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A practical algorithm for managing Alzheimer's disease: what, when, and why?

Alzheimer's disease (AD) is the most common form of dementia and its prevalence is increasing. Recent developments in AD management provide improved ways of supporting patients and their caregivers throughout the disease continuum. Managing cardiovascular risk factors, maintaining an active lifestyle (with regular physical, mental and social activity) and following a Mediterranean diet appear to reduce AD risk and may slow cognitive decline. Pharmacologic therapy for AD should be initiated upon diagnosis. All of the currently available cholinesterase inhibitors (ChEIs; donepezil, galantamine, and rivastigmine) are indicated for mild-to-moderate AD. Donepezil (10 and 23 mg/day) and rivastigmine transdermal patch (13.3 mg/24 h) are indicated for moderate-to-severe AD. Memantine, an N-methyl-d-aspartate receptor antagonist, is approved for moderate-to-severe AD. ChEIs have been shown to improve cognitive function, global clinical status and patients' ability to perform activities of daily living. There is also evidence for reduction in emergence of behavioral symptoms with ChEI therapy. Treatment choice (e.g., oral vs. transdermal) should be based on patient or caregiver preference, ease of use, tolerability, and cost. Treatment should be individualized; patients can be switched from one ChEI to another if the initial agent is poorly tolerated or ineffective. Memantine may be introduced in moderate-to-severe disease stages. Clinicians will regularly monitor symptoms and behaviors, manage comorbidities, assess function, educate and help caregivers access information and support, evaluate patients' fitness to drive or own firearms, and provide advice about the need for legal and financial planning. Review of caregiver well-being and prompt referral for support is vital.


Introduction
Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-80% of cases. 1 In the United States, one in nine people aged ≥65 years has AD (twothirds of whom are women), and one person develops AD every 67 sec. 1 Alzheimer's Disease International estimates that the prevalence of AD will increase by 225% by 2050, affecting more than 115 million people globally, 2 and more than 13.8 million people in the United States. 1 AD is associated with initial memory loss, followed by impairments in cognitive function, language, visuospatial skills and executive function, coupled with behavioral changes. 3 Terminally, patients may become bedridden, incontinent and unable to communicate. 4 AD imposes an intolerable burden on healthcare systems, society, patients and their families, and is one of the leading contributors to disability among elderly people. 5 Most patients require assistance with activities of daily living (ADL), and many eventually require full-time care and supervision. 2,4 Caring for a patient with AD can be stressful, especially if the patient displays neuropsychiatric symptoms, such as irritability, dysphoria or delusions. 6 Clinicians play a key role in the medical management of AD, and provide recommendations and advice to patients and families/caregivers on a broad range of issues, including psychosocial problems, and legal and financial resources. 7 Specialists involved in AD diagnosis and management include neurologists, geriatricians and geriatric psychiatrists.
Therapeutic nihilism (disbelief in the efficacy or clinical value of a therapy) is a key issue in dementia management, particularly among clinicians, due to negative associations and stigma associated with this progressive illness. 8 These perceptions should be overcome as they may delay diagnosis, referral, and treatment. 8 This review provides recommendations on managing AD based on current knowledge and available pharmacologic agents. Support for patients, families, and caregivers is also discussed, from early recognition to difficult decisions around end-stage care. The goal of this approach is to maximize quality of life throughout the course of this complex disease. Data sources include pivotal clinical studies of donepezil, galantamine, rivastigmine, memantine, and medical foods identified using PubMed in 2014 and the relevant United States prescribing information. English-language articles considered of relevance to primary care physicians in relation to AD, its diagnosis and management, are included. Previous guidelines and management recommendations were reviewed. The recent meta-analysis of brain health activities by Alzheimer's Disease International was a key document. 9 General Brain Health and Wellness

