Approximately 6.9 million people in the United States 65 years and older live with Alzheimer disease, a number expected to double by 2060. Although there is no cure for Alzheimer disease, treatments are available to manage symptoms.
Alzheimer disease (AD) is a progressive and fatal neurodegenerative condition marked by the accumulation of amyloid beta plaques and hyperphosphorylated tau proteins as neurofibrillary tangles.1,2 These tangles lead to neuron degeneration, cerebral atrophy, and memory loss, followed by a decline in daily functioning.1,2 The amyloid accumulation hypothesis suggests that genetics, lifestyle, chronic diseases, and environmental factors influence this process.2 As of 2024, about 6.9 million people in the United States 65 years and older have AD; this number is projected to reach 13.8 million by 2060.3 Current prevalence rates by age in the United States are 5% (65 to 74 years), 13.2% (75 to 84 years), and 33.4% (85 years and older).3 Although there is no cure for AD or medications to prevent cognitive decline, a few treatments are available to manage symptoms and enhance quality of life for people with AD.1,2,4 Treatment aims to address cognitive decline, alleviate specific symptoms, and support patients and their caregivers.1,2
BEST PRACTICES IN GERIATRIC MEDICINE
| Recommendation | Sponsoring organization |
|---|---|
| Do not use antipsychotics as the first choice to treat behavioral and psychological symptoms of dementia. | American Geriatrics Society |
| Do not prescribe cholinesterase inhibitors for dementia without periodic assessment for perceived cognitive benefits and adverse gastrointestinal effects. | American Geriatrics Society |
| Do not prescribe a medication without reviewing a patient's drug regimen. | American Geriatrics Society |
For supporting citations and to search Choosing Wisely recommendations relevant to primary care, see https://www.aafp.org/pubs/afp/collections/choosing-wisely.html.
SORT: KEY RECOMMENDATIONS FOR PRACTICE
| Clinical recommendation | Evidence rating | Comments |
|---|---|---|
| Music therapy can be recommended to minimally improve behavioral disruption, mood, and cognition in patients with mild cognitive impairment or dementia.14,15 | B | Systematic reviews of limited studies |
| Donepezil (Aricept) shows minor improvements in cognitive function, activities of daily living, and overall clinician-rated clinical state. Benefits of the 23-mg daily dosage are not significantly greater than those of the 10-mg daily dosage.42 | A | Systematic review of RCT |
| Brexpiprazole (Rexulti) is approved for agitation caused by Alzheimer disease, and risperidone is more effective than placebo for acutely treating neuropsychiatric symptoms in people with dementia; however, antipsychotics should not be used routinely because of an elevated risk of mortality.47,50,51 | B | Systematic review of RCTs, and a single RCT on brexpiprazole |
| Monoclonal antibody treatments have not demonstrated a meaningful benefit in patient-centered outcomes such as cognition; despite U.S. Food and Drug Administration approval, there are safety concerns, including amyloid-related imaging abnormalities.23,25,54 | B | Meta-analysis of RCTs with a mix of disease-oriented and patient-oriented outcomes |
| There is no evidence that vitamin E benefits cognition in patients with mild cognitive impairment or dementia.58 | B | Systematic review of RCTs |
RCT = randomized controlled trial.
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.
EVALUATION
According to the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., a diagnosis of major neurocognitive disorder requires a significant decline in one or more of the six cognitive domains that cause interference with independence in carrying out activities of daily living.5,6 The domains are complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.5,6
Diagnosing dementia requires a comprehensive approach, including medical history, cognitive and neurologic examinations, and input from patients and caregivers. Modern screening instruments aid in identifying patients who require further evaluation and in detecting cognitive impairment (Table 16–9). However, the U.S. Preventive Services Task Force and the American Academy of Family Physicians found no consistent evidence that general screening for cognitive impairment improves patient or caregiver outcomes.7,10,11 Free cognitive resources from the American Academy of Family Physicians are available to assist with evaluation, management, and support of patients with cognitive impairment (https://www.aafp.org/family-physician/patient-care/care-resources/cognitive-care.html).
