Chapter 65. Dementia Including Alzheimer's Disease
Cynthia M. Carlsson, Carey E. Gleason, Luigi Puglielli, Sanjay Asthana
Managing Patients with Alzheimer's Disease
Managing patients with AD involves a comprehensive, multidisciplinary team approach including presentation of the diagnosis, initiation of medical therapy, assessment and treatment of concomitant depression and/or behavioral concerns, development of a social support network, education of patients and caregivers, provision of caregiver support, and initiation of appropriate safety measures. While not all medical centers have access to multidisciplinary team resources, effective care can still be given by focusing on providing established medical treatment, identifying a few strategies to maintain patient safety and providing basic education and caregiver support.
Presenting the Diagnosis
Presenting the diagnosis of AD to a patient is difficult, as it may generate significant emotional responses from the patient and their family and trigger fear of the future. Frequently, patients and family members suspect the diagnosis before it is presented, but how they respond to the news depends on personal coping mechanisms, cultural influences, family dynamics, and their preconceived understanding of AD.
Clinicians may help patients and families adjust to this diagnosis by using an empathetic, yet honest approach and by providing them with educational and support resources, including those provided by agencies such as the Alzheimer's Association and the National Institute on Aging Alzheimer's Disease Education and Referral (ADEAR) Center. In addition, the clinician should emphasize the goals of diagnosing AD in order to take steps to protect the patient's memory, delay the progression of the disease, and to maintain the person's safety. In general, it is recommended to tell both the patient and family the diagnosis using the term "Alzheimer's disease", thus, providing patients and families with a starting point for education. Encouraging both persons with the disorder and caregivers to utilize resources such as local support groups and the Alzheimer's Association is an important part of the patient management plan.
Treatment of Cognitive Symptoms
 Acetylcholinesterase inhibitors (AChEIs) are the mainstay of therapy for AD, and until several years ago, were the only medications approved in the United States for the treatment of AD. AChEIs increase the levels of the neurotransmitter acetylcholine in neuronal synapses, thereby enhancing cholinergic activity in the affected brain regions. Although 18% to 48% of persons may experience improvements in cognition after taking these medications, the majority of patients do not have any noticeable improvement, but instead experience a plateau or slowing of their rate of cognitive decline. This lack of noticeable improvement has led to controversies regarding the benefit of using cholinesterase inhibitors. However, given the chronic nature of AD, delaying the progression of cognitive decline may lead to improvements in quality of life, reduced caregiver burden, and reduced economic cost associated with long-term care.
 Four AChEIs have been approved for use in the United States by the Food and Drug Administration (FDA). These medications include tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®).
Excessive gastrointestinal side effects have made use of tacrine less favorable given the improved safety and tolerability profiles noted with the newer agents. Dosing recommendations for the commonly used AChEIs are shown in Table 65-8. In general, the most common adverse effects associated with AChEI use are nausea, anorexia, and diarrhea. Gastrointestinal side effects may be alleviated by taking the medications with food. Sleep disturbances are also common, and may improve with altering the dosing schedule.
Table 65-8 FDA-Approved Medications for the Treatment of Alzheimer's Disease*
While used for many years in Europe, the United States' FDA-approved memantine (Namenda®) for use in moderate to severe AD in 2003. Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.  At high concentrations, memantine can inhibit mechanisms related to learning and memory, but at lower concentrations, it can preserve or enhance memory in animal models of AD. Memantine can protect against the excitotoxic destruction of cholinergic neurons and may inhibit -amyloid production. In persons with moderate to severe AD, memantine slows the progression of cognitive decline either alone or when used in conjunction with AChEIs. In addition, studies support that use of memantine showed better outcomes on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. While early trials show promising results, additional studies are needed before memantine can be recommended for early stages of AD. In most circumstances, it is appropriate to add this medication to cholinesterase inhibitor therapy in persons with moderate to severe AD. Current prescribing recommendations for memantine are shown in Table 65-8. In persons who do not tolerate cholinesterase inhibitors, memantine may be used as first-line therapy. With use of either AChEIs or memantine, clinicians should educate families on what to expect with use of the medications, namely that they work to delay the progression of the disease and not to significantly improve their cognition.
Consideration should be given to the modest expected benefit and cost of both medications per month.
Currently there are no FDA-approved disease-modifying therapies available, but research is making progress in identifying pathways that could serve as targets for such therapies.  A variety of agents targeting -amyloid metabolism are in various stages of development, including A immunotherapy, agents inhibiting A fibrillization and reducing soluble A, selective amyloid lowering agents (SALAs), and - and -secretase inhibitors. In addition, potential disease-modifying agents with known cardiovascular benefits, such as statins and omega-3 fatty acids, are currently being studied in large clinical trials.