Modifying risk factors for cognitive dysfunction
There are potential risk factors for, or protective factors against, cognitive dysfunction. It is reasonable to recommend modifying these, based on the available evidence. Recommendations for maintaining brain health in adults with and without AD are summarized in Box 1.
Observational studies point to a protective role for certain nutrients and dietary patterns (Mediterranean diet). However, data from randomized controlled trials have been inconsistent. Whether factors such as cooking processes and other dietary components explain these inconsistencies is uncertain. The potential mechanisms by which certain nutrients may protect brain health also remain to be established. 10 Long-term studies on the relationship between physical activity and the incidence of noncommunicable diseases in general is limited. However, the few available studies indicate that physical activity in healthy people is an important factor preventing the development of cognitive impairment and AD. 11 Depression is associated with cognitive decline, 12 supporting the management of depressive symptoms in the elderly. Further, there is clinical rationale to actively manage hyperlipidemia and diabetes. 13 Untreated hypertension is associated with rapid decline in cognitive function in vulnerable individuals. 14 A family history of AD is a risk factor for the disorder; family members should be encouraged to adopt a brainhealthy lifestyle.

Lifestyle considerations for patients with AD
Despite evidence that omega-3 fatty acids slow cognitive decline in the elderly, findings in patients with AD are inconsistent. [15][16][17] One trial reported benefits of omega-3 fatty acid and lipoic acid treatment on cognition and ADL performance. 16 However, due to small sample sizes, further studies are required. 16 Folic acid and vitamin B supplements may help to preserve brain function. 18 A small, double-blind, randomized, controlled trial reported that folic acid supplementation may improve response to cholinesterase inhibitor (ChEI) therapy. 19 Time to institutionalization and daily living functioning have improved following vitamin E supplementation. 20,21 As with all interventions, the benefit-risk ratio of supplements should be considered. A recent meta-analysis concluded that high blood levels of docosahexaenoic acid and eicosapentaenoic acid are possibly associated with increased risks of high-grade prostate cancer. 22 These findings should be interpreted with caution due to the multifactorial etiology of prostate cancer, and the complex metabolism of longchain omega-3 fatty acids. 22 Box 1. Recommendations for maintaining brain health in elderly patients with and without AD • Consider following a Mediterranean-style diet, with fish, vegetables, legumes, fruit, cereals, unsaturated fatty acids (e.g., olive oil), and a limited amount of meat or dairy products.
• Keep alcohol intake to a low-to-moderate level (e.g., one glass of wine per day with dinner).
• Engage in regular physical activity.
• Maintain leisure and social activitieskeep socially engaged. • Continue or take up activities that help to stimulate the brain, e.g., Tai Chi, dancing, puzzles.
• Become educated about AD and seek support from others with AD, e.g., the Alzheimer's Association, Alzheimer's Foundation of America, Keep Memory Alive, and other community groups.
• Include music in daily lifelistening to music, playing an instrument, singing.
• Maintain regular sleep patterns.
• Manage stressstop doing things if they are becoming too stressful (e.g., volunteer work, answering the telephone), keep to a regular daily schedule, include relaxing activities (e.g., playing with pets, massage, and aromatherapy).
Dementia symptoms are stressful for patients, caregivers, and families. [23][24][25][26] Patients who believe nothing can be done about their illness are more likely to experience depression, 27 and clinicians should educate patients about steps they can take to preserve function (Box 1). Learning about AD and seeking support early in the disease course can help reduce stress and improve coping and healthrelated behaviors. 28 Artistic pursuits may help maintain a sense of identity and self-expression, improve aspects of behavior, and enhance communication. [29][30][31] Music therapy reportedly improves language functions in patients with dementia 32 and symptoms of anxiety and depression in patients with mild-to-moderate AD. 33 Interactions with pets may reduce agitation and anxiety in some patients with dementia. 34 Patients and caregivers can also reduce stress by adjusting activities to suit the patient's abilities, and keeping to a regular daily routine that includes relaxing activities. 35 Clinicians should urge patients with AD to participate in leisure activities, where possible, preserving function and quality of life. 23,25,36 Cognitive training may improve function, so patients should be encouraged to learn new skills or hobbies and undertake activities that stimulate mental activity. 12,37 Social interactions may be difficult for patients with AD, and they may withdraw due to selfconsciousness, depression, or apathy. 23,25 Participation in specialized adult day programs for patients with dementia may enhance the benefits of drug therapy and improve sleep quality, by keeping the patient engaged and reducing inactivity. 38 Specialized memory rehabilitation programs for patients with AD have also proven valuable, 39 but are not widely available.

