential to worsen memory in those with MCI.
Diagnosis
A patient with dementia should be offered neuroimaging at least once, to exclude treatable causes; a computed tomography scan or magnetic resonance imaging will demonstrate common structural alterations in the brain. No specific pattern in imaging is diagnostic of Alzheimer's dementia. Brain atrophy in neuroimaging is common in older adults; although seen in AD, atrophy by itself is not diagnostic of cognitive impairment. Lately, there is increasing awareness of the role of positron emission tomography (PET) imaging in early diagnosis of Alzheimer's dementia through measurement of decreased localized glucose metabolism correlating with loss of cognition. PET scans have the potential to help make the diagnosis before advanced clinical manifestations develop, with reasonable sensitivity (84%-93%) and specificity (93%) even in the stage of MCI.16 The scan also helps distinguish Alzheimer's dementia from other dementias.10
Although no single laboratory test is diagnostic of AD or dementia, routine and some individualized tests can be used to delineate any treatable cause. Genetic testing for AD is not routinely offered at this time.17
Finally, the differential diagnosis of Alzheimer's dementia includes other causes of dementia, including vascular dementia, Lewy body dementia, frontotemporal dementia, dementia of Parkinson's disease, normal pressure hydrocephalus, and reversible causes, such as hypothyroidism and B12 deficiency, among others. Delirium, a short-term disorder that causes alteration in level of mentation and difficulties in sustaining attention, as well as depression, can mimic or complicate dementia; these are reversible and their treatments differ from that of Alzheimer's dementia.
Management
Early diagnosis of Alzheimer's dementia helps plan the future, and initiation of therapy with cholinesterase inhibitors (ChEIs) to maximize benefit in preserving functional status. Besides cognition, many aspects of AD demand attention.18
Behavioral manifestations of dementia are foremost in AD, demanding caregiver attention and difficulties in management of wide-ranging moods; in one study, apathy, agitation, aggressive behavior, and depression were most common, whereas hallucinations and delusions, anxiety, and wandering were less common.19 Sudden alterations in behavior warrant a search for causes that precipitate delirium, such as infection, pain, electrolyte imbalance, or medication-related adverse effects. Approaches to treatment include empathy, tact, ensuring safe environments, and pharmacotherapy. Therapeutic touch (namely, a meditative, compassionate hand touch to help or heal) can help minimize agitation.20
Visual and hearing impairments are common with aging and contribute to even greater handicaps in Alzheimer's dementia. Because they may be a cause of behavioral changes, glasses and hearing aids should be available at all times.
Several simple measures can be instituted to provide a safe environment in the home, hospital, or institution. Measures for environment safety minimize falls. These include appropriate carpeting (avoid scatter rugs); avoidance of slippery floors (in bathrooms) and clutter; use of cordless phones, handrails, and proper lighting; and so on.
Difficult decisions may lead to frustration and agitation.21 When patients are agitated, arguments are pointless. Restraints are discouraged, and should be used short-term, weighing the benefit against the burden. Cognitive training may benefit daily functional activities. In aimless wanderers, precipitating factors need to be looked for and rectified.
Sleep disturbances are handled through regular sleep schedules, evening exercises, avoidance of bright light and noise, and limiting fluids in the late hours to decrease bathroom visits at night. Regular ongoing physical activity correlates with cognitive improvement.22 Worsening confusion at night or evenings ("sundowning") is addressed by reducing sensory stimuli, use of night lights, and familiar contacts and environment.
As the disease progresses, dietary restrictions are minimized, with quality of life (QOL) gaining greater importance. In terminal stages, a common consideration is the insertion of a percutaneous endoscopic gastrostomy (PEG) tube for enteral feeding, a decision fraught with ethical dilemmas.23 Studies have not confirmed that PEGs prolong life, improve QOL or nutritional status, or lower the likelihood for pressure ulcers and aspiration pneumonia. Nearly half of terminal AD patients who receive PEG tubes die within a year.23
Advance directives are ideally implemented early when the patient still has some capacity to make decisions. A durable power of attorney for healthcare (healthcare proxy) can make decisions on behalf of the patient who loses capacity in advanced disease. Hospitals and institutions are required to document whether patients have advance directives and if they do not, offer an opportunity to execute one. In general, we address advance directives inadequately; in our hospital, we have demonstrated that efforts by health providers result in vastly improved responses from patients.24
Pharmacotherapy
Goals of pharmacotherapy (Table 2) in AD are to preserve cognition and function to the extent that is possible, slow progression of the disease, and address behavioral disturbances.25
Cholinesterase Inhibitors
Several ChEIs (acetylcho linesterase, butyrylcholinesterase) are the mainstay of treatment based on the principle of enhancing neurotransmitter function and acetylcholine availability at the neurons. No agent prevents neuronal death.
