Alzheimer’s Dementia Pharmacotherapy

The chart below addresses common clinical questions about the pharmacotherapy of Alzheimer’s dementia. The focus of this chart is information to help you initiate, and when appropriate, discontinue cholinesterase inhibitors and memantine. Other resources pertaining to dementia include our chart, Pharmacotherapy of Dementia Behaviors, and our Pharmacotherapy of Dementia Behaviors Algorithm. See our chart, Parkinson’s Dementia and Dementia with Lewy Bodies, to learn about special considerations and pharmacotherapy options in these patients. For caregiver information and support, see Alzheimer’s Society of America (http://alzheimerssocietyofamerica.org/) or Alzheimer Society Canada (https://alzheimer.ca/en/Home).

Clinical question

Pertinent information or resources

How effective are cholinesterase inhibitors for dementia?

Most studies of cholinesterase inhibitors have been in mild to moderate dementia.12 Efficacy is modest, at best.3 There is no proven disease-modifying therapy for Alzheimer’s dementia.3

Benefits demonstrated in clinical trials (i.e., improvement on cognitive tests) may not translate into clinically significant benefits that patients and caregivers notice.7

In clinical studies, the efficacy of drugs for dementia is assessed using several validated assessment tools administered by trained clinicians.14 These tools measure cognition, global assessment, function, and less commonly, behavior.14 The ADAS is a commonly used outcome measure.14 One subscale of the ADAS, the 70-point ADAS-cog, is used to evaluate attention, memory, orientation, language, and speech.3,14 For patients with mild to moderate disease, a change of four points in the ADAS-cog is considered clinically significant.14 Global response is usually measured using the CIBIC, CIBIC with caregiver input (CIBIC-plus), and variations thereof.14 These tools assess patients in general, and their cognition, behavior, and ability to perform activities of daily living.14 MMSE is a 30-point measure of cognition.3,14 A change of three points on the MMSE is considered clinically significant.15 The SIB measures the cognitive areas of attention, orientation, language, and speech in moderate to severe dementia.14

Cholinesterase inhibitors improve the ADAS-Cog by three points, and the MMSE by one point, at best.3 These cognitive benefits are consistent across agents, and seem to be dose-dependent.3

They have a small benefit for ADL and caregiver burden (<1 hour/day difference from placebo), but evidence of benefit for quality of life is inconsistent.3,32 They are not likely to help agitation or aggression.10

In a meta-analysis, NNT for any improvement on a global assessment score was 12. However, to obtain marked improvement, the NNT was 42. For clinically significant cognitive benefit, the NNT was 10.13

Only open-label studies suggest that cholinesterase inhibitor may help patients avoid nursing home placement for several months.8,9,31

What are the side effects of cholinesterase inhibitors and memantine?

One in 12 patients taking a cholinesterase inhibitor will experience a side effect.13

Common side effects include nausea, vomiting, diarrhea, and anorexia.3 To improve tolerability, follow the labeled titration schedule, or increase even more slowly, and advise taking with food (except donepezil, which is not affected by food).16,27 An antiemetic could be prescribed if needed.16

Less commonly, cholinesterase inhibitors have been associated with bradycardia, putting patients at risk for syncope, fractures, and pacemaker insertion.

Memantine is well-tolerated. Common side effects include dizziness, confusion, headache, and constipation.3

When should a cholinesterase inhibitor or memantine be prescribed for dementia?

In the U.S., cholinesterase inhibitors are commonly prescribed for mild cognitive impairment.3 However, efficacy is not proven in mild cognitive impairment without dementia.2,3 Benefit, if any, at this stage is very small and not clinically significant.3

Evidence does not support a disease-modifying benefit for cholinesterase inhibitors or memantine, so there is no rush to start them.3

Memantine’s efficacy is not apparent until the patient has at least moderate disease.3

Consider patient/caregiver preferences in regard to starting pharmacotherapy.3

What points should be covered with patients/caregivers before starting a cholinesterase inhibitor?

Prescribers and patient/caregiver should set easily measured, practical treatment goals so that efficacy can be determined.7

Explain that stabilization is a more realistic expectation than improvement.3

Emphasize that most patients will not benefit. As many patients benefit as experience a side effect (1 in 12).13

Review side effects and ways of addressing them.

Introduce the concept of deprescribing before starting, and continue to discuss even during treatment.17

How do you choose among cholinesterase inhibitor products?

