Donald Weaver, University of Toronto
March 9, 2025
Why are researchers still fumbling in the quest to cure what is arguably one of the most important diseases confronting humankind — Alzheimer’s disease? Despite decades of research, there is still no curative treatment for Alzheimer’s – no “magic bullet” that stops this devastating degenerative brain disease in its tracks.
Not surprisingly, finding the magic bullet has become the holy grail for Alzheimer’s researchers. But it’s proving to be an immense challenge. A magic bullet is a drug that completely cures a disease, doing so with few if any side-effects.
Penicillin is a great example of a magic bullet. Penicillin kills bacteria, leading to cures for infectious diseases like strep throat, while causing minimal side-effects. Aspirin (acetylsalicylic acid), on the other hand, is definitely not a magic bullet. It is a symptomatic agent reducing fever and pain in diseases like strep throat, but fails to actually cure the underlying disease.
Alzheimer’s needs a magic bullet, not an aspirin-like agent.
Two doctors in Frankfurt in 1907
The Nobel Prize-winning idea that scientists could invent magic bullets was first put forth in 1907 by Paul Ehrlich, a physician studying infectious illnesses at the Institute of Experimental Therapy in Frankfurt, Germany.
At the same time Ehrlich was developing his theory, Auguste Deter was a patient in a Frankfurt hospital just a short distance from his laboratory. She had been admitted under the care of neurologist Alois Alzheimer for evaluation of her undiagnosed cognitive decline.
In the same year as Ehrlich’s breakthrough publication, Alzheimer published Deter’s autopsy findings and case history, describing the new disease that now bears his name. There is no evidence that Ehrlich or Alzheimer ever met. More than a century later, their legacies have yet to cross paths, and we still do not have a magic bullet for AD.
It has not been for lack of effort. In the 1980s, AAlzheimer’s was thought to be caused by a deficiency of a brain chemical messenger called acetylcholine. This theory, called the “cholinergic hypothesis,” inspired extensive research resulting in several drugs being introduced in the late 1990s, namely donepezil, rivastigmine and galantamine. Regrettably, these three agents offer only limited symptomatic effects, temporarily improving memory and cognition but doing nothing to address the underlying disease processes. They are “aspirins.”
Theories of Alzheimer’s disease
And so, over the past 25 years, the search for the magic bullet for Alzheimer’s has intensified.
Disappointingly, since 2010, more than 200 magic bullet discovery programs have failed. Although these unsuccessful drugs targeted a variety of different approaches to Alzheimer’s, a large number of them were designed to prevent the folding and aggregation of beta-amyloid protein.
This is the so-called “amyloid hypothesis,” which conjectures that Alzheimer’s is caused by the aberrant production of a protein called beta-amyloid that twists itself into an abnormal shape to form disease causing brain toxic clumps.
Though most amyloid-targeting drugs based have failed, two recent therapeutics, lecanemab and donanemab, have shown limited success, but demonstrate significant side-effects and definitely are not cures. The search continues.
Why are we struggling to find the magic bullet for Alzheimer’s disease? Brain complexity is a major factor.
The brain is the most complex structure in the human body and Alzheimer’s is arguably one of the most complex diseases of the brain. Finding a drug to fix such a complicated network is daunting.
For years, scientists have been so focused on devising treatments to block brain-damaging amyloid clumps that we have fallen into an intellectual rut, sometimes neglecting other worthwhile explanations. And there is a wealth of viable alternatives.
For example, a growing number of scientists think Alzheimer’s is caused by inflammation, like arthritis of the brain. Similarly, others regard it as an autoimmune disorder of the brain. Some maintain it’s the end-result of a brain infection, with bacteria from the mouth as the potential culprit.
Other scientists believe that Alzheimer’s is primarily a disease of miniscule cellular structures called mitochondria — the energy factories that convert glucose from our food and oxygen from the air into the energy required for thinking and remembering. Still others suggest that the disease may arise from the brain’s mishandling of metals, possibly copper or iron.
This diverse range of mechanisms reflects our still evolving but currently inadequate understanding of the complex causes of Alzheimer’s. To make matters worse, these multiple disease processes — amyloid clumping, inflammation, diseased mitochondria — probably begin 20 to 30 years before the afflicted person becomes symptomatic. Such complexity is defeating magic bullet discovery efforts.
The ‘shotgun’ approach
Perhaps it’s naive to think we can ever devise a magic bullet for Alzheimer’s.
Consider another common medical disorder, high blood pressure. There is no single magic bullet for treating hypertension. No such drug exists. Rather, there are many different drugs, working through different mechanisms to reduce blood pressure, and these drugs are often used in combination.
If we cannot find a magic bullet for hypertension, which is mechanistically trivial compared to Alzheimer’s, what makes us think we can find one such a complex brain disease?
However, all is not hopeless. Diseases like hypertension or cancer in which multiple complementary drugs are successfully co-administered may provide a valuable clue. The answer to Alzheimer’s may lie in modifying Ehrlich’s magic bullet into a magic shotgun blast. Like a person trying in vain to shoot a tin can off a fence with a single shot, sometimes it’s simpler to use a shotgun blast. Shotgun shells, after all, usually contain multiple small shot pellets that hit a broader area than a single bullet.
In Alzheimer’s, a strong case exists for concurrently using multiple drugs hitting multiple targets — a combination therapy shotgun blast hitting beta-amyloid, inflammation and mitochondria targets (or others) all at once. This would seem to offer a better shot at a cure.
However, this will require new ways of doing clinical trials and significant changes in the established regulatory, statistical and operational procedures of clinical research.
But we must make these changes, whether we like it or not. Passionate scientists with polarized points of view may need to accommodate different perspectives and competitors may need to collaborate.
We may already have curative drugs, we just haven’t used them in the right combination. For the millions of people living with Alzheimer’s, we need to be more innovative and less dogmatic, discovering the path that will finally enable Ehrlich and Alzheimer to meet.
Donald Weaver, Professor of Chemistry and Senior Scientist of the Krembil Research Institute, University Health Network, University of Toronto
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This article is republished from The Conversation under a Creative Commons license. Read the original article.