Diagnosis
In clinical trials, the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria are commonly used to diagnose dementia of the Alzheimer's type. 40 Recently, an updated version, DSM-5, was published; key updates are the change in dementia to the newly named entity "major neurocognitive disorder (NCD)", and recognition of a less severe level of cognitive impairment, termed "mild NCD". 41 The most recent diagnostic guidelines from the National Institute on Aging and Alzheimer's Association define three stages of AD: 42 • Preclinical phase: neuropathologic changes occur, no overt (or only subtle) symptoms.
• Phase of mild cognitive impairment: symptoms become apparent; ADL are preserved; the patient does not have dementia.
There may be preclinical neurologic changes in the form of cerebrospinal fluid or amyloid imaging biomarkers. 43 However, AD diagnosis is principally based on clinical criteria (Fig. 1); 44,45 biomarkers can be used to define AD as the probable underlying cause of cognitive impairment, but are not strictly necessary for diagnosis. 42,45 The accuracy of diagnosis is enhanced by integration of biomarkers. Table 1 outlines the recommended diagnostic steps. 46

Pharmacotherapy
There are a number of Food and Drug Administration (FDA)-approved pharmacotherapies for AD ( Table 2). These may improve symptoms or delay decline; none impact the underlying neurodegenerative process. 47 It is important for patients and their caregivers to understand this, so they can make informed treatment decisions and have realistic expectations regarding the impact of treatment. 48