Cognitive Assessment Instruments
| Screening instrument | Time | Sensitivity | Specificity | Comments | Cognitive domain assessed | Accessibility |
|---|---|---|---|---|---|---|
| Mini-Cog | 3 minutes | 67% to 100% | 54% to 85% | Minimal education or language bias Available in 23 languages other than English | Executive function, language, visuomotor skills | Free at https://mini-cog.com |
| Mini-Mental State Examination, 2nd ed. | 6 to 10 minutes | 89% | 81% | Patient's education level must be considered when interpreting the results Available in 75 authorized translations | Attention, language, memory, orientation, visuospatial perception | Available for purchase at https://www.parinc.com/Products/Pkey/238 |
| Montreal Cognitive Assessment | 10 minutes or less | 91% to 97% | 81% | Most common and preferred screening tool for mild cognitive impairment Available in more than 100 languages and dialects | Attention, executive function, language, memory, orientation, visuospatial perception | https://www.mocacognition.com Registration and waiver required to download the forms for free; training may require payment |
| Saint Louis University Mental Status Exam | 5 to 10 minutes | 92% to 100% | 81% to 98% | Takes less time to administer compared with Montreal Cognitive Assessment Available in 23 professionally translated languages | Concentration, immediate recall, language function, naming, orientation, praxis, visuospatial perception | Free at https://www.slu.edu/medicine/internal-medicine/geriatric-medicine/aging-successfully/assessment-tools/mental-status-exam.php |
NONPHARMACOLOGIC MANAGEMENT
Nonpharmacologic interventions are first-line treatments for all patients with dementia and their caregivers and target behavioral and psychological symptoms (Table 21,12–16). Treatment goals are to sustain cognitive function and activities of daily living while addressing accompanying issues such as depression, sleep disturbances, and agitation.12 These interventions are cost-effective and have minimal adverse effects.12,13 They encompass cognitive/emotion-oriented interventions, sensory stimulation interventions, other psychosocial interventions, and structured care practice.13 Evidence supporting these interventions varies; only modest benefits have been linked to their use.12,13
Nonpharmacologic Therapies for Patients With Dementia
| Therapy | Intervention | Potential effect | Evidence | Comments |
|---|---|---|---|---|
| Exercise | Structured and repetitive movement (aerobic or nonaerobic) to improve or support one or more components of physical fitness | May increase sleep duration and decrease nighttime awakenings No randomized controlled trial evidence to support the benefit of exercise on cognition, neuropsychiatric symptoms, or depression | Evidence shows inconsistent results on behavioral symptoms and functional status Variations in exercise intensity, baseline dementia severity, and outcome measures make it difficult to draw a conclusion | Evidence supports that midlife exercise is associated with a reduced risk of Alzheimer disease Benefits of exercise after the onset of dementia are unclear |
| Music therapy | Sing old songs, listen to music, play an instrument, or do group exercises while listening to music | May reduce agitation in the short term, potentially enhances cognitive skills and social/emotional skills | Evidence shows cognitive improvements, short-term mood improvement, and a decrease in behavioral disruption, but it does not demonstrate long-term benefits Well-conducted studies are lacking | It can potentially reduce agitation in patients with dementia in the short term It has the strongest evidence for reducing emotional disorders |
| Reality orientation | Orienting the patient to time and place to decrease confusion and behavioral symptoms using games, puzzles, calendars, and reality orientation boards | Improves cognitive function | Evidence supports benefits for cognition and behavioral symptoms in patients with dementia | Valuable, low-cost, long-term, complementary intervention for Alzheimer disease dementia |
| Reminiscence therapy | Recall past events, activities, and experiences using familiar items such as photographs, videos, and music | May improve mood and depression | Evidence supports improvement in emotional disorders but does not support its use for the treatment of behavioral symptoms of dementia | Moderate effect on depressive symptoms; some impact on functional capacity Reminiscence therapy, with music therapy and other psychological interventions, has the strongest evidence for reducing emotional disorders |
