Surprisingly good news about the acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine)

When I first started practicing neurology in 1989, there were absolutely no medications that mitigated cognitive deterioration in patients with Alzheimer’s disease. There were drugs for some of the unwanted symptoms like sleep reversal, depression, anger outbursts, and seizures, but nothing to address the underlying progressive brain damage leading to cognitive impairment, dementia, and ultimately death. I remember feeling very frustrated that I could offer nothing at all, not even hope. Then in 1993, the first acetylcholinesterase inhibitor (AChEI), tacrine, was approved by the FDA for treatment of dementia. This class of medication is thought to work by raising levels of acetylcholine, an important neurotransmitter in the brain.  There was a lot of excitement about the approval of tacrine, but almost immediately severe side effects including severe liver damage were encountered, and the use of the drug dwindled and disappeared almost overnight. I don’t think I ever wrote a prescription for tacrine. Three years later the first relatively safe AChEI, donepezil (trade name Aricept), was approved and it is still going strong.  Within a few years, two similar drugs, rivastigmine and galantamine, were approved.  They all were about equally effective.  They all had similar side effects, but sometimes a person could tolerate one better than another.  For an individual patient, it was hard to tell for sure if it was effective or not.  A few of my patients had remarkable improvement and others didn’t seem to change much at all. For others, the side effects were intolerable.  Most common were nausea, cramps and diarrhea as well as nightmares and insomnia. I found that starting my patients at a very low dose, lower than recommended, and very slowly increasing the dose over several months would usually avoid the side effects. When I started taking donepezil myself a few years ago, I went through the usual GI upset, but what bothered me most were terrible nightmares almost every night. I asked my neurologist and learned that nightmares are common and can usually be avoided by taking the daily dose in the morning, not at bedtime.  Sure enough, that did the trick.  Now I have no side effects at all.  But is it helping me?  Hard to know.  At times I think it has helped, but the placebo effect is strong.  Information from one patient’s experience is really of no use in evaluating a treatment despite what you hear every night from the plethora of TV advertisements for memory enhancing products.  What is needed is a large, carefully controlled clinical trial. Most of the small trials in the past showed a modest slowing of cognitive impairment for a few years but little if any benefit in the severe dementia stage. No one had claimed that this class of medications could allow people with Alzheimer’s disease to live longer.

Recently, a paper in Nature described an observational study to evaluate the rate of cognitive decline, as well as the overall survival, in a large sample of patients affected by dementia, treated or not treated with AChEIs, in a real-world setting. The data were retrieved from a large database, the National Alzheimer’s Coordinating Center Uniform Data Set, and included 4,032 subjects with Alzheimer’s disease, Lewy body disease, and vascular dementia. Subjects were carefully matched to eliminate confounding differences leaving 786 who had received AChEIs and 786 who had not. Cognitive status was assessed with the Mini Mental Status Exam (MMSE). The results were remarkable.  First, subjects with Lewy body disease had no cognitive benefit from treatment.  However, those with Alzheimer’s disease who received an AChEI had almost no change in the MMSE score for six years while subjects not taking an AChEI continued to decline.  At the end of follow up in year twelve, subjects with Alzheimer’s taking an AChEI had a 5.7 decrease in MMSE score from onset compared to those not taking an AChEI who decreased an average of 10.8 points. Keep in mind that the top score on the MMSE is 30 and the cutoff for dementia is 23 and below, so the AChEI treated subjects, shown on the red line, had on average remained above the dementia cutoff until near the end of the study.

The same pattern although not as pronounced was seen in subjects with vascular dementia. I suspect this reflects the high incidence of comorbidity: nearly a half of dementia brains seen at autopsy have both Alzheimer’s and vascular dementia pathology.

In addition to the slowing of cognitive decline, there was a strong association between AChEI therapy and lower all-cause mortality. This was true even for subjects with Lewy body disease who had no cognitive benefit from taking AChEI drugs.  This suggests to me that the increased survival associated with these drugs must have a different mechanism than that resisting cognitive decline.

This paper has forced me to change my opinion of AChEIs in the treatment of Alzheimer’s disease.  As a neurologist I was skeptical that they had much benefit, but because they were relatively safe to take, I routinely prescribed them.   For those patients of mine who struggled with side effects, I would have a low threshold for stopping the drug. Now, if I were still seeing patients with Alzheimer’s disease or vascular dementia, I would strongly encourage persisting with the drug, starting out at very low doses if necessary, and increasing the dose very slowly as needed. The benefit seems to be real, even in the later stages of the disease.