ChEIs
Three ChEIs (donepezil [Aricept â ; Eisai Inc., Woodcliff Lake, New Jersey], galantamine [Razadyne â ; Janssen Pharmaceuticals Inc, Titusville, New Jersey] and rivastigmine [Exelon â capsules and Exelon â Patch; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey]) are indicated for mild-to-moderate AD in the United States; donepezil and rivastigmine transdermal patch are also indicated for severe AD. [49][50][51][52] All three ChEIs are approved in oral formulations; [49][50][51] rivastigmine is the only ChEI also approved for delivery via a transdermal patch. 52 Approval of high-dose 23 mg/day donepezil for moderate-to-severe AD was based on a randomized clinical trial that demonstrated greater cognitive efficacy versus the standard dose (10 mg/day). 53 The high-dose (13.3 mg/ 24 h) rivastigmine patch was approved for mild-to-moderate and severe AD, based on positive findings in the OPTIMA (OPtimising Transdermal Exelon In Mild-tomoderate Alzheimer's disease) and ACTION (ACTivities of daily living and cognitION) studies, respectively. 54,55 All three ChEIs have demonstrated clinical benefits on cognitive function, global clinical status, [54][55][56][57] and performance of ADL. [54][55][56]58 There are no proven clinically meaningful differences between the agents in terms of efficacy. 56,57,59 Efficacy and tolerability associated with ChEIs are dose dependent, 60 so while high doses may be efficacious, adverse events (AEs) can be dose limiting. The agents have similar tolerability profiles, with nausea, vomiting, and diarrhea being the most common AEs. 56 Gastrointestinal (GI) AEs typically arise due to peaks in plasma drug concentrations. 61  Is dementia present? i.e. cognitive and behavioral (neuropsychiatric) symptoms that: 1. Interfere with the ability to function at work or at usual activities; and 2. Represent a decline from previous levels of functioning and performing; and 3. Are not explained by delirium or major psychiatric disorder.
• Cognitive impairment is detected and diagnosed through a combination of (1) history-taking from patient and a knowledgeable informant and (2) an objective cognitive assessment • The cognitive or behavioral impairment involves ≥2 of the following domains: • Impaired ability to acquire and remember new information • Impaired reasoning and handling of complex tasks, poor judgement • Impaired visuospatial abilities • Impaired language functions • Changes in personality, behavior, or comportment Probable AD  dosing frequency, lower peak plasma concentrations, and reduce the rate at which peak concentrations are reached may improve tolerability. 62 A sustained-release formulation of donepezil was developed to provide access to high therapeutic doses, while avoiding the rapid rises in peak drug plasma concentrations. 53 Donepezil 23 mg/ day is associated with greater cognitive benefits in moderate-to-severe AD than donepezil 10 mg/day IR; however, there is an dose-related increase in AEs. 53 A pharmacokinetic analysis predicted lower peaks in plasma drug concentrations, but a similar area under the curve, with extended-release (ER) galantamine compared with the IR formulation. 63 During a clinical study, both once-daily galantamine ER and twice-daily galantamine IR (flexible dosing of 16 or 24 mg/day) demonstrated superiority to placebo on cognition in patients with mildto-moderate AD, with a similar incidence of AEs observed in all three groups. 64 By providing sustained delivery over a 24-h period, transdermal delivery may improve GI tolerability and permit easier access to high-dose efficacy compared with oral dosing. 62 Relative to 6 mg twice-daily oral rivastigmine, 9.5 mg/24 h rivastigmine transdermal patch was associ-ated with comparable efficacy and two-thirds fewer GI AEs. 65 Rivastigmine patch treatment is initiated with the 4.6 mg/24 h dose, with up-titration to the minimum effective dose of 9.5 mg/24 h patch after at least 4 weeks, assuming good tolerability. 52 After an additional 4 weeks, if well-tolerated, the dose may be increased to 13.3 mg/24 h patch. 52 Continued use of the 4.6 mg/24 h dose can be considered in patients weighing less than 50 kg with tolerability concerns, or patients with mild-tomoderate hepatic impairment. 52 Transdermal delivery may be associated with application site reactions in some patients; the occurrence can be minimized by following the recommendations in the rivastigmine patch United States prescribing information. 52 These include: rotating the application site; applying the patch only to clean, dry, hairless skin that is free of redness, irritation, cuts, or burns; and ensuring the skin is free of creams, lotions, or powders prior to patch application. 52 After initiating ChEI treatment, patients should be assessed after 2-4 weeks for the development of AEs, 7 and after 3-6 months for effects on cognitive function and other behaviors/abilities. 7 ChEI doses should be Table 1. Steps in the diagnosis and assessment of a patient with suspected AD in primary care. 46 Step Purpose Tools/information required Step 1: Prediagnostic tests Identify risks for neurocognitive disorders • Risk factor assessment • Medical history • Laboratory tests to identify risk factors and define comorbidities and early warning signs of preclinical dementia Step 2: Assess performance Cognitive assessment • Cognitive tests e.g., MMSE, 126 Mini-cog, 127 MoCA, 128 SIB-8 129 • Informant-rated tools e.g., AD8 130 Step 3: Assess daily functioning Determine level of independence and degree of disability • Daily function assessment tool e.g., ADCS-ADL 131 Step 4: Assess behavioral symptoms Determine presence and degree of behavioral symptoms • Behavioral assessment tool e.g., NPI-Q 132 • Assess for other potential causes of behaviors (e.g., drug toxicity, medical or psychiatric comorbidity) Step  70 Memantine can be used as monotherapy 71 or in combination with a ChEI. 7,47 Combining two agents with different mechanisms of action, may improve efficacy relative to single-agent therapy, and the use of memantine with oral ChEIs may ameliorate ChEI-related GI AEs. 47

