By Kimberly McGhee
Subject Matter Experts: Steven L. Carroll, M.D., Ph.D., David L. Bachman, M.D., David G. Clark, M.D., and Andreana Benitez, Ph.D.
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Better understanding and meeting the needs of patients with Alzheimer’s disease (AD) and their caregivers is increasingly a matter of national necessity. More than five million Americans have AD, the most common cause of dementia in those 65 and older, and that number is expected to triple by 2050 due to the aging population.1 Health, long-term, and hospice care for patients with dementia due to AD or other causes cost the nation $226 billion in 2015.1 In addition, more than 15 million Americans provided almost 18 billion hours of informal (i.e., unpaid) care for patients with AD, at an estimated value of $218 billion.1 It is feared that the projected increase in AD prevalence would overwhelm Medicare/Medicaid, the health care system, caregivers, and nursing homes. For these reasons, the Centers for Disease Control and Prevention have declared the rising prevalence of AD to be a public health crisis.
Although most AD develops late in life (i.e., late-onset AD), with risk doubling every five years after age 65, it is not a normal part of aging. Whereas some slowing of mental processes is expected with the natural aging process, AD is a neurodegenerative disease that leads to gradual but irreversible cognitive and functional decline as it disables and destroys neurons and other brain tissue. The neurons of patients with AD do not function properly due to the accumulation of amyloid plaques and the formation of neurofibrillary (tau) tangles in the axons’ microtubules. Changes in the brain’s white matter, the myelin sheath that covers the axons and helps them conduct messages more effectively, could also be implicated.
It is not well understood what causes these changes in brain cells and tissue, but it is thought that genetic, environmental, and lifestyle factors all have a role to play. For example, patients who carry a copy of the APOE-є4 allele, which is thought to promote amyloid plaque formation, are at an increased risk of late-onset AD but not all go on to develop the disease. Lifestyle modifications such as more aerobic exercise and a healthy diet2 as well as better sleep, less stress, and increased social interaction may decrease the risk of developing AD or improve cognitive symptoms in those with the disease.
Detrimental changes to the brain are thought to begin a decade or more before the first symptoms of AD appear, and this “preclinical” stage may represent the best opportunity for therapeutic intervention. A number of monoclonal antibodies targeting amyloid plaque formation are in clinical trials. Although phase 3 trials of a number of these agents (e.g., bapineuzumab3 and solanezumab4) yielded disappointing results in mild to moderate AD in 2014 and 2015, post hoc analysis of the results suggested that the agents could provide benefit if administered in the preclinical or very early stages of the disease,5 and most new trials of these and other anti-amyloid monoclonal antibodies are focused on demonstrating such a signal.
There is a great deal of optimism about the preventive promise of these amyloid-targeting monoclonal antibodies, and intensive efforts are under way to develop better cerebrospinal fluid and imaging biomarkers of preclinical AD so that these agents can be administered to the appropriate patients.
For example, amyloid scans, a form of positron emission tomography in which small molecules capable of binding to amyloid plaques are injected before imaging, hold promise for identifying patients at risk of developing the amyloid plaques that are one of the hallmarks of AD. Although these scans have a growing role in identifying appropriate participants for AD clinical trials and may be useful when there is considerable diagnostic uncertainty, they are not currently recommended for widespread clinical use and, with few exceptions, are not reimbursed by the Centers for Medicare & Medicaid Services.
While excitement is growing over the development of amyloid biomarkers and targeted anti-amyloid therapies, it should be remembered that amyloid plaques are only one piece of the Alzheimer’s puzzle. As such, agents solely targeting them may be limited in their therapeutic efficacy. Ultimately, as in other chronic diseases, a combination regimen may be required to target not only amyloid but also tau as well as the white matter changes associated with the disease.
Primary care providers (PCPs) are likely to be the first responders to this public health crisis, as most patients with memory concerns consult with their PCP. Primary care physicians, however, are already overwhelmed trying to manage complex diseases such as hypertension, diabetes, and heart disease within the context of the typical fifteen-minute visit. As a result, 27% to 81% of patients with AD go unrecognized in primary care.6
Early detection of dementia due to AD in a primary care setting is vital if patients are to benefit both from current treatments that may stabilize the disease for a time and also the targeted therapies that are nearing the clinic. It also opens the door to much-needed educational and support services for patients and their caregivers and provides patients time to plan for their future care, put their affairs in order, and take any necessary legal or financial steps. It also enables a strong relationship to develop between the PCP, the patient, and the family, one that will enable them as a team to meet challenges, such as the behavioral problems that can develop in late-stage disease, while maintaining a good quality of life for patients and caregivers and delaying institutionalization.