| Validation therapy | Validate the feelings of the patient instead of focusing on reality and confused status | Alleviates stress, enhances contentment, decreases behavioral disturbances, provides comfort | Mixed evidence Some evidence of reducing responsive behaviors Other studies show insufficient evidence for behavioral symptoms, depression, and emotional state associated with dementia | Benefits are limited to mild to moderate disease |
A systematic review from 2010 to 2017 comprehensively searched the nonpharmacologic interventions available for dementia in residential care.13 Music, sensory stimulation, simulated presence, and validation therapies show some evidence for reducing responsive behaviors.12,13,15 Music therapy, reminiscence therapy, and other psychological interventions have the strongest evidence for reducing emotional disorders.14,15 Specifically, music therapy appears to minimally improve behavioral disruption, mood, and cognition.14,15
Exercise and light therapy improve or maintain activities of daily living, and reminiscence therapy and cognitive stimulation improve cognition. Midlife exercise is linked to a reduced risk of AD, but its impact on cognitive function in people with existing AD is uncertain.1,17 Physical exercise is recommended for overall health benefits, including reducing cardiovascular risk.1,17 Cognitive training may help maintain cognition and quality of life, but its effectiveness in advanced dementia, particularly for behavioral and psychological symptoms of dementia, lacks strong evidence.1,6,17
PHARMACOLOGIC MANAGEMENT
Initiating pharmacologic treatment for AD requires careful consideration of disease stage, symptom severity, and individual patient characteristics. Guidelines stress early and accurate diagnosis before starting medications.17 Decisions to begin treatment involve evaluation of comorbidities, tolerance to adverse effects (mainly gastrointestinal), and shared decision-making with patients and caregivers.6Table 3 lists medications for the treatment of AD.1,6,17–38
Medications for the Treatment of Alzheimer Disease
| Medication | Mechanism of action | Dosing | Benefits | Adverse effects | Comments | Cost* |
|---|---|---|---|---|---|---|
| Acetylcholinesterase inhibitors | ||||||
| Donepezil (Aricept) | Reversible acetylcholinesterase inhibitor Increases acetylcholine availability at the synapses in the central nervous system | Oral immediate release: 5 mg nightly for 4 to 6 weeks; may increase to 10 mg nightly (maintenance dosage) Oral sustained release: if tolerated, may increase to 23 mg nightly after 3 weeks of a maintenance dosage | Improves symptoms of cognition and behavior in mild, moderate, and advanced AD | Atrioventricular block, bradycardia, decreased appetite, diarrhea, dizziness, drowsiness, fatigue, headache, insomnia, muscle cramps, nausea, QT prolongation, syncope, vivid dreams, vomiting, weight loss | Donepezil is the longest FDA-approved medication for AD Available as generic and covered by most health insurance plans Higher dosages are less tolerable in select patients Elevated drug levels may occur in patients with hepatic impairment and with the use of CYP2D6 or CYP3A4 inhibitors | 10 mg: $4 ($515) 23 mg: $19 ($460) |
| Galantamine (Razadyne) | Reversible acetylcholinesterase inhibitor Increases acetylcholine availability at the synapses in the central nervous system | Oral immediate release: 4 mg twice daily; if tolerated, increase by 4 mg twice daily at least every 4 weeks, until 12 mg twice daily (maintenance dosage) Oral extended release: 8 mg daily; if tolerated, increase by 8 mg daily at least every 4 weeks until 24 mg daily (maintenance dosage) Renal dosing: if CrCl is 9 to 59 mL per minute per 1.73 m2 (0.15 to 0.99 mL per second per m2), maximum dosage of 16 mg daily; if CrCl less than 9 mL per minute per 1.73 m2, avoid use | Improves symptoms of cognition and behavior in mild and moderate AD | Atrioventricular block, bradycardia, decreased appetite, diarrhea, dizziness, falls, headache, insomnia, muscle cramps, nausea, syncope, vivid dreams, vomiting, weight loss | Available as oral solution Elevated drug levels may result in renal and hepatic impairment In CYP2D6, slow metabolizers Caregivers reported an improvement in their quality of life | Immediate release: $20 (—) Extended release: $30 ($315) |