Medical foods
Several medical foods are available in the United States for management of AD and/or cognitive impairment, including: • Caprylidene (Axona â ; Accera Inc., Broomfield, California), a proprietary formulation of medium-chain triglycerides, intended for dietary management of mild-tomoderate AD. 72 • Cerefolin NAC â (PAMLAB, LLC, Covington, Louisiana), a combination of folic acid, vitamin B12, and Nacetylcysteine, intended for dietary management of mild cognitive impairment. 73 • Vayacog â (VAYA Pharma Inc., Greenville, South Carolina), a combination of phosphatidylserine, docosahexaenoic acid, and eicosapentaenoic acid, intended for dietary management of lipid imbalances associated with early memory impairment. 74 Noncarriers of the apolipoprotein e4 allele have shown significant improvements in cognitive function with caprylidene. 75 Currently, there is limited published evidence to support using folic acid, vitamin B12, and N-acetylcys-teine, 76 except in the setting of hyperhomocysteinemia. However, in older adults receiving folic acid supplementation for 3 years, plasma homocysteine levels were reduced and memory function improved compared with placebo. 77 A 15-week, randomized, double-blind study reported that phosphatidylserine-containing omega-3 fatty acids improved cognitive performance in elderly with memory complaints without dementia, although further studies are required to confirm these findings. 78 Souvenaid â (Nutricia Advanced Medical Nutrition, Schiphol, The Netherlands) a combination of omega-3 fatty acids, uridine, choline, vitamins C, E, B6, and B12, selenium, and folic acid is not yet available in the United States. Souvenaid â is available in Europe (Food for Special Medical Purpose) as a dietary means of supporting synaptic integrity. In clinical trials of patients with mild AD, this combination demonstrated a significant improvement in delayed verbal memory, 79,80 but not global cognition, 79 or performance of ADL. 81 No single agent or combination will suit every patient, so clinicians should construct a comprehensive, integrated, multifaceted treatment plan that reflects the preferences of the patient and caregiver, and the most recent scientific guidance. Clinicians should be prepared to reassess their approach to achieve optimal therapeutic benefit/outcomes. The optimal duration of ChEI treatment has not been established, but patients in clinical trials have shown benefit for up to 4 years, 82 so continuing treatment as long as patients tolerate the medication and families support treatment is reasonable. Maintaining open discussions with the family on disease progression and treatment outcomes may guide the clinician regarding whether or not to maintain treatment, and help the family to prepare for the eventual need for long-term residential placement.

