Do Alzheimer’s Medications Really Help?

This article explores the pros and cons of the currently approved medications for Alzheimer's disease.

More than 100 medications are currently being investigated for use in the treatment of Alzheimer's disease. Patients, families, and clinicians are eagerly awaiting the availability of agents that will more effectively control the symptoms of this most common of dementias. Even more exciting, doctors hope for medications that will halt the progress of cognitive decline or even reverse the destructive process that impedes cognitive functions and ultimately kills brain cells.

While clinicians await the arrival of new treatments, they currently have access to two classes of medications approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. These widely used medications have sparked controversy between those who consider them valuable treatment tools and those who regard them as hazardous and costly. Let’s look at the pros and cons of these medications from an evidence-based, yet practical viewpoint. The FDA approved “cognitive enhancers” fall into two classes.

Cholinesterase Inhibitors

Donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) are inhibitors of the enzyme acetylcholinesterase. They work by diminishing the brain’s normal breakdown of the neurotransmitter called acetylcholine, an important player in the transformation of thought and experience into retrievable memories—a miracle so familiar to us that we may take it for granted unless we have seen the chaos that results from its disruption.  Each of these medications is available generically. Although this limits their cost, the associated copayments under some insurance plans can pose a significant burden.

Donepezil and rivastigmine have been approved for mild, moderate, and severe Alzheimer’s disease. Galantamine is approved for mild and moderate stages of the disease. Donepezil is also available in a new and relatively higher dose pill, and rivastigmine is the only one yet available in a skin patch delivery system, suitable for use by patients more amenable to a patch than a pill, or unable to tolerate the gastrointestinal side effects of this class of drugs. These medications share several other side effects that can be clinically significant: disruption of sleep, enhanced risk for bleeding, and slowing of the heart rate to the point of potential danger from fainting or disrupted heart rhythm.

Memantine

The other class of cognitive enhancers approved for Alzheimer's treatment contains one lonely member, memantine (Namenda). Memantine’s unique mechanism of action involves enhancement of the brain’s sensitivity to an important excitatory amino acid neurotransmitter, glutamate. Glutamate plays a key role in uniting the brain cells that must collaborate to form a specific memory. Glutamate also plays a more sinister role in the brain, contributing to the neuron-destroying process called apoptosis (programmed cell death). Memantine is approved for middle and late stages of Alzheimer's disease and is often combined with a cholinesterase inhibitor once a patient passes beyond the early stage. Memantine’s side effects are often minimal, though occasionally memantine can enhance or initiate confusion, agitation, constipation, or headache. 

Pros and Cons

The effectiveness of these medications appears to be modest but significant for a large number of patients who can tolerate their side effects. On average,  the cognitive enhancers slow down for six months or more the encroachment of Alzheimer's disease on multiple areas of functioning. Some patients benefit for a longer time, but some for shorter periods. These medications have been shown to facilitate thinking, to improve performance of activities of daily living, to contribute to the management of some non-cognitive behavioral disturbances, and to reduce the burden of caregiving by an average of about one hour per day.

Critics of these medications point out that their effects differ from those of placebo (inert medication) by only a few points on scales that include many points. They also criticize the potential of the cholinesterase inhibitors to induce distressing side effects such as severe diarrhea or fainting. A practical approach to the use of these medications requires periodic reassessment of their side effects and benefits.

Many clinicians believe that the cognitive enhancers continue to play a useful role late into the course of Alzheimer's disease. They cite studies showing that significant clinical deterioration can occur even after discontinuation during a late stage of the dementia. In some cases, however, it is appropriate to discontinue these medications, particularly when side effects have exceeded tolerability or the patient’s functional decline has progressed to a very severe stage. Side effects will diminish quickly after discontinuation, but clinical benefits will also dissipate as few as six weeks after they are stopped. Except when abrupt discontinuation is medically necessary, it is advisable to taper the cholinesterase inhibitors and memantine rather than stop them suddenly. In all cases, family and care providers should strive to consider what the patient’s choice would be, even when the patient can no longer articulate that choice.

On the Horizon

As we enter the decade of the 2020s, a new group of medications will be proposed for the treatment of Alzheimer’s Disease. Unlike their predecessors, these are considered to be “disease-modifying” medications capable of altering the course of Alzheimer’s Disease’s progression. The first of these, aducanumab, currently under consideration by the FDA for indication in the treatment of AD, is a monoclonal antibody shown to reduce brain amyloid load while also slowing decline on measures of cognitive function. Others with similar and different mechanisms will follow. The clinical significance of these new medications as well as the magnitude of their adverse effects remain to be determined.

Summary

The outstanding efforts of many researchers have made clear that medications are only one part of the successful care of patients with Alzheimer's disease. Education of the patient and family, support of caregivers, attentive medical assessment to reduce additional sources of distress, use of resources such as adult day care programs, and behavioral assessments and interventions each contribute to the successful care of individuals suffering from dementia. In time, there is every reason to hope for medications of great effectiveness to enhance our other treatment elements. Until then, the currently available cognitive enhancers continue to play a useful role in optimizing care.