| Rivastigmine | Reversible acetylcholinesterase inhibitor Increases acetylcholine availability at the synapses in the central nervous system | Oral: 1.5 mg twice daily with meals; if tolerated, increase by 1.5 mg twice daily every 2 to 4 weeks until 6 mg twice daily (maintenance dosage) Transdermal patch (Exelon): apply 4.6-mg patch to upper back daily; if tolerated, increase after 4 weeks to 9.5 mg per day and after another 4 weeks to 13.3 mg per day (maximum dosage) Change the patch location periodically to minimize skin irritation | Improves symptoms of cognition and behavior in mild and moderate AD | Abdominal pain, allergic dermatitis (both formulations), atrioventricular block, bradycardia, decreased appetite, diarrhea, dizziness, falls, fatigue, headache, insomnia, irritation at the application site (patch), muscle cramps, nausea, syncope, tremors, vivid dreams, vomiting, weight loss | Available in transdermal patch Avoid in combination with beta-blocker therapy Reduced clearance in hepatic and moderate renal impairment; increased in severe renal impairment and among smokers Higher dosages are less tolerable in select patients Approved to treat mild to moderate dementia associated with Parkinson disease | Oral: $20 (—) Transdermal: $50 ($700) |
| N-methyl- | ||||||
| Memantine (Namenda; Namenda XR) | Noncompetitive antagonist of the glutamate receptor subtype known as N-methyl- | Oral immediate release: 5 mg daily; if tolerated, increase after 1 week by 5 mg weekly until 10 mg twice daily (maintenance dosage) Oral extended release: 7 mg daily; if tolerated, increase by 7 mg weekly until 28 mg daily (maintenance dosage) Renal dosing: CrCl 5 to 29 mL per minute per 1.73 m2 (0.08 to 0.48 mL per second per m2) to immediate release 5 mg daily and extended release 14 mg daily (maximum dosage for both) | Neuroprotective and slows neurotoxicity in moderate to severe AD | Well tolerated Adverse effects may include confusion, constipation, diarrhea, dizziness, headache, hypertension, hypotension, vomiting | Reduced clearance in hepatic and renal impairment and alkaline urine Do not use concurrently with amantadine Can be combined with an acetylcholinesterase inhibitor | Immediate release: $10 ($450) Extended release: $25 ($480) |
| Combination therapy | ||||||
| Memantine/donepezil (Namzaric) | Noncompetitive antagonist of the glutamate receptor subtype known as N-methyl- | Oral: 7 mg extended release/10 mg immediate release nightly for 4 weeks; if tolerated, increase by 7 mg/10 mg weekly until 28 mg/10 mg nightly (maintenance dosage) Renal dosing: CrCl 5 to 29 mL per minute per 1.73 m2: 14 mg/10 mg nightly | Slows neurotoxicity in moderate to severe AD and improves symptoms of cognition and behavior in all stages of AD | Atrioventricular block, confusion, constipation, diarrhea, dizziness, headache, insomnia, loss of appetite, nausea, syncope, vivid dreams, vomiting | Combination therapy is a good option for patients previously exposed to one or both drugs without adverse effects Caution in patients with hepatic and renal impairment | $— ($600) |
| Symptomatic therapies | ||||||
| Brexpiprazole (Rexulti) | Second-generation antipsychotic drug Partial agonist at serotonin 5-HT1a and dopamine D2 receptors; antagonist at serotonin 5-HT2a receptors | Oral dosing: Week 1: 0.5 mg daily Week 2: if tolerated, increase to 1 mg daily Week 3: 2 mg daily (maintenance dosage) After 2 weeks, if tolerated and a positive clinical response has been shown, increase to 3 mg daily (maximum dosage) Renal dosing: CrCl less than 60 mL per minute per 1.73 m2 or moderate to severe hepatic impairment (Child-Pugh B or C): 2 mg once daily | Improves agitation symptoms in older adults with dementia secondary to AD | Akathisia, constipation, dizziness, fatigue, headache, nasopharyngitis, sleep disturbances, somnolence, tremors, urinary tract infection, weight gain | First drug approved by the FDA for agitation due to AD Black box warning for increased risk of death in older adults with dementia-related psychosis Drugs that inhibit CYP3A4 or CYP2D6 may increase serum concentrations of brexpiprazole Brexpiprazole was not compared with other second-generation antipsychotics for this indication | 0.5 mg to 3 mg, 7 days: $— ($1,500) Price is the same regardless of dosage |
| Suvorexant (Belsomra) | Orexin-receptor antagonist that blocks OX1R and OX2R | Oral: 10 mg nightly, 30 minutes before bedtime May increase to 20 mg nightly (maximum dosage) | May reduce amyloid beta and tau phosphorylation concentrations in the central nervous system | Abnormal dreams, driving impairment, hallucination, muscle weakness, sedation, sleepwalking, somnolence, suicidal ideation | First FDA-approved drug for treating sleep disorders in mild to moderate AD Enhances polysomnography-derived total sleep time in patients with AD and insomnia Sleep disturbances are linked to AD development by increasing amyloid beta plaque formation 10-mg dose did not produce the same effect on amyloid beta and tau phosphorylation as 20-mg dose Schedule IV controlled substance | $— ($460) |