Tacrine (Cognex), the first ChEI developed, is no longer used because of its adverse effects; 3 additional ChEIs are generally similar in effectiveness. Clinicians should choose a pharmacologic agent based on tolerability, adverse effects, cost, and ease of use; the evidence to compare the effectiveness is weak based on review of studies presented in recent guidelines.26,27 They differ in pharmacokinetics and side effects. Significant anecdotal and unproved use of combinations also exist.28 Peak efficacy is attained in 3 months.25
In mild-to-moderate forms of AD, a single ChEI is typically used. In moderate-to-severe stages, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, memantine (Namenda) may be indicated (with or without a ChEI) to enhance cognition, function, and behavior-related measures. Memantine is an antiglutamatergic agent; glutamate is a neurotransmitter essential for learning and memory through facilitation of NMDA receptors.27
For those with dysphagia, liquid formulations are available. Another option is transdermal rivastigmine (Exelon), associated with better gastrointestinal tolerance and potentially improved adherence to regimen.29
Withdrawal of a drug may lead to rapid loss of efficacy and clinical deterioration, whereas appropriate use can delay nursing home placement, a stated priority for caregivers, and help manage adverse behaviors.28
Antipsychotics
When behavioral disturbances become worse and nonpharmacologic approaches fail, medications may be tried for that purpose. General principles of psychotropic therapy that apply to the elderly include a "start low, go slow" approach, understanding the pharmacokinetic changes with aging, and monitoring for side effects.
Drug therapy should be considered short-term (3-6 months), with intent to terminate therapy after resolution of symptoms, as adverse events evolve with time.28 Antipsychotics include the traditional haloperidol (Haldol) and risperidone (Risperdol) and the atypical antipsychotics olanzapine (Zyprexa) or quetiapine (Seroquel). The antidepressants paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa); valproic acid (Depakote); and others are used for agitation or difficult behavior.2,28
Keeping the dose low minimizes adverse effects, such as movement disorders. Some atypical drugs have been linked to the development of glucose intolerance and vascular complications with long-term use.
Caregiver Burden
The majority of patients (70%) with AD—with or without dementia—live in the community and are dependent on caregivers, typically a woman (wife or daughter); hence the need to understand the existence of "caregiver burden" requiring support.
Caregivers need education and counseling to understand the course of AD and the means to deal with the family member who has the disease. A pilot study demonstrated that home care agencies can assess specific caregiver needs and help improve caregiver mastery to decrease strain.30 Caregivers of demented individuals tend to devote precious time for caregiving, often at the expense of their own occupational or leisure activities, and suffer from physical, mental, and emotional stress.31 Caregivers often suffer from depression, musculoskeletal disorders, and hypertension.
Institutionalization of patients with AD associated with dementia results from 1 or more variables that are patient-related (aggressive behavior, incontinence, feeding difficulties, terminal dementia) or caregiverrelated (poor health, financial impact, poor support, depression, impaired QOL).
Medicare Coverage for Care in AD
The majority of patients with AD and dementia are likely to be older than 65 years of age and eligible for Medicare, which includes coverage for:
- Hospital stay at variable rates (which is influenced by illness severity, management strategies, and duration of stay)
- Skilled nursing care only after a hospital stay of 3 days or more (and demonstrating a need for skilled care)
- Home healthcare and "reasonable and necessary" physician visits.
The 2003 Medicare Modernization, Improvement, and Prescription Drug Act (Part D) introduced voluntary prescription drug coverage applicable to Medicare beneficiaries. The Centers for Medicare & Medicaid Services requires health plans to cover essentially all protected drug classes used in AD (eg, antipsychotics and antidepressants), as well as two thirds of the drugs used in AD in nonprotected classes.
Although ChEIs are covered by Medicare to the tune of 67% to 100% (depending on a given drug within the class), prior authorization is required 12% to 25% of the time.32 Similar formulary coverage is available for antipsychotics. Nursing homes and pharmacies identify a set of preferred drugs in each class, with some choices available.32
Medicare provides coverage for PET scans, based on documentation of recent dementia and cognitive decline of at least 6-month duration, and when the patient meets diagnostic criteria for AD and frontotemporal dementia, as ascertained by the provider. Finally, it is apparent that patients with Alzheimer's dementia manifest more comorbidity than matched controls, and therefore cost more to care for. Annual costs are 34% higher for patients with Alzheimer's dementia compared with those without dementia; outpatient pharmacy is a major cost factor.33
Future Perspectives
Earlier diagnosis of AD may help alter its course. Detection of tau protein and Aß42 measurements in cerebrospinal fluid have the potential to discriminate early Alzheimer's dementia from other causes of memory loss.34 The role for PET scans and genetic testing in the diagnosis may change in the future. Exploring the region-specific decline in cerebral glucose metabolism in AD may be a novel approach in the future.
