Alzheimer dementia: Starting, stopping drug therapy

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Alzheimer disease is the most common type of dementia. Two classes of cognition-enhancing drugs are approved to treat the symptoms, and both have provided modest benefit in clinical trials. Psychotropic drugs are sometimes used off-label to treat behavioral symptoms of Alzheimer disease. All these medications should be continuously evaluated for clinical efficacy and, when appropriate, discontinued if the primary benefit—preservation of cognitive and functional status and a reduction in behaviors associated with dementia—is no longer being achieved.


  • In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease; by 2050, the prevalence is expected to be 13.8 million.
  • Cognitive enhancers (cholinesterase inhibitors and an N-methyl-d-aspartate receptor antagonist) have shown modest efficacy in preserving cognitive function.
  • When evaluating therapy with a cognitive enhancer, practitioners need to consider the potential adverse effects, especially gastrointestinal effects with cholinesterase inhibitors.
  • Discontinuation should be considered when the dementia reaches the advanced stage and the initial intended purpose of these drugs is no longer achievable.



Alzheimer disease is the most common form of dementia. In 2016, an estimated 5.2 million Americans age 65 and older had Alzheimer disease. The prevalence is projected to increase to 13.8 million by 2050, including 7 million people age 85 and older.1

Although no cure for dementia exists, several cognition-enhancing drugs have been approved by the US Food and Drug Administration (FDA) to treat the symptoms of Alzheimer dementia. The purpose of these drugs is to stabilize cognitive and functional status, with a secondary benefit of potentially reducing behavioral problems associated with dementia.


Cognitive enhancers approved for Alzheimer disease

Two classes of drugs are approved to treat Alz­heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor antagonist (Table 1).

Cholinesterase inhibitors

The cholinesterase inhibitors act by reversibly binding and inactivating acetylcholinesterase, consequently increasing the time the neurotransmitter acetylcholine remains in the synaptic cleft. The 3 FDA-approved cholinesterase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the first approved cholinesterase inhibitor, was removed from the US market after reports of severe hepatic toxicity.2

The clinical efficacy of cholinesterase inhibitors in improving cognitive function has been shown in several randomized controlled trials.3–10 However, benefits were generally modest, and some trials used questionable methodology, leading experts to challenge the overall efficacy of these agents.

Severity, associated symptoms, and recommended treatment

All 3 drugs are approved for mild to moderate Alzheimer disease (stages 4–6 on the Global Deterioration Scale; Table 2)11,12; only donepezil is approved for severe Alzheimer disease. Rivastigmine has an added indication for treating mild to moderate dementia associated with Parkinson disease. Cholinesterase inhibitors are often used off-label to treat other forms of dementia such as vascular dementia, mixed dementia, and dementia with Lewy bodies.13

NMDA receptor antagonist

Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing neuronal calcium ion influx and its associated excitation and toxicity. Memantine is approved for moderate to severe Alzheimer disease.

Combination therapy

Often, these 2 classes of medications are prescribed in combination. In a randomized controlled trial that added memantine to stable doses of donepezil, patients had significantly better clinical response on combination therapy than on cholinesterase inhibitor monotherapy.14

In December 2014, the FDA approved a capsule formulation combining donepezil and memantine to treat symptoms of Alzheimer dementia. However, no novel pharmacologic treatment for Alzheimer disease has been approved since 2003. Furthermore, recently Pfizer announced a plan to eliminate 300 research positions aimed at finding new drugs to treat Alzheimer disease and Parkinson disease.15


Cholinesterase inhibitors

Adverse effects of cognitive enhancers: Percent of patients affected

Adverse effects of cholinesterase inhibitors are generally mild and well tolerated and subside within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and vomiting. They are transient but can occur in about 20% of patients (Table 3).

Other potential adverse effects include bradycardia, syncope, rhabdomyolysis, neuroleptic malignant syndrome, and esophageal rupture. Often, the side-effect profile helps determine which patients are appropriate candidates for these medications.

As expected, higher doses of donepezil (23 mg vs 5–10 mg) are associated with higher rates of nausea, diarrhea, and vomiting.

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