| Anti-amyloid monoclonal antibodies | ||||||
| Aducanumab (Aduhelm) | Humanized immunoglobulin gamma 1 monoclonal antibody Selectively binds amyloid beta plaques in the brain | Intravenous: 45- to 60-minute infusion every 4 weeks (at least 21 days apart) 1st and 2nd infusions: 1 mg per kg 3rd and 4th: 3 mg per kg 5th and 6th: 6 mg per kg 7th and beyond: 10 mg per kg (maintenance dosage) | Decreases the brain's amyloid beta plaques | ARIA may occur in approximately 40% of patients: attributable to edema and effusion (30.7%); attributable to microhemorrhage and hemosiderosis (30%) 70% of ARIA are asymptomatic; however, adverse effects may include confusion, dizziness, headache, nausea, seizures, visual disturbance Non-ARIA may include altered mental status, diarrhea, falls, headache, urticaria | Most recent drug for AD since 2003; in January 2024, the manufacturer discontinued development and further studies FDA-approved through accelerated pathway for mild cognitive impairment or mild AD Reduction of brain amyloid plaque burden is dose- and time-dependent ARIA to edema and effusion is more prevalent in APOE-4 gene carriers, with higher dosages, and in the first 8 months of treatment Medications approved by the FDA's accelerated pathway restricts Medicare coverage | NA (NA) |
| Lecanemab (Leqembi) | Humanized immunoglobulin gamma 1 monoclonal antibody Selectively binds amyloid beta plaques in the brain | Intravenous: 60-minute infusion every 2 weeks of 10 mg per kg | Decreases the brain's amyloid beta plaques and may reduce cognitive and functional decline | ARIA may occur in approximately 20% of patients: attributable to edema and effusion (12.6%); attributable to microhemorrhage and hemosiderosis (17.3%) Most patients are asymptomatic; however, adverse effects may include confusion, dizziness, headache, visual disturbance Non–ARIA may include angina, atrial fibrillation, falls, headache, infusion-related reactions, syncope | ARIA attributed to edema and effusion are more prevalent in APOE-4 gene carriers and in the first 3 months of treatment Potential risk of ARIA might be reduced due to differences in pharmacologic profile Medications approved by the FDA's accelerated pathway restricts Medicare coverage No need for dose titration | $26,500 a year† |
| Donanemab (Kisunla) | Humanized immunoglobulin gamma 1 monoclonal antibody Selectively binds amyloid beta plaques in the brain | Weeks 1–3: 700 mg intravenously over 30 minutes Week 4 and beyond: 1,400 mg intravenously over 30 minutes | Decreases the brain's amyloid beta plaques and may modestly slow disease progression | ARIA (edema or microhemorrhage; 36.8% donanemab vs. 14.9% placebo) Three deaths in the donanemab group and one in the placebo group were considered treatment related | FDA approved in July 2024 ARIA incidence greater in APOE-4 gene carriers No direct comparisons available between lecanemaband donanemab | $32,000 a year‡ |
| Uncertain therapies | ||||||
| Vitamin E | Lipid-soluble vitamin and strong chain-breaking antioxidant | Oral: 200 to 2,000 IU daily of alpha-tocopherol | Potentially slows functional decline in mild to moderate AD | Blurred vision, diarrhea, dizziness, headache, heart disease, hemorrhage, hypertension, weakness, worsening symptoms of diabetes mellitus | Vitamin E becomes toxic at high dosages, typically exceeding 3,000 IU daily May decrease caregiver burden Contraindicated in patients with bleeding disorders or coronary artery disease | 2,000 IU: $4 |
AD = Alzheimer disease; CrCl = creatinine clearance; CYP = cytochrome P450; FDA = U.S. Food and Drug Administration; NA = not available.
*—Estimated lowest GoodRx price for 1 month of treatment, unless otherwise noted. Actual cost will vary with insurance and by region. Generic price listed first; brand name price in parentheses. Information obtained at https://www.goodrx.com (accessed June 12, 2024; zip code: 66211).
†—Estimated price for 1 year of treatment. Actual cost will vary with insurance and by region. Information obtained from Nguyen HV, Mital S, Knopman DS, et al. Cost-effectiveness of lecanemab for individuals with early-stage Alzheimer disease. Neurology. 2024;102(7):e209218. Accessed July 21, 2024.