Primary care physicians now have the tools they need to detect cognitive decline early. In 2011, as part of the Affordable Care Act, Medicare began paying for annual wellness examinations that include cognitive assessment for patients 65 and older.6 The Alzheimer’s Association has developed a toolkit for conducting the cognitive assessment during the annual wellness examination, with a detailed algorithm illustrating when these assessments should be administered and which clinical decisions need to be made based on their results. It recommends three screening tools—the Memory Impairment Screen (MIS), the General Practitioner Assessment of Cognition (GPCOG), and the Mini-Cog—because, among other reasons, they require five minutes or less to administer, have been validated in a primary care setting, and can be used without copyright concerns for clinical care.6 These tools are easy to administer and an assessment can be performed by medical staff as well as by physicians. For the three-minute Mini-Cog, for example, the patient is asked to remember three words in order, and then, as a distractor, told to draw a clock face with hands indicating a specific time, before being asked to recall the three words. For the clock drawing, “10 after 11” is often used because correctly drawing the clock hands as facing 11 and 2 requires several cognitive steps that can be challenging for people with AD. If the results from this or another screen arouse concern, the PCP can perform a full dementia evaluation or refer to a behavioral neurologist or other dementia specialist for further assessment before communicating concerns to the patient.
The Alzheimer’s Association provides many resources to PCPs to help them identify and manage patients with AD, including a checklist of ten warning signs for AD and a new app that offers not only an interactive form of the cognitive assessment algorithm but also both physician and patient educational resources about AD, diagnostic tools, and information about the latest AD trials.
One additional resource for early detection is the patient’s family or caregiver. The early symptoms of AD can be subtle, noticeable by those who know the patient well but not evident to a physician in a brief office visit. Patients themselves are often not aware of their cognitive decline. Family members may feel frustrated, and the diagnosis may be delayed, if their concerns go unheeded because patients display their best behavior for the PCP. Family members may be hesitant to mention evidence of cognitive decline in the presence of the patient, so PCPs who suspect memory or other cognitive problems due to screening or observation will likely benefit by interviewing the family member separately, perhaps using an informant screening tool that is meant to distinguish between normal aging and AD.
It is helpful to order laboratory tests to identify thyroid problems and B12 or other vitamin deficiencies that could lead to cognitive problems and to obtain magnetic resonance imaging (MRI) to look for evidence of vascular disease or damage due to compromised blood flow to the brain.7 Having these results in hand, the PCP or specialist is much better equipped to interpret information gleaned from a detailed patient history and thorough physical, cognitive, functional, and neuropsychological assessments of the patient.
For example, vascular dementia would be more likely in patients with MRI evidence of vascular damage and reflexes that are brisk on one side, suggesting damage to one of the cerebral hemispheres. A smoking history also increases risk—a 2010 study that showed that a large cohort of people who smoked heavily in middle age doubled their risk of developing vascular dementia or AD later in life.8 Tremor or rigidity would suggest dementia due to Parkinson’s.
Family and medication histories are also crucial. Having a family member with AD increases the patient’s risk of developing the disease. A careful inventory of the patient’s current medications could reveal a pharmacological cause of cognitive decline. For example, some first-generation over-the counter antihistamines such as diphenhydramine (oral) and other medications on the Beers list (updated in 2015) can make elderly patients more forgetful and can have especially negative effects on patients with AD.
Useful information about the patient’s cognitive capacities can be gleaned by asking whether he or she is repeating questions often, misplacing items, struggling to think of words, or getting lost in familiar settings. If these answers elicit concern, a more comprehensive cognitive assessment using tools such as the Mini-Mental State Examination or the Montreal Cognitive Assessment (MoCA) should be performed. The Mini-Mental is widely used and helpful for detecting established dementia, whereas MoCA is more sensitive and better able to detect very early signs of the problem. The patient should also be screened for depression, which can be comorbid with AD, especially in its early stages.
It is equally important to ascertain a patient’s functional status by asking if he or she can perform routine tasks such as paying bills, driving a car, cooking, or managing medications. A private conversation with a caregiver can provide additional information as the patient with AD is not always insightful about his or her condition. A patient is considered to have dementia when he or she can no longer perform tasks that are required for independent living.
A neuropsychological assessment can also provide clues on the underlying causes of dementia. For example, visual hallucinations occur more frequently and earlier in patients with diffuse Lewy body disease than patients with AD, whereas the gradual onset of worsening memory and word-finding difficulty in an elderly individual is especially concerning for AD. As more targeted AD treatments become available, it will become increasingly important to exclude non-AD causes for dementia, since patients with those types of dementia are unlikely to benefit from amyloid-targeted AD therapy.
