Don’t Just Look Where the Light Is Shining

Switching Focus on Treatments for Alzheimer’s disease

There is an old joke in science about a police officer walking his beat one dark and gloomy night when he comes upon a man furiously searching for something beneath a streetlight. “What are you looking for?” the officer asks the man. “I lost my car keys,” the man replies. “Is this the area where you lost them?” the officer queries. “No, but it is the only place on the whole block where there is any light,” is the man’s answer.

         Those keys could, of course, be anywhere, and the decision to limit the search to the place where the streetlight shines strikes us as clearly irrational and a bit funny. Not so funny, however, when logic like this seems to inhibit progress in learning the causes of and treatments for a life-limiting disease. This, unfortunately, appears to be what has happened in the case of Alzheimer’s disease research. We wrote a year ago about the then recently U.S. Food and Drug Administration (FDA)-approved drug Aduhelm, which is essentially an antibody directed against an abnormal protein called beta-amyloid that is found in plaques on postmortem examination of brains from people who had Alzheimer’s dementia during their lifetimes.

         It has always been unclear if Aduhelm actually works to prevent or reverse memory loss in patients with Alzheimer’s disease. There has been a strong outcry from the scientific community protesting the FDA approval of the drug because the evidence that it does more good than harm for people with Alzheimer’s disease is thin. Because there are currently no effective treatments for Alzheimer’s disease, it might be understandable that an agency would want to err on the side of approval. The FDA, however, is supposed to make its decisions based on solid scientific evidence for efficacy and lack of harm, not out of sentiment. Why, in the face of very little solid evidence for efficacy, was this anti-amyloid drug approved? Why do scientists and regulators persist in pursuing the anti-amyloid strategy at all?

Amyloid Plaques Seem a Likely Culprit

Ever since Alois Alzheimer first described changes in the brains of people that had the disease that bears his name, scientists have focused on the idea that the buildup of amyloid plaques in the brain is the cause of the severe memory loss experienced by patients with Alzheimer’s disease and reckoned that eliminating them would somehow improve cognitive function and slow the inevitable progression of the disease to death. Directing antibodies against the proteins that are the main ingredients of the amyloid plaques seems like a logical idea. In a recent STAT piece, Howard M. Fillit, a neuroscientist and geriatrician at the Icahn School of Medicine at Mount Sinai and co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, explained that “When Alzheimer’s disease was believed to be caused solely by the accumulation of amyloid protein in the brain, pinning all hopes on an amyloid-targeting drug like Aduhelm…made sense.”

Amyloid plaques build up between neurons in the brains of people with Alzheimer’s disease. They have been the target of enormous amounts of research and clinical trials, but it is now seeming less likely that they are the central cause of the illness (image: Shutterstock).

         Indeed, enormous amounts of research funding and effort have been expended on understanding the biology of the amyloid plaque and trying to figure out how to eliminate it from the brain. Amyloid plaques collect between neurons in the brains of people with Alzheimer’s disease and there is no question that they are toxic to brain function. On autopsy, amyloid plaques are easy to see under a light microscope and extracting the proteins that make them also relatively straightforward. This makes them an ideal research target. It is, after all, where the light seems to be shining.

Anti-amyloid Drugs Persistently Fail

But there have always been signals that the buildup of amyloid plaques is probably not the only cause of Alzheimer’s, if it is even one of the causes at all. For example, Alzheimer’s disease generally begins in a part of the brain called the entorhinal cortex, a brain region critical for short-term memory and navigation through physical space. Yet, plaques are “not primarily observed in the entorhinal cortex.”  One attempt after another to prevent or treat cognitive function loss in Alzheimer’s disease by targeting amyloid plaques has failed. One thought that occurred to scientists after the first few failures was that perhaps by the time a patient has advanced disease it is too late to induce improvements by trying to reduce the amyloid plaque burden. So, researchers decided to pursue clinical trials with anti-amyloid drugs involving people with the earliest signs of Alzheimer’s disease.

         This strategy, unfortunately, also seems like a dead end. In June, the Roche drug company announced the failure of its experimental drug crenezumab in a much anticipated study. The study involved people with a relatively rare genetic mutation that causes early-onset Alzheimer’s disease. Crenezumab is another antibody-based medication that targets amyloid plaque protein, and in this trial it was compared to placebo in study participants with the mutation who did not yet have signs of the disease. Yet crenezumab did no better than placebo in preventing onset of or slowing cognitive decline, indicating that even addressing Alzheimer’s disease in its earliest stages with anti-amyloid drugs does not seem to work.

         The perseverance of interest in amyloid plaques as the main treatment target for Alzheimer’s disease, while understandable, represents one not uncommon problem with research, perhaps especially relevant when it involves diseases of the brain. Despite the ever-increasing sophistication of methodology in neuroscience and human brain imaging, the brain remains relatively impenetrable compared to other organs of the body. Sometimes psychiatrists and neurologists who are specialists in brain disorders think that even black holes in outer space are easier to study than the human brain. When something pops up that seems to make sense, scientists grab hold and invest all their time and money to study it in every possible aspect.

These MRI scans show the severe loss of brain tissue that occurs in patients with Alzheimer’s disease. Research now suggests that there are probably multiple different causes of the illness and clinical trials are beginning to address some of them (image: Shutterstock).

         This of course runs the risk of overlooking other areas that might be more fruitful for scientists to pursue. Fortunately, scientists, perhaps reeling from all the failures of anti-amyloid drugs, finally seem willing to look at other pathways to ameliorate Alzheimer’s disease. As Fillit notes, “More than three in four treatments currently in clinical development work against non-amyloid targets.  These include drugs to reduce inflammation in the brain, improve blood flow, clear misfolded proteins, improve how the brain metabolizes energy, and more.” In fact, scientists have long known that there are multiple things wrong with the brains of people with Alzheimer’s disease besides the accumulation of amyloid plaques. Amyloid plaques might even be a reaction to one of these other disease processes. For example, Alzheimer himself identified another abnormal protein in the Alzheimer’s disease brain, called hyperphosphorylated tau protein. Misfolded tau proteins form what are called neurofibrillary tangles that collect inside of neurons and may be more central to the cause of Alzheimer’s disease than amyloid plaques. Drugs that rid the brain of neurofibrillary tangles are now under investigation.

         There is also strong interest in the likelihood that Alzheimer’s disease involves some abnormalities in the brain’s blood circulatory or vascular system. This is because many of the same factors that increase the risk for heart disease and stroke also appear to increase the risk for Alzheimer’s disease, including high blood pressure (hypertension), elevated cholesterol levels, smoking, diabetes, and obesity. Exercise and healthy diets may help reduce cognitive decline. So might social engagement and mentally challenging pursuits.

         Scientists, like everyone else, can have trouble abandoning what seems like a very good idea, even when experience should be telling us it is time to move on. In the case of anti-amyloid drugs, so much money has been invested in researching them and so many scientific careers devoted to their biology that moving on to new areas of work has clearly been difficult. Yet it seems it is time to do so. Unless we are surprised by an anti-amyloid drug that really shows strong clinical evidence for being effective, the FDA should stop approving drugs that target amyloid plaque proteins and the NIH and other funding bodies should begin to switch their grant-making priorities to other, more promising avenues. It is time to acknowledge that just because there happens to be a streetlight at one spot along a long block doesn’t mean that’s where our lost keys are to be found.

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