‡—Estimated price for 1 year of treatment. Actual cost will vary with insurance and by region. Information obtained from The Medical Letter. 2024;66(1709):129–131.
Treatment goals typically include slowing disease progression, managing symptoms, and enhancing quality of life, including addressing behavioral and psychological symptoms.6 Regular monitoring post-initiation is essential to assess treatment response and potential adverse effects.4,6 Although pharmacologic treatment provides symptomatic relief and may slow progression, it does not cure AD.6 Discontinuing pharmacologic treatment for AD requires consideration of the treatment response, patient preferences, and care goals.39 Concerns that may prompt the decision to discontinue treatment include lack of effectiveness, intolerable adverse effects, and advanced disease stage.4,39 Regular monitoring and gradual deprescribing are essential under health care supervision to manage potential withdrawal effects, which may include worsening cognitive, neuropsychiatric, and functional status; however, evidence supporting these risks is limited and of low certainty.39,40 Individualized reassessment of treatment decisions is necessary when changes in health status occur.39,40
Acetylcholinesterase Inhibitors
Acetylcholinesterase inhibitors, including donepezil (Aricept), galantamine (Razadyne), and rivastigmine, enhance cholinergic neurotransmission, showing positive outcomes for 1 patient out of 12 treated.1,41 However, adverse effects necessitating discontinuation occur in 1 out of 16 patients.41 Lower dosages of donepezil (10 mg daily) demonstrate comparable effectiveness to higher dosages (23 mg daily).41,42 Donepezil, the most commonly prescribed drug for AD, is approved to treat all stages of the disease.42 Studies suggest it may be more effective than galantamine, although direct comparisons are lacking.41 Moderate-quality evidence indicates that individuals with AD experience modest improvements in cognitive function, activities of daily living, and overall clinical state when treated with donepezil for 12 or 24 weeks.42
In clinical trials, galantamine improved global function, cognitive abilities, and activities of daily living, reducing caregiver distress.43 Rivastigmine showed modest improvements in cognitive function and activities of daily living, but it was associated with a higher risk of gastrointestinal adverse effects, specifically the capsule form.44 Galantamine and rivastigmine are approved for mild to moderate AD. Medication choice should depend on the patient's response to adverse effects, which can be observed and managed through slow dose titration.44 A moderate maintenance dose may help mitigate adverse effects because the highest dosage may not provide additional clinical benefit.44 Ongoing studies suggest these medications may slow cognitive decline despite challenges related to tolerability and adherence, ultimately enhancing patient outcomes.42
-Methyl-
Memantine (Namenda) is the only N-methyl-d-aspartate receptor antagonist approved by the U.S. Food and Drug Administration (FDA) for moderate to severe AD. Memantine provides modest clinical benefits and excellent tolerability compared with cholinergic compounds.21 Combination therapy (memantine/donepezil [Namzaric]) in moderate to severe AD demonstrates better outcomes in cognition, global assessment, activities of daily living, and neuropsychiatric symptoms based on a meta-analysis of 54 studies, but with lower tolerability.45 In persons with AD, the Alzheimer's Disease Assessment Scale–Cognitive Subscale showed the best improvement with combination therapy of memantine/donepezil, followed by donepezil alone and memantine alone.45 The Severe Impairment Battery scale similarly ranked memantine/donepezil first in effectiveness, followed by donepezil alone and memantine alone.45 Fixed-dose combination extended-release memantine/donepezil (Namzaric XR) enhances adherence and reduces caregiver burden, especially for patients with dysphagia, poor adherence, and limited caregiver support.46 Switching to memantine alone is preferable for patients unable to tolerate the memantine/donepezil combination.45 The treatment choice should be based on patient preferences, clinical circumstances, and AD progression.45
Symptomatic Therapies
Agitation and insomnia cause significant complications for the caregiver and have limited management options. Atypical antipsychotics, widely used for psychosis, agitation, hallucinations, and aggression in AD, increase the risk of death when used in people with AD (odds ratio = 1.54; 95% CI, 1.06 to 2.23; P = .02).47 Because of this safety concern, nonpharmacologic strategies to manage noncognitive symptoms should be explored before prescribing medications.47 Agitation is a prevalent challenge in AD, affecting 30% to 50% of patients and often leading to nursing home placement due to caregiver distress.48 Although atypical antipsychotics are not recommended due to limited effectiveness and established risks, such as falls and extrapyramidal effects, they are commonly used off-label for dementia-related behaviors.49