Data on the role for testosterone, estrogen, vitamins E and C,35 and beta-carotene are inconsistent with regard to benefits in Alzheimer's dementia. And the evidence that gingko biloba has a role in preventing or delaying cognitive decline is similarly not convincing.36
Tarenflurbil (Flurizan), a selective Aß42-lowering agent, is an investigational agent with a new mechanism of action and is currently in clinical trials. It promises benefits for ADLs and global functioning in mild AD.37
In preliminary studies, nonsteroidal anti-inflammatory drugs were believed to lower Aß production by modulation of gamma-secretase activity or through anti-inflammatory actions. However, they are yet to deliver these expected benefits in randomized controlled trials. Similarly, a potential was suggested for beta- and gamma-secretase inhibitors to decrease formation of insoluble Aß or alternatively the upregulation of alpha-secretase to increase soluble amyloid formation; these are promising concepts, but are yet far from reality.
Testosterone supplementation in those with low testosterone levels failed to improve either cognition or function for patients with AD,38 but a recent study indicated that serum bioavailable (not total) testosterone had lower risk for MCI.39
Peroxisome proliferator-activated receptor-gamma agonists, such as rosiglitazone (Avandia), may be novel therapeutic agents for improved memory and cognition.40
Immunotherapy (eg, vaccination) to target Aß protein and tau protein has been tried, but active immunization was fraught with development of aseptic meningoencephalitis in humans. Passive immunization trials are now under way.41
Statins show promise in slowing cognitive decline. The mechanisms postulated include cholesterol lowering, lessening vascular damage, and anti-inflammatory and antioxidant effects. Epidemiologic data suggest lower incidence of Alzheimer's dementia for those using statins.
Anecdotal reports suggest that the Mediterranean diet42 and fruits and vegetable juices43 delay the progression of AD. Finally, maintaining appropriate folate levels may prove useful, and acetyl-L-carnitine may also be beneficial.
Conclusion
AD with dementia is characterized by gradual memory loss and cognitive impairment, followed by personality changes and behavioral problems. Although several risk factors are implicated, a precise etiology is not delineated. AD may be the result of interplay between aging, genes, and environment. The result is a severe burden to caregivers and to society, placing a heavy toll on healthcare resources. And as the prediction is for AD to become more prevalent, we need to plan wisely to allocate appropriate resources to meet the demands of the disease, while continuing to channel research funds to delay onset, slow progress, or reverse the disease.
References
1. Kidd PM. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev. 2008;13:85-115.
2. Kawas CH. Early Alzheimer's disease. N Engl J Med. 2003;349:1056-1063.
3. Cummings JL. Alzheimer's disease. N Engl J Med. 2004;351:56-67.
4. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939-944.
5. Alzheimer's Association. Alzheimer's disease facts and figures. 2008. www.alz.org/national/documents/report_alzfactsfigures2008.pdf. Accessed August 19, 2008.
6. Hendrie HC. Epidemiology of dementia and Alzheimer's disease. Am J Geriatr Psychiatry. 1998;6(2 suppl 1):S3-S18.
7. Alzheimer's Association. Alzheimer's Association Report Alzheimer's Disease Facts and Figures. 2007. www.alz.org/national/documents/PR_FFfactsheet.pdf. Accessed August 19, 2008.
8. Geldmacher DS. Cost-effective recognition and diagnosis of dementia. Semin Neurol. 2002;22:63-70.
9. Rice DP, Fox PJ, Max W, et al. The economic burden of Alzheimer's disease care. Health Aff (Millwood). 1993;12:164-176.
10. Leifer BP. Early diagnosis of Alzheimer's disease: clinical and economic benefits. J Am Geriatr Soc. 2003;51(5 suppl dementia):S281-S283.
11. Alzheimer's Disease and Chronic Health Conditions: the Real Challenge for 21st Century Medicare. Alzheimer's Association. www.alz.org/national/documents/report_chroniccare.pdf. Accessed August 11, 2008.
12. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008;148:427-434.
13. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985-1992.
14. Cummings JL. Understanding and Treating Alzheimer's Disease: A Primer. Teaneck, NJ: Elsai Inc, and Pfizer, Inc; 1997:4-37.