Managing Comorbidities
In one study of 679 patients with AD in the United States, 61% had ≥3 medical comorbidities, and the number increased with advancing dementia severity. 83 After controlling for other variables, higher medical comorbidity was associated with worse cognitive function and poorer self-care. 83 Other data show that patients with AD are 55% more likely to be admitted to hospital than people without AD. 84 Common medical comorbidities in patients with AD include cardiovascular disease, thyroid dysfunction, sleep apnea, osteoporosis, glaucoma, cancer, falls, depression, infections, anorexia, rheumatoid conditions, and incontinence. 85,86 One key treatable comorbidity is sleep apnea. In addition to being a risk factor for hypertension, stroke, and mortality, 87,88 sleep apnea has been reported as a significant risk for dementia in older women, nearly doubling the risk for mild cognitive impairment and dementia over 5 years. 89 It is therefore important for clinicians to evaluate the presence of sleep disordered breathing as another modifiable risk. It is important for clinicians to manage conditions comorbid to AD (Box 2). This can limit cognitive and functional decline, 85 and reduce the risk of hospital admission, which can be disorienting, distressing, and lead to medication discontinuation. Moreover, medical illness and pain are common triggers for agitation or aggression in patients with AD, 47 so early recognition and treatment of comorbid medical conditions can limit neuropsychiatric and behavioral symptoms.
Neuropsychiatric symptoms are a key component of AD, affecting almost all patients over the disease course. 90 Studies suggest that more than 90% of patients with AD show behavioral or neuropsychiatric symptoms, including depression, agitation, anxiety, psychosis, hallucinations, apathy, eating disorders, disinhibition, and sleep distur- In contrast to FDA-approved drugs, no premarket review process exists for medical foods: data supporting their effectiveness (if such data exist) have not undergone the same rigorous scientific scrutiny as approved drugs. AD, Alzheimer's disease; ChEI, cholinesterase inhibitor; ER, extended release; NMDA, N-methyl-D-aspartate; PDD, Parkinson's disease dementia; PO, per os (oral administration); TD, transdermal.
bances. [91][92][93] The first step in management is to rule out potential medical and/or somatic causes, for example, lower urinary tract infection, 7,86,94 and recommend nonpharmacologic interventions (Table 3). 7 ChEIs or memantine may delay or relieve symptoms, 7,86,95 but some patients may require targeted pharmacotherapy, such as antipsychotics or antidepressants. Although antidepressant agents may be efficacious in treating depression in patients with AD, the supporting evidence is limited, and no agent has been approved specifically for depression or psychosis of AD. 96,97 A cross-sectional study reported that treatment of neuropsychiatric symptoms in elderly patients with dementia residing in care homes is generally not syndrome specific, and included use of neuroleptics and other substances not indicated for dementia. 98 Antipsychotic use has been associated with an increased risk of death due to pneumonia in elderly patients with dementia, 94 highlighting the importance of investigating the underlying cause of behavioral symptoms prior to prescribing treatment. Patients with AD exhibiting agitation and other neuropsychiatric symptoms often receive anticonvulsants, such as divalproex, as a second-line treatment. 99,100 However, data from controlled clinical studies suggest divalproex accelerated brain atrophy, and did not benefit patients with moderate AD in terms of neuropsychiatric symptoms, functional abilities, and cognition. 101,102 There is significant potential for polypharmacy in patients with AD. 103 Clinicians should be aware of potential drug interactions when introducing new medications and of difficulties in maintaining compliance/adherence with complex drug regimens. 103 Attempts should be made to simplify the medication regimen, for example, use of alternate modes of delivery that are more user friendly. 103

Societal and Financial Impact
Residential care is a major contributor to the financial impact of AD. In several studies ChEI treatment was associated with a delay in time to nursing home placement, 104 an effect that is reportedly dose dependent. 105 Similarly, evidence suggests cost-savings with memantine compared with nonpharmacological treatment in moderately severeto-severe AD, 106 as well as some benefit for combined ChEI/memantine therapy based on health-care data from France. 107 Nonpharmaceutical interventions in the management of behavioral symptoms and mood disorders have also been linked to improved cognitive and functional ability, enhanced patient and caregiver quality of life and delayed institutionalization. 7

Other Considerations
Clinicians responsible for patients with AD should pay attention to several areas that may impact well-being, and not only medication (Box 3). • Investigate potential medical, somatic, or medication-related reasons for any new change in function or behaviors.
• Promptly treat acute medical illnesses to reduce the risk of hospital admission.
• Offer caregiver education and support to help manage neuropsychiatric or behavioral symptoms (Table 3).
• Initiate psychoactive medication as necessary, balancing the benefits and risks, and document a discussion with the patient and/or family members in the medical record.
• Be aware of adverse impact of polypharmacy and potential for drug-drug interactions.

Safety
Keeping the person with AD safe is important, to prevent injuries, maximize function, minimize stress and agitation, and reduce caregiver burden. 7 A home assessment may be useful to identify hazards that could increase the risk of falls. Patients with AD may no longer remember how to use appliances correctly, identify toxic substances, or handle sharp objects, so caregivers should ensure that potentially harmful objects are removed. 7 The Alzheimer's Association, Alzheimer Foundation of America, and other advocacy groups have resources on how to assess and manage patient safety in the home. 108 Approximately 60% of US households that have a family member with dementia have a gun. 109 Few laws regulate gun ownership in relation to age or cognitive function. 110 Since patients with dementia may develop aggressive behaviors toward themselves and others as the disease progresses, 111 firearms pose a risk of serious injury. 110 When it comes to gun ownership, clinicians need to balance the patient's right to autonomy against the need for safety. 7,112 Patients with AD will have to stop driving when their limitations make it unsafe. Discussing this possibility early in the disease course can help planning. 113 Clinicians should be familiar with their state's regulations regarding minimum cognitive requirements for licensure, and legal requirements for reporting the diagnosis. The American Occupational Therapy Association website (http://www.aota.org) identifies resources for people with AD and their families, including a national database of driving specialists, who can evaluate and offer strategies to reduce driving risk.