Brexpiprazole (Rexulti), the first FDA-approved medication for AD-associated agitation, demonstrates significant improvement vs. placebo in reducing symptoms over 12 weeks.50 Risperidone has also shown effectiveness and tolerability in addressing neuropsychiatric symptoms, according to a meta-analysis of randomized controlled trials.51 Insomnia is a prevalent issue in AD, and suvorexant (Belsomra), an orexin receptor antagonist, has shown effectiveness in improving total sleep time by inhibiting neuropeptides that induce wakefulness without significant physical dependence.34 However, there are uncertainties about the optimal duration of therapy for cognitive and functional decline at different disease stages.17
Anti-Amyloid Monoclonal Antibodies
Aducanumab (Aduhelm), the first FDA-approved amyloid beta plaques monoclonal antibody for mild cognitive impairment and mild AD, was found to reduce brain amyloid beta plaques in the PRIME, ENGAGE, and EMERGE double-blinded, placebo-controlled trials, with effectiveness dependent on dosage and treatment duration.22,52 Confirmatory amyloid tests, such as positron emission tomography or cerebrospinal fluid biomarker analysis, are required before treatment.22,52 This evidence is focused only on disease markers rather than patient-oriented outcomes that matter, such as improvement in cognitive function.53 The FDA approval sparked controversy due to a lack of patient-oriented benefit and safety concerns, with 30% to 40% of patients potentially developing amyloid-related imaging abnormalities (ARIA), including brain edema and effusion, and microhemorrhage and hemosiderosis.23 Symptoms of ARIA in aducanumab therapy are primarily asymptomatic, with headaches being the most common.24 In January 2024, Biogen announced it was discontinuing the development of aducanumab and terminating the ENVISION study, a phase 4 confirmatory trial required by the FDA, with plans to focus on other treatments such as lecanemab (Leqembi).36
Lecanemab, similar to aducanumab, is an amyloid beta monoclonal antibody with a stronger affinity for soluble protofibrils, posing greater toxicity to neurons.25,27 Confirmatory amyloid tests are necessary before starting infusions, especially for patients who are APOE-4 homozygote carriers and have a higher risk of developing ARIA than noncarriers (32.6% vs. 5.4%).27 Magnetic resonance imaging to monitor for ARIA is recommended before and intermittently during treatment.27 Lecanemab is administered intravenously every 2 weeks without titration37 (Table 31,6,17–38). Although lecanemab has shown a reduction in amyloid beta plaques and minor cognitive improvements, these outcomes fall short of clinically meaningful changes, and there are potentially severe adverse effects associated with its use.25,27,52,54
Another monoclonal antibody, donanemab (Kisunla), received FDA approval in July 2024 for patients with mild cognitive impairment or mild dementia. Similarly, it has shown improvements on cognitive scales that may not be clinically meaningful and increased risk of ARIA.38,54,55
Ongoing research focuses on medications targeting amyloid beta plaques and tau protein buildup, neuroinflammation, immune response, and metabolic changes.56 Due to the complexity of AD, a patient-centered approach evaluating each intervention's benefits and risks is essential.17
OTHER THERAPIES
The potential benefits of vitamin E in managing dementia are uncertain. Trials exploring doses from 200 to 2,000 IU daily have not determined an optimal dose.57 A Cochrane review found no evidence that vitamin E improves cognition or slows the progression of mild cognitive impairment or dementia.58 Moderate-quality evidence from a single study suggests that vitamin E (2,000 IU) could serve as an adjunct therapy to cholinesterase inhibitors, potentially slowing the functional decline in individuals with mild to moderate AD.20,58
Most studies find no evidence for the prevention or mitigation of dementia progression for ginkgo biloba; nonsteroidal anti-inflammatory drugs; vitamins C, D, and B; omega-3 fatty acids; estrogen replacement therapy; coconut oil; caprylidene; ergoloid mesylates; and statins.2,59,60 Epidemiologic evidence suggests a modest protective effect of a Mediterranean or plant-based diet for dementia. World Health Organization guidelines recommend the Mediterranean diet to reduce cognitive decline and dementia risk.2,59,60