15. Chew ML, Mulsant BH, Pollock BG, et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56:1333-1341.
16. Herholz K. PET studies in dementia. Ann Nucl Med. 2003;17:79-89.
17. Bird TD. Genetic factors in Alzheimer's disease. N Engl J Med. 2005; 52:862-864.
18. Dharmarajan TS, Pais WP. Managing Alzheimer's dementia. Resid Staff Physician. 2004;50:9-16.
19. Lyketsos CG, Steinberg M, Tschanz JT, et al. Mental and behavioral disturbances in Alzheimer dementia: findings for the Cache County Study on Memory and Aging. Am J Psychiatry. 2000;157:708-714.
20. Woods DL, Dimond M. The effect of therapeutic touch on agitated behavior and cortisol in persons with Alzheimer's disease. Biol Res Nurs. 2002;4:104-114.
21. Cora VL. Helping family caregivers of older adults with dementia: providing education and support during these difficult times. Elder Care. 2006;6:1-4.
22. Rolland Y, Abellan van Kan G, Vellas B. Physical activity and Alzheimer's disease: from prevention to therapeutic perspectives. J Am Med Direct Assoc. 2008;9:390-405.
23. Dharmarajan TS, Unnikrishnan D, Pitchumoni CS. Percutaneous endoscopic gastrostomy and outcome in dementia. Am J Gastroenterol. 2001;96:2556-2563.
24. Imtiaz M, Bojanapally P, Dharmarajan TS, et al. Improving the process of advance directives in healthcare: role for demographics and other characteristics. Presentation at the American College of Physicians Internal Medicine Annual Meeting; May 15-17, 2008; Washington, DC.
25. Geldmacher DS. Alzheimer's disease: current pharmacotherapy in the context of patient and family needs. J Am Geriatr Soc. 2003;51(5 suppl dementia):S289-S295.
26. Qaseem A, Snow V, Cross JT Jr, 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.
27. Standridge JB. Current status and future promise of pharmacotherapeutic strategies for Alzheimer's disease. J Am Med Direct Assn. 2005;6:194-199.
28. Xiong G, Doraiswamy PM. Combination drug therapy for Alzheimer's disease: what is evidence-based, and what is not? Geriatrics. 2005;60:22-26.
29. Guay DR. Rivastigmine transdermal patch: role in the management of Alzheimer's disease. Consultant Pharmacist. 2008;23:598-609.
30. Mittelman MS, Roth DL, Clay OJ, Haley WE. Preserving health of caregivers: impact of spouse caregiver intervention. Am J Geriatr Psychiatry. 2007;15:780-789.
31. Ory MG, Hoffman RR 3rd, Yee JL, et al. Prevalence and impact of caregiving: a detailed comparison between dementia and nondementia caregivers. Gerontologist. 1999;9:177-185.
32. Stevenson DG, Huskamp HA, Keating NL, Newhouse JP. Medicare Part D and nursing home residents. J Am Geriatr Soc. 2007;55:1115-1125.
33. Kuo TC, Zhao Y, Weir S, et al. Implications of comorbidity on costs for patients with Alzheimer disease. Med Care. 2008;46:839-846.
34. Hampel H, Mitchell A, Blennow K, et al. Core biological marker candidates of Alzheimer's disease: perspectives for diagnosis, prediction of outcome and reflection of biological activity. J Neural Transm. 2004; 111:247-272.
35. Boothby LA, Doering PL. Vitamin C and vitamin E for Alzheimer's disease. Ann Pharmacother. 2005;39:2073-2080.
36. DeKosky ST, Furberg CD. Turning over a new leaf: ginkgo biloba in prevention of dementia? Neurology. 2008;70:1730-1731.
37. Wilcock GK, Black SE, Hendrix SB, et al. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomized phase II trial. Lancet Neurol. 2008;7:483-493.
38. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008;299:39-52.
39. Chu LW, Tam S, Lee PW, et al. Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol (Oxf). 2008;68:589-598.
40. Landreth G, Jiang Q, Mandrekar S, Heneka M. PPAR-gamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics. 2008;5:481-489.
41. Hawkes CA, McLaurin J. Immunotherapy as treatment for Alzheimer's disease. Expert Rev Neurother. 2007;7:1535-1548.
42. Scarmeas N, Luchsinger JA, Mayeux R, Stern Y. Mediterranean diet and Alzheimer disease mortality. Neurology. 2007;69:1084-1093.
43. Dai Q, Borenstein AR, Wu Y, et al. Fruits and vegetable juices and Alzheimer's disease: the Kame project. Am J Med. 2006;119:751-759.