Ongoing follow-up
Clinicians need to regularly assess the patient for changes in daily functioning, cognitive status, comorbidities, behavioral symptoms, medication requirements, and care needs; any sudden changes require attention. 7 Weight loss occurs in~40% of patients with AD. 114 Patients showing signs of weight loss should be offered nutritional supplementation and advice on increasing daily calorie intake. Dosing modifications may also be appropriate for these patients.

Abuse
Clinicians are well placed to identify potential patient abuse and neglect, or signs of overwhelming stress and abuse in caregivers. 7 It is important to recognize that abuse may be exerted by the patient on the caregiver or vice versa. 7 Effective management of aggressive symptoms or psychiatric comorbidities is essential, as is timely referral to support services. Across the United States, a number of elder abuse multidisciplinary teams exist, which provide expert consultation to service providers, and identify service gaps and systems problems when managing cases of abuse. 115 Residential care and legal aspects The most common reasons for patients to move to residential care are the need for more skilled care than the caregiver can provide, the caregiver's health, and the patient's dementia-related behaviors. 116 Discussing the potential future need for residential care early in the disease course, and identifying the threshold for such decisions, can ease the process. Clinicians should advise patients and their caregivers to plan for when the patient will have diminished capacity, and seek legal advice to put in place the necessary powers of attorney, as well as documentation around end-of-life preferences, such as wills and advance directives/living wills. 7

Caregiver well-being
The importance of shaping policy and practice to support the caregiver cannot be overemphasized. 117

Support
• Are you regularly assessing how the caregiver is coping and the caregiver's physical health? 124 • Have you provided the caregiver with information on how to access local support services? 125 caregivers increase as the disease progresses, and may include managing bathing, dressing, feeding, and toileting. 86 Caregivers must cope with sometimes challenging behaviors while dealing with the emotional impact of the changes to their relationship with the patient. They are essential in providing information to healthcare profes-sionals about symptomatic and functional changes in the patient. 118 Clinicians should pay careful attention to the physical and psychological health of caregivers. 119 Education, support, counseling, respite care, and referral to other services may be required. Involving a social worker early in the course of the disease can help caregivers gain Diagnose (Figure 1 and Table 2) Evaluate cognition, function and behavior

Considerations throughout the disease course
Refer to Box 1, Box 2, Box 3 and Table 3 Moderate-to-Severe AD Initiate ChEI treatment at following doses: Donepezil   access to local support services and provide advice around financial assistance. 7 Summary AD is one of the most challenging chronic conditions to manage. Treatment must be individualized for the symptoms, functional status, comorbidities, behaviors, and the psychosocial situation of each patient, and requires regular reassessments for changes in the patient's and caregiver's medical, mental, and psychological states. Figure 2 shows an algorithm for how to manage AD in primary care. Early diagnosis, referral to specialists, and treatment initiation are key; as are understanding and conveying realistic expectations of treatment. Patients respond individually to different interventions, so clinicians should be willing to change medications to maximize patient and caregiver quality of life, and to engage the assistance of other healthcare professionals (e.g., geriatricians, neurologists, psychiatrists, psychologists, physical or occupational therapists, social workers). It should be emphasized to patients and caregivers that, while the progressive course of AD cannot be reversed, lifestyle changes and medication can delay the progression of cognitive and functional symptoms of AD and maximize quality of life.