There are three cholinesterase inhibitors available for Alzheimer’s disease: donepezil, galantamine, and rivastigmine.2

  • Indications: all are approved for mild to moderate Alzheimer’s disease. Donepezil is also approved for severe disease.
  • Dosage forms:
    • Donepezil is available as a tablet (Aricept, generics), orally disintegrating tablet (Aricept RDT [Canada]; generics), an extended-release capsule in combination with memantine (Namzaric; U.S. only).
      • Note that the 23 mg donepezil tablet (U.S.) is not much more effective than the 10 mg tablet (2.2 points on the SIB), but has a higher risk of GI side effects (21% vs 5.9%), especially in patients with lower body weight.3
    • Galantamine is available as a tablet (Razadyne, generics; U.S. only), an extended-release oral capsule (Razadyne ER [U.S.], generics), or oral solution (U.S. only).
    • Rivastigmine is available as a capsule (Exelon [Canada], generic) and once-daily transdermal patch (Exelon, generic). The patch provides steady drug delivery that minimizes side effects, but it can cause skin irritation.3,23
  • Efficacy and side effects: direct comparisons are too limited to identify one agent as more effective than another. If a patient does not respond well to one, or has adverse effects, another agent can be tried.3 Oral rivastigmine may have more GI side effects due to inhibition of GI cholinesterase.22 Donepezil seems to have the least GI effects.29
  • Drug interactions: donepezil and galantamine are metabolized by CYP2D6 and CYP3A4.3
  • Use in hepatic or renal impairment: In hepatic impairment, levels of cholinesterase inhibitors may be increased.3 Patients with mild to moderate hepatic impairment or moderate to severe renal disease may only be able to tolerate low doses of rivastigmine (Canada: contraindicated in severe hepatic impairment).18,33 Titrate slowly.18 Galantamine has specific dosing recommendations for renal and hepatic impairment.5,6

What is the role of memantine in dementia?

Efficacy is modest, at best.2 Not all studies have shown benefit.2 In a meta-analysis, memantine benefited global response, cognition, and activities of daily living.3

Memantine does not appear to be effective in mild disease; nevertheless, it is commonly prescribed.3

Memantine is generally better tolerated than the cholinesterase inhibitors.3 If cholinesterase inhibitors are intolerable, consider switching to memantine in moderate to severe disease. However, it may not work as well [Evidence level B-1],4 and may worsen pre-existing agitation.3

When should memantine be used in combination with a cholinesterase inhibitor?

Combination therapy can be considered in patients with moderate to severe disease.3,4,19,20

  • Almost 300 noninstitutionalized patients with moderate to severe Alzheimer’s disease (mini-mental state exam score 5 to 13) who had been taking donepezil for at least three months were randomized to continue donepezil 10 mg daily, discontinue donepezil, add memantine, or switch to memantine (DOMINO-AD trial).4 The patients were followed for a year. Two hundred eighteen patients completed the study, but one hundred fourteen patients had less than 70% adherence (n=114). Adherence was better in the dual therapy arm, suggesting perhaps that caregivers noticed a benefit. Intent-to-treat analysis was used. There was no cognitive benefit to adding memantine to donepezil, but this study may have been underpowered to show a difference. There was benefit for behavioral symptoms (a secondary outcome measure), per the neuropsychiatric inventory [Evidence level B-1].
  • A previous larger (n=404) study of memantine plus donepezil versus donepezil alone in moderate to severe Alzheimer’s disease (MMSE score 5 to 14) showed a statistically significant benefit of combination therapy in both cognitive and functional performance.20 Primary efficacy measures were the SIB and the ADCS-ADL19 (modified 19-item Alzheimer’s Disease Cooperative Study-Activities of Living Inventory), a measure of function. The intent-to-treat method using the last observation carried forward was used for missing data. The SIB increased 0.9 points in the group using both memantine plus donepezil, but decreased by 2.5 points in the donepezil-only group, a difference of 3.4 points (p<0.001). There is no accepted clinically important change for the SIB.14 However, for comparison, in validity testing of the SIB, the six-month rate of change was a decrease of about 3 points in patients with MMSE scores of 5 to 15 who were not taking dementia meds.21 The ADCS-ADL19 decreased by 3.4 points in the placebo group and by 2 points in the memantine group (p=0.03).20 This is a relatively small change on a 0 to 54-point scale. Secondary measures of global response and behavior also improved with the combination. Differences in treatment groups occurred early and were maintained through six months. No additive effect on adverse events was noted with combination therapy [Evidence level A-1].
  • A subsequent study (n=433) included patients with a MMSE score of 10 to 22 (mild to moderate disease) who had been taking a stable dose of a cholinesterase inhibitor.19 Patients were randomized to receive, in addition to their cholinesterase inhibitor, memantine 20 mg once daily or placebo. Primary outcome measures were the ADAS-cog and the CIBIC+. Three hundred eighty-five patients completed the study, and 427 were included in the intent-to-treat analysis. There was no statistically significant difference between memantine and placebo. Combination therapy was not associated with an increased risk of adverse effects.
  • Meta-analyses suggest modest benefit of combination therapy on cognition, global response, behavior, and ADL, especially in patients with moderate-to-severe disease.3

When should you consider stopping memantine or cholinesterase inhibitors for dementia?