While clinical trials have not conclusively shown that treating vascular risk factors delays the development or progression of AD, aggressive treatment of vascular risk factors in many patients with memory complaints, including those associated with AD, may be warranted. Vascular risk factor modification has known cardiovascular benefits that may lead to reduction of coronary artery bypass grafting, cerebrovascular disease, and stroke—factors strongly linked to cognitive decline. Trials are underway to clarify if vascular risk factor reduction and improved cerebral perfusion modify the course of AD. Until the completion of such trials, clinicians should follow established cardiovascular prevention guidelines for patients presenting with memory complaints, taking into account the patient's comorbid illnesses, quality of life, treatment costs, and life expectancy.
Currently there are no established preventive therapies for AD. Evidence supports that future therapies that either delay or prevent the onset of AD may need to be started in midlife in high-risk populations in order to significantly influence the onset and course of the disease. As the underlying pathologic changes that eventually lead to clinical AD begin decades before the onset of symptoms, primary prevention trials with conversion to AD as their primary outcome may prove costly and time-consuming. Integrating biomarkers with strong relationships to clinically relevant outcomes into such primary prevention trials may allow for earlier identification of disease-modifying effects of potential preventive therapies. Given the multifactorial nature of AD, future preventive strategies will most likely target a variety of mechanisms related to disease progression, similar to that used in cardiovascular disease prevention.  Some potential prevention therapies currently under investigation include vascular risk factor modification, anti-inflammatory medications, antioxidants, lifestyle interventions such as exercise, social engagement, and cognitive stimulation, and novel compounds targeting A metabolism.
 AD is frequently associated with behavioral disturbances that include agitation, emotional or physical outbursts, and sexual inappropriateness.
Such behaviors may be more distressing to family and caregivers than the actual memory decline. Such behaviors may be managed by nonpharmacologic as well as pharmacologic interventions. Nonpharmacological therapies should be explored and exhausted before using pharmacologic therapy, unless the person's agitation threatens his or her safety or living situation. Addressing physical pain or other medical symptoms or distressing situations that could be contributing to agitation is key prior to any pharmacologic intervention. Identifying and correcting physical or emotional stressors may alleviate agitation. Potential medication side effects should be considered to see if they are contributing to agitation symptoms. After nonpharmacologic measures have been tried, consideration may be given to use of low-dose atypical antipsychotics taking into account potential risks associated with these medications. Selective serotonin reuptake inhibitors (SSRIs) may reduce symptoms of sexual inappropriateness. Wandering symptoms typically do not respond to pharmacologic therapy. Taking patients for a walk or giving them busy tasks to do may help reduce wandering. Frequently, it is the behavioral changes associated with AD and other dementias that are most distressing to family members and provide the greatest challenge for primary care physicians who are managing the care of persons with AD.
Referral to a multidisciplinary memory disorders clinic is appropriate for patients with significant behavioral concerns. More information is dedicated to this topic in Chapter 73.
 Reviewing common safety concerns in persons with dementia may help identify significant risks and provide an opportunity for educating family members and caregivers on what areas to monitor closely and what safeguards they can take to protect the person with AD.
Some patients may require further evaluation to assess driving safety, which can be done through occupational or physical therapy departments or local driving schools. Pill boxes or other similar medication planners may facilitate correct administration of medications and allow family or caregivers to help in setting up the medications properly. Other safety concerns such as proper use of the stove, woodworking equipment, hunting rifles, etc. should be discussed and appropriate supervision arranged.
 Evidence is accumulating that the effects of AD are felt not only by the patient but also by the caregivers. Caregivers have increased depression, missed work, and health problems compared to those not caring for a family member with dementia. Use of respite services from family, friends, neighbors, and local adult day centers may allow for caregivers to take the appropriate time needed to maintain their own health and social connections
Upon diagnosis of AD, many patients and families have questions as to what to expect in the years ahead. As the rapidity of progression of AD may depend not only on genetic and environmental factors but also comorbid medical conditions, the course of decline can be difficult to predict in some persons. Once on medical treatment for AD and when all potentially reversible contributing factors have been addressed, obtaining repeat cognitive testing will give the clinician an idea of the trajectory of decline of the individual and help inform the family on what to expect in the years ahead.  Providing information early in the disease course on end-of-life planning may help smooth this difficult transition later in the disease. Use of respite services and home health aides or family members may help the person with AD stay in the home longer.
If the social network of the patient cannot support the patient as the care needs increase, then nursing home placement frequently is necessary. Involving hospice can help with symptom management late in the course of the illness. Involvement in Alzheimer support groups can provide support during the unique grieving process related to dementia, as family and caregivers watch the cognitive and personality transformations in their family member with AD.