It is estimated that only 45% of PCPs in South Carolina disclose a suspicion of AD or dementia to patients (Interview, Sam Wiley, South Carolina Chapter of the Alzheimer’s Association). Studies have shown that failure to disclose an AD diagnosis stems from uncertainty over the diagnosis and fear that either the patients will not be able to understand the information or, if they do, will lose hope and motivation.9 Although AD can be definitively diagnosed only post mortem, 80% of cases can be identified with the previously mentioned screening and diagnostic tools along with a detailed history and a careful physical examination. In contrast to physicians that may be hesitant to disclose a diagnosis, most patients with memory concerns and their caregivers prefer to be told about the disease so that they can plan for future care and access needed resources.10
When a diagnosis of AD is to be disclosed, the PCP should ask the patient to bring a family member or close friend to the visit for emotional support. The PCP should go over test results that led to a diagnosis of AD and should explain briefly to both the patient and family member what to expect as the disease progresses. Because receiving this news is highly unsettling, the PCP needs to reassure the patient and caregiver that the PCP will remain their champion and point of contact for navigating the care system and for accessing community resources. The PCP should also emphasize to the family the importance of beginning to make a long-term care plan for the patient and obtaining legal documents such as health care proxies. A follow-up visit should be scheduled within a few weeks to assess whether the patient and caregiver have absorbed the diagnosis, begun to tap into community resources, and taken the necessary financial and legal steps to ensure the best possible long-term care for the patient.
On the day of diagnosis, the PCP should provide a written list of organizations providing AD education and support to the patient and caregiver. The local chapter of the Alzheimer’s Association offers classes to help patients and caregivers better understand the disease, including detailed information on what to expect at each stage of the disease and resources for providing appropriate care. In addition, the chapter offers a free 24/7 help line (1-800-272-3900) staffed by licensed social workers and counselors. They can provide information on AD-related legal and financial matters, point patients and caregivers toward support groups, provide information on the latest clinical trials, and help families find sitters, apply for financial aid for respite care, and locate nursing home beds. Safety programs are also available to ensure the safe return of patients who wander.
Many families also find it helpful to read accounts of how others have faced the challenges associated with caring for a patient with AD, such as Nancy Mace’s The 36-Hour Day: A Family Guide to Caring for Persons with Alzheimer Disease–Related Dementing Illnesses, and Memory Loss in Later Life.
Although no disease-modifying therapies are currently approved for AD, a number of medications help mitigate some of its symptoms for a time. The U.S. Food and Drug Administration has approved two classes of drugs to treat the memory and other cognitive problems associated with AD. These include the cholinesterase inhibitors donepezil, rivastigmine, and galantamine (for all patients with AD and some non-AD patients as well) and the glutamate modulator memantine (for patients with moderate to severe disease). Memantine is seldom given alone but instead combined with one of the cholinesterase inhibitors when monotherapy with cholinesterase inhibitors does not provide benefit. These medications provide patients a “cognitive boost” and can be continued long-term until patients are severely impaired. As with any neuroactive agent in the elderly, these drugs should not be terminated abruptly but tapered slowly.
In later-stage AD, behavioral problems often develop and can contribute to caregiver burnout and institutionalization. It is important to realize that these problems can be the patient’s way of communicating an underlying physiological problem such as pain or an infection6 and that it is important to perform a thorough physical examination, review medications, and run laboratory tests to rule out such a possibility. If there is evidence of comorbid depression, a selective serotonin reuptake inhibitor should be prescribed as psychotherapy does not typically provide benefit in these patients. However, physicians should be aware that certain antidepressants, such as citalopram, can cause QT prolongation, especially at higher doses. Atypical antipsychotics are often used to control agitation in AD and are sometimes necessary when patients have psychotic symptoms, such as hallucinations or delusions. However, it is important to bear in mind that antipsychotics have a black box warning in this population. It is best to use the lowest effective dose for the shortest time possible. Physicians should try non-pharmacological options, developing a treatment plan with the family to avoid behavioral triggers and monitor results.7 If pharmacological intervention is deemed necessary, anticholinesterase medications that have been approved to relieve the symptoms of AD should be tried before antipsychotics if possible.
Early detection of AD by the PCP is integral to addressing both the private and public faces of the crisis and tools and algorithms exist to make it feasible in primary care practice. New therapies are on the horizon that will work best if administered early. Patients and caregivers alike feel less marginalized and invisible when their needs are recognized and access to community services and resources provided. Learning to read the behavior of the patient with AD may help signal underlying physiological or environmental problems that can be corrected, delaying institutionalization. Ultimately, the public health crisis posed by AD and the immense burdens it represents for the nation will be averted in one primary care practice at a time, in individual acts of empathy and compassionate care.
1 Alzheimer’s Association. 2015 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2015;11(3)332+.
2 Norton S, et al. Lancet Neurol 2014;13:788–794.
4 Doody RS, et al. N Engl J Med 2014 Jan 23;370(4):311-21.
6 Cordell CB, et al.Alzheimers Dement 2013; 9:141-150.
7 Geldmacher DS and Kerwin DR. Prim Care Companion CNS Disord 2013; 15(4): PCC.12r01474.
8 Rusanen M, et al. Arch Intern Med 2011 Feb 28;171(4):333-339.
9 Johnson H, et al. Int Psychogeriatr 2000;12(2):221-229.
10 Elson P. Int J Geriatr Psychiatry 2006; 21: 419-425.
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Dr. David G. Clark is the principal investigator for the MUSC site of the Biogen-sponsored ENGAGE study of aducanumab. Dr. Steven L. Carroll, Dr. David L. Bachman, Dr. Andreana Benitez, and Kimberly McGhee have no financial relationships to disclose.