Consider discontinuing if:

  • Side effects occur.3
  • End-of-life care becomes the focus of therapeutic goals.3 Admission to a nursing home or hospice might be a good time to consider whether dementia medications should be continued.
  • Desired effects (improvement or stabilization) are not seen in about three to six months.7,8
  • There is rapid or persistent deterioration in cognition, function, and behavior, and delirium has been ruled out.17 These severely impaired patients may be incontinent; unable to groom, dress themselves, or communicate effectively; or have a MMSE score ≤10.
  • The patient is refusing or having problems swallowing meds.17

Are there risks to stopping cholinesterase inhibitors or memantine?

In the DOMINO-AD study described above in noninstitutionalized patients, the primary outcome measures were the mini-mental state exam score and the Bristol Activities of Daily Living Scale (BADLS).4 Compared to patients who discontinued donepezil, the MMSE score of patients who continued donepezil was 1.9 points higher (95% CI 1.3 to 2.5, p<0.001), indicating better cognitive function. They also had a 3-point lower BADLS score on average (95% CI 1.8 to 4.3, p<0.001), indicating better function. However, these small difference in BADLS and MMSE are probably not clinically meaningful. Patients with less severe disease benefited most from continuing donepezil.

In a more recent discontinuation study (n=40), institutionalized patients with moderate to severe dementia were assessed using the CGI-C scale.11 In this pilot study, there was no difference in clinical worsening between patients randomized to continue their cholinesterase inhibitor vs those randomized to placebo. Behavior was not adversely affected by discontinuation. However, this study may have been underpowered to detect differences.

In an analysis of U.S. Medicare data, discontinuation of cholinesterase inhibitors was associated with a decreased risk of falls and fractures in nursing home patients with severe dementia.12 It did not increase the risk of emergency department visits, hospitalization, or death.12

Eight studies (open-label discontinuation, chart review, and discontinuation after a clinical trial) have examined the effect of memantine discontinuation, but none were randomized comparisons of continuation vs discontinuation. Three found worsening symptoms.17

Should memantine and cholinesterase inhibitors be tapered when discontinued?

Cut the dose by 50% every four weeks until the lowest available dose is reached (e.g., reduce donepezil dose to 5 mg once daily for four weeks, then stop).4,17

Monitor closely and restart quickly at the previously minimum effective dose in the event of severe deterioration.17,30 Rule out other causes of deterioration, such as infection.30

Withdrawal may cause a discontinuation syndrome, beginning within a week of discontinuation:17

  • Cholinesterase inhibitors: difficulty concentrating, altered consciousness, delirium, hallucinations, insomnia, agitation, anxiety, or labile mood.24,26
  • Memantine: insomnia, aggression, delusions, and disinhibition.25

What are some talking points for patients/caregivers regarding deprescribing memantine or cholinesterase inhibitors?

Most patients tolerate medication withdrawal.4,11,12,17 If caregivers are concerned about care burden, consider referral to support services.30

Withdrawal of cholinesterase inhibitors does not hasten death.12

Withdrawal of cholinesterase inhibitors reduces adverse effects (e.g., falls), pill burden, medication management burden for caregivers, and cost.12,17,30 Adherence to other medications may be improved.30

Discontinuing pharmacotherapy may pose a risk of cognitive and behavioral decline, so the patient should be monitored closely so that the medication can be reinstituted quickly if needed.17 This would occur two to six weeks after dose reduction or cessation of therapy.17

Decline noticed after stopping the medication may be due to disease progression rather than medication withdrawal. This is likely the cause of deterioration noted six weeks to three months after dose reduction or cessation.17

Ensure caregivers know what to monitor and what to do in the event of deterioration or withdrawal reaction.17

An example of deprescribing information in an algorithm form is available at https://cdpc.sydney.edu.au/wp-content/uploads/2019/06/algorithm-for-deprescribing.pdf.

