Alzheimer’s is a terrifying disease. Since no new medications for this condition have been introduced for about two decades, it is certainly understandable that any new drug that receives regulatory agency approval attracts media attention. This is indeed the case for Aduhelm (aducanumab), recently approved by the U.S. Food and Drug Administration. That approval, however, is riddled with controversy.
First, a little Alzheimer’s history. In 1901, a fifty-one-year-old patient who would go down in history as “August D,” was admitted to a hospital in Frankfurt seemingly suffering from senile dementia. What an interesting patient this was! She was confused, her memory was impaired, and her behavior was unpredictable. When asked what she was eating after being served pork and cauliflower for lunch, she replied, “spinach.” The patient then went on to offer a surprisingly insightful self-diagnosis: “I have lost myself,” she explained. Little wonder that this unusual case captivated the imagination of her attending physician, Dr. Alois Alzheimer. He followed her deterioration carefully for five years, wondering what was going on in that eroding brain. Finally, when Auguste died in 1906, he got his chance to find out. Alzheimer’s post mortem microscopic examination revealed that her brain had undergone some very peculiar changes. A sort of sticky material had deposited in the space between the nerve cells, some of which themselves harbored tiny twisted fibers. Just a few months after the patient’s death, at a conference of German psychiatrists, Alzheimer described the “neurofibrillary tangles” and “senile plaques” that have since become the hallmark of Alzheimer’s disease.
Simply put, in Alzheimer’s disease the brain’s machinery becomes “gummed up.” In a healthy brain, nerve cells communicate with each other through the release of special chemicals called neurotransmitters, but this communication is impaired by the presence of tangles and plaques. Then, as these abnormal structures accumulate, nerve cells die, the brain shrinks and mental and physical incapacity sets in. Once autopsies of numerous Alzheimer’s patients had confirmed the presence of plaques and tangles as a characteristic feature of the disease, obvious questions were raised. What are these abnormal deposits and why do they form? The “what” has now been established. Both the sticky plaques and tangles result from accumulations of proteins; “beta-amyloid” in the case of plaques, and an abnormal, insoluble form of a protein called “tau” in the case of the neurofibrillary tangles. The “why” question has been far more difficult to answer. Some genes predispose people to Alzheimer’s, but most patients do not have these genes. Only age has been shown to be a clear-cut risk factor in the disease, with about one in ten people over the age of 65 and one in two over 85 being afflicted. To complicate matters further, not everyone with plaques and tangles in the brain shows symptoms of Alzheimer’s disease.
At this point there is no cure for Alzheimer’s and even the efficacy of drugs for symptomatic treatments is questionable. Generally, researchers have focused on increasing the levels of acetylcholine, the neurotransmitter that is short supply in the brains of Alzheimer’s patients by using drugs that block the action of acetylcholinesterase, the enzyme that normally degrades acetylcholine. The most popular such drug is “Aricept” (donepezil), which can in some cases slow the decline somewhat, but it is not impressive. Now for the first time there is a medication that purports to treat not the symptoms, but the underlying cause of the disease by disassembling the amyloid plaques. This is done with an antibody that has been engineered to recognize the deposits as a foreign substance that should be eliminated.
The trials have documented with brain scans that aducanumab does indeed attack the amyloid proteins and reduces plaques. However, there is no clear evidence that these plaques are the cause rather than the consequence of the disease. The pertinent question is whether the drug has a significant effect on brain function. This does not appear to be the case. As measured by tests of cognition and function, the difference between aduhelm and placebo was a fraction of a point on an 18-point scale. While there was no improvement in symptoms, there was some slowing of the rate of cognitive and functional decline. However, this came at the expense of non-trivial side effects. In two clinical trials, about 40% of subjects who got the approved dose of aduhelm developed painful brain swelling with headache, dizziness, visual disturbances, nausea, and vomiting. About 18% of patients had microhemorrhages, or small bleeds in their brain. Then there is the cost. Estimated to be about $56,000 per patient per year!
Some media reports have breathlessly talked about a “major breakthrough” with a “revolutionary new drug, although such descriptions are not warranted based on the evidence. What we have here is an incremental advance and a drug that has been approved by the FDA without meeting its own criteria of requiring proof of efficacy in at least two clinical trials. The approval was based more on offering some hope for desperate patients than on evidence, which is rather poor.