Evidence-Based Reviews

Which cholinesterase inhibitor for early dementia?

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Consider drug differences, patient factors to find a good match.



Using a cholinesterase inhibitor (ChEI) makes sense for any disorder with a significant cholinergic deficit, such as Alzheimer’s disease (AD) and other forms of mild-to-moderate dementia (Box 1).1-3 Yet the ChEIs tacrine, donepezil, rivastigmine, and galantamine have pharmacologic differences, and individual patients respond differently to them.

To help you choose the safest, most effective treatment for each patient, we discuss:

  • three cases that show how ChEIs differ in mechanism of action, administration, and side effects
  • evidence of ChEIs’ efficacy in AD—for which they are approved—and in other dementias for which they have been tried
  • when to switch agents, and how long to continue treatment.

Box 1

Is it Alzheimer’s? One-third of dementias are something else

Probable Alzheimer’s disease (AD) accounts for 64% of all dementias in the United States. Less-common causes include:

  • vascular dementia (5%)
  • combined vascular dementia and AD (10%)
  • probable dementia with Lewy bodies, Parkinson’s dementia, or diffuse Lewy body disease (9%)
  • Lewy body variant of AD, or AD and dementia with Lewy bodies (6%)
  • frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, or Creutzfeldt-Jakob disease (6%).2,3

In our experience, many primary care physicians choose to follow their patients with dementia, even when clinical features are atypical or suggest unusual causes. Psychiatrists are asked most often to assist in diagnosis and management of patients with:

  • uncommon dementias, including frontotemporal dementia or dementia with Lewy bodies
  • rapidly progressive dementia
  • dementia in a patient age
  • dementia with psychiatric comorbidities or severe behavior disturbances.4

How Cheis Differ

Although dementia remains incurable, recognizing cognitive decline early allows you to start ChEI therapy before substantial neuronal loss occurs (Box 2).3,4 The goal of early treatment is to improve or stabilize cognition, behavior, and activities of daily living for as long as possible.

In comparison studies,5,6 ChEIs have shown differences in tolerability but not consistent differences in efficacy for mild to moderate AD—though these studies had methodologic limitations. Because the agents appear similarly effective, the initial ChEI choice often depends on how their differences might benefit your patient (Table 1). Consider the following cases:

Box 2

Dementia diagnosis: Earlier is better

An early dementia diagnosis enables you educate the patient and family (Box 3) and begin the most effective treatment for the person with cognitive decline. Although dementia remains incurable, early recognition presents the opportunity to start cholinesterase inhibitors before substantial neuronal loss occurs.3,4

Patient workup. The Alzheimer’s Association offers online information for health care professionals on AD diagnosis and treatment protocols (see Related resources). A detailed history, physical examination, and Mini-Mental State Examination (MMSE) are necessary if you suspect Alzheimer’s or a related dementia.

Also recommended are a comprehensive metabolic screen, complete blood counts with differential, urine analysis, serum B12 and folate studies, homocysteine levels, thyroid studies, chest radiography, ECG, lipid profile, and brain scan (MRI or CT). Perform studies such as the rapid plasma reagin test for syphilis and HIV testing as appropriate.

Table 1

Similarities and differences among cholinesterase inhibitors

AdministrationFour times dailyOnce dailyTwice daily with full mealsOnce daily (extended-release formulation)
AChE inhibitorYesYesYesYes
BuChE inhibitorYesNoYesNo
Allosteric modulation of nicotinic receptorNoYesNoYes
Pharmacodynamic nicotinic/muscarinic effectYesYesYesYes
GI side effectsPresentPresentPresentPresent
Drug–drug interactionsYesYesNone reportedYes
AChE: acetylcholinesterase
BuChE: butyrylcholinesterase
CYP-450: cytochrome P-450 hepatic isoenzymes

Case 1: Gradual Memory Loss

Mrs. J, age 76, has experienced a slow, insidious memory decline across 5 years. She has become socially withdrawn and shows some language difficulties. She has had peptic ulcer disease and often does not take medications as prescribed.

Her psychiatrist diagnoses probable AD and chooses donepezil with its easy dosing schedule because of Mrs. J’s history of nonadherence. Donepezil’s GI tolerability is also a factor in this choice because of the patient’s peptic ulcer disease.

Case 2: Dementia And Motor Deficits

Mr. L, age 82, has gradually developed memory loss and parkinsonian symptoms, including slowness of movement and shuffling gait. He has visual hallucinations of people and episodic confusion. His medications include warfarin and digoxin for atrial fibrillation and congestive heart failure.

Mr. L is diagnosed with probable dementia with Lewy bodies. His psychiatrist chooses rivastigmine because it has shown efficacy in this type of dementia and is not known to interact significantly with cardiovascular medications.

Case 3: Stroke, Then Rapid Decline

Mrs. D, age 68, has a history of hypertension and suffered a stroke in the past. Her family says her memory and behavior—anger outbursts and excessive irritability—have worsened rapidly across 2 years. Examination reveals some focal neurologic deficits.

Her psychiatrist diagnoses probable vascular dementia and chooses galantamine for its efficacy in patients with this dementia type. Mrs. D has no history of GI illness and will likely tolerate the drug’s GI side effects. Follow-up care will include monitoring for tolerability.


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