What is the role of Aduhelm (aducanumab) in the treatment of dementia?

Aduhelm is a monoclonal antibody against amyloid beta plaque. It is given as a one-hour infusion every four weeks.34

Aduhelm is FDA-approved only for Alzheimer's patients with mild cognitive impairment or mild dementia, the population in which it was studied.34 Patients included in the clinical trial had a positive amyloid PET (positive emission tomography) scan and met clinical criteria for either prodromal or mild Alzheimer's disease.38

Aduhelm was FDA-approved using the accelerated approval pathway, which can be used for drugs for serious diseases for which there are few good treatments.35 This kind of approval can be based on a surrogate endpoint.35 Aduhelm approval was based on a small reduction in amyloid beta plaques; however, reduction in amyloid beta plaques has not been shown to be a marker for clinical benefit.34,36

Two phase III Aduhelm studies were stopped when early data suggested futility in regard to the primary efficacy endpoint (CDR-SB, a measure of cognitive and functional decline).37 But later analysis suggested possible benefit (e.g., modest improvement in ADCS-ADL-MCI, a measure of functional impairment) in one study.37,38 Studies to confirm benefit must be done by 2030.36

A common (≥10%) and potentially serious side effect of Aduhelm is amyloid-related imaging abnormalities: edema and hemosiderin deposition (microhemorrhage and superficial siderosis). Patients must be monitored for these abnormalities with MRI within a year before starting treatment, and before the 7th and 12th infusions.34

Bottom line: this is an expensive drug (~$56,000/year) with serious side effects, but unknown benefits.36

What can be done to reduce the risk dementia?

To reduce the risk of cognitive decline or dementia, some evidence (not high-level) supports the following:

For adults who smoke, offer interventions for cessation.1

  • For adults with normal cognition or mild cognitive impairment who abuse alcohol, offer interventions for reduction or cessation of drinking.1
  • For adults with normal cognition or mild cognitive impairment, a Mediterranean-like diet may be recommended.1
  • For older adults with normal cognition or mild cognitive impairment, cognitive training may be offered.1
  • For adults, management of hypertension, diabetes, dyslipidemia (at mid-life), and weight (at mid-life) may be offered.1

Review med lists for opportunities to reduce the use of anticholinergics and benzodiazepines; they are associated with increased risk of dementia.

Are any natural products effective for dementia?

In summary, no supplements can be recommended for Alzheimer’s disease based on current evidence.10 Information regarding specific supplements commonly of interest are provided below:

  • Vitamin B, vitamin E, multivitamins, or ginkgo should not be recommended to reduce the risk of cognitive decline or dementia.1,28
  • In patients with dementia, Vitamin E 2,000 IU/day has a modest benefit (comparable to cholinesterase inhibitors), but increases bleeding risk.28
  • There are no published studies of Prevagen (apoaequorin) for the treatment of Alzheimer’s disease.
  • Studies of ginkgo biloba for Alzheimer’s disease suffer from high dropout rates.10 Although not consistently beneficial, it may improve cognitive symptoms, ADL, and neuropsychiatric symptoms.28 If patients/caregivers are interested in trying it for mild to moderate Alzheimer’s disease, suggest 240 mg/day of an extract prepared to contain approximately 24% to 25% flavone glycosides and 6% terpene lactones, which are similar to the preparations used in studies.28

Which meds should be avoided in patients with dementia?

Use our chart to identify Drugs With Anticholinergic Activity; they may worsen cognition.

Other drugs that can affect cognition, and possible alternatives, can be found on our chart, Potentially Harmful Drugs in the Elderly: Beers List.

Abbreviations: ADAS = Alzheimer’s Disease Assessment Scale; ADCS-ADL-MCI = Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version); ADL = activities of daily living; CDR-SB = Clinical Dementia Rating scale-Sum of Boxes; CIBIC = Clinician-Based Impression of Change; CGI-C = clinician’s global impression of change; CrCl = creatinine clearance; GI = gastrointestinal; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; SIB = Severe Impairment Battery.


Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

Project Leader in preparation of this clinical resource (360704): Melanie Cupp, Pharm.D., BCPS; last modified July 2021.

References

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  2. Rabins PV, Rovner BW, Rummans T, et al. Guideline watch (October 2014): practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/alzheimerwatch.pdf. (Accessed Jun 4, 2020).
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Cite this document as follows: Clinical Resource, Alzheimer’s Dementia Pharmacotherapy. Pharmacist’s Letter/Prescriber’s Letter. July 2020.

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