The lowdown on Alzheimer’s disease drugs

Question: How effective are the currently available Alzheimer’s disease drugs?

Answer: They are only modestly effective.

Presently, there are four drugs approved by Health Canada for the treatment of Alzheimer’s disease. Three of the drugs belong to the same class, called “cholinesterase inhibitors”: donepezil (Aricept™), galantamine (Reminyl™) and rivastigmine (Exelon™). These drugs are believed to work based on their effect on a brain chemical called acetylcholine. The fourth drug belongs to a different class called “NMDR receptor antagonists”: memantine (Ebixa™). This drug is thought to work by its effect on the brain chemical glutamate.

These four drugs — available for over 20 years — are not cures, but rather improve some symptoms of the disease for a period of time. The improvements are often subtle, and can be difficult to detect, even for your doctor. In dozens of studies, however, when patients treated with these drugs are compared to untreated patients, they show benefits on cognitive tests, activities of daily living, and even behaviour for at least six to 12 months. While both treated and untreated patients will continue to decline over time, the differences persist, and if the drugs are discontinued, the treated patients lose the benefits even after years of treatment, and can decline significantly.

When I start a patient on one of these drugs, I emphasize their modest benefits, and warn patients and families that side-effects often appear immediately, while benefits may take several months to become evident. I explain that unlike an obvious improvement in memory, some of the benefits may be very subtle. These could include being brighter, more engaged in activities, calmer, and more communicative.

Cholinesterase inhibitors

The cholinesterase inhibitors like donepezil appear to work for mild, moderate and severe Alzheimer’s disease. Because they increase the chemical acetylcholine everywhere in the body — not just the brain — they can potentially cause a variety of side-effects, which can be quite troubling for some patients. These include gastrointestinal side-effects like nausea, vomiting, diarrhea/loose stools, and loss of appetite. Cholinesterase inhibitors can also cause slowing of the heart rate, dizziness, falls and headaches. Some of these effects can be minimized by starting at the lowest doses available, and only increasing slowly (after at least a month).

All three drugs in this class appear to be equally effective, but if a patient cannot tolerate one of them, a trial with a second, or even a third, may be worthwhile. All three are available as pills, but rivastigmine is also available as a patch, which might be preferable for some patients and their caregivers.

Many treatment guidelines recommend starting one of these drugs immediately after Alzheimer’s disease is diagnosed, regardless of what stage the patient is in. If the patient is tolerating the drug, the recommendations are typically to remain on them until the final stages of illness (e.g. no longer communicative, bed-bound, no longer able to participate in any activities of daily living).

Memantine (Ebixa™)

Memantine appears to be effective only for moderate and severe Alzheimer’s disease. It is well-tolerated, with none of the gastrointestinal side-effects the other three drugs can cause. Although rare, memantine can cause sedation, and caution is required in patients who have problems with their kidney function. Memantine is generally added to one of the cholinesterase inhibitors once a patient has progressed from mild to moderate disease. In the U.S., memantine is often started in mild disease. In Canada, based on the best available evidence, we only use memantine in mild disease for patients who couldn’t tolerate a cholinesterase inhibitor.

Alzheimer’s drugs & other dementias

These drugs are also used for some of the other dementias. For example, some patients with vascular dementia, mixed dementia and Parkinson’s disease dementia may benefit. In fact, patients with Dementia with Lewy Bodies can experience greater benefits than the typical Alzheimer’s disease patient with dramatic improvements in cognition and behaviour. These drugs are generally not effective in mild cognitive impairment and clearly do not reduce the risk of conversion from mild cognitive impairment to dementia.

Finally, provincial drug benefit formularies differ in their reimbursement for these drugs. In Ontario, the three oral cholinesterase inhibitors are only covered for mild to moderate Alzheimer’s disease, while the rivastigmine patch and memantine are not covered at all.

The answer to the question about how effective these drugs are is likely disappointing to most patients and their families. And that is why, if we are to find a cure, research and participation in clinical trials is so important. There are currently many trials going on in Canada examining drugs and other therapies that may not only provide more symptomatic benefits, but may truly modify the disease course of the illness by delaying the onset and slowing the progression.

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