By Sungho Han, PhD, and Allan I. Levey, MD, PhD
When science changes, it often takes a long time for nonscientists to catch up.
The prevailing belief for many decades was that humans are born with a fixed number of brain cells, or neurons, and those hardy cells needed to last a lifetime. But many would unfortunately be lost prematurely due to the use of alcohol and participation in violent sports.
Nothing could be further from the truth. Nearly 50 years ago, researchers discovered new neurons in the brains of rats. We now have a clearer understanding of how neurogenesis—the formation of new neurons and other types of brain cells—occurs in specific parts of the brain throughout life. The no-new-neuron orthodoxy had been overthrown.
Nevertheless, the general public—and even some scientists—still believe the “no new neurons” doctrine. Just a few years ago, when applying for a government grant to support a drug discovery platform, one of us (Han) faced scathing personal criticism from a cell biologist. During a meeting in support of Han’s grant application, the visibly irritated cell biologist insisted that it was “absolute nonsense” to say that adults had neural stem cells capable of differentiating to mature neurons.
We now know that olfactory neurons, responsible for the sense of smell, and hippocampal neurons, responsible for memory and other cognitive processes, are renewed throughout the human lifespan. But as to the ultimate causes of Alzheimer’s disease (AD), there is much left to uncover. Although we know that AD has a strong genetic component, we still don’t fully understand AD’s underlying genetic factors and how they interact with environmental and lifestyle risk factors.
An urgent need to consider new ideas
Some scientists and drug companies, driven by the pathological features of AD, have been heavily attached to the persistent but as-yet-unproven toxic amyloid hypothesis. This view of AD focuses drug development on the prevention or removal of amyloid beta plaques, accumulations of extracellular protein that are AD’s pathological hallmark. While there is still debate on whether the plaques cause or result from sporadic AD,1 many companies have pursued treatments that target the plaques. One of these companies is Biogen, the developer of Aduhelm, an amyloid beta–directed antibody that was approved by the U.S. Food and Drug Administration (FDA) last summer.
The deliberations over Aduhelm were fraught, and the drug’s approval quickly sparked controversy. We see the issues with Aduhelm as representative of the difficulties of treating a disease with multiple complex factors and an as-yet-unknown cause. Indeed, some researchers now fear the FDA’s approval could stymie development of novel, more effective AD treatments.2 They believe more companies will focus on drug mechanisms similar to the one for Aduhelm. Drug candidates that support different theories of the causes of AD could languish, while “a flood of drugs targeting amyloid plaques could be unleashed.”3
But the need to defeat AD is more urgent than ever. As the population in the developed world ages, more people than ever are expected to develop late-onset AD, straining caregivers, the healthcare system, and government resources. The number of people with AD is expected to triple by 2050.4 Already, there are more than 6 million people with AD in the United States.
Arizona, which has a high percentage of retirees, is expected to face an unusually severe crisis. In 2020, the Alzheimer’s Association projected that in Arizona, the number of adults aged 65 and older with AD would increase by a whopping 33% by 2025.5
Prerequisites for taking a moonshot approach
This devastating but entirely predictable health crisis requires a new approach toward solving the mysteries of degenerative neurological diseases and finding effective treatments. The “moonshot” approach—inspired by President Kennedy’s 1961 speech calling for the United States to land men on the moon by the end of the decade—has become a sort of cultural shorthand for solving a societal challenge with a determination to succeed and an urgent, all-hands-on-deck attitude. And that is exactly what’s called for in defeating AD. Here’s how we can do it:
- Overhaul the regulatory framework for AD. If new drug development for AD were treated more like orphan drug development is treated by the FDA, communications between drug companies and FDA regulators would be facilitated at the preclinical R&D stage. This would speed discovery and clinical development and help companies make more efficient use of R&D expenditures.
- Cultivate a more open science ecosystem. Although research collaborations and open sharing of data are increasing—the National Institutes of Health’s Accelerating Medicine Partnership for Alzheimer’s Disease is a good example—much progress is still thwarted by researchers hoarding data and samples in both academia and industry. The Collaborative Trajectory Analysis Project, a nonprofit bringing together all stakeholders in the fight against Duchenne muscular dystrophy, provides a useful example of how drug companies, academics, and patient advocates can share data and work together to speed development of new treatments.
- Organize a drug manufacturing consortium. For amyotrophic lateral sclerosis in particular, companies and researchers need help manufacturing enough drug substance and establishing manufacturing processes for small clinical trials, especially for early-phase trials. This is an enormous expense. A not-for-profit consortium for GMP manufacturing of experimental treatments across borders would speed trials.
- Arrange long-term longitudinal trials. Long-term longitudinal trials can enhance our understanding of how AD slowly evolves in the 20-year period before patients show symptoms.
Projects that could be expedited with a moonshot approach
After a combined 60 years in neuroscience research and drug development, we do not expect miracles. It is unlikely we will see a new, paradigm-shifting treatment approved within the next five years. But researchers will advance new theories of the cause of AD, and clinical trials will bring experimental treatments closer to patients in need. In particular, we expect to see progress on a number of fronts:
- Neuroprotection and neuroregeneration. Better neuroprotective therapeutics will help maintain homeostasis in the brain to preserve neurons and functional neural circuits, and better regenerative therapeutics will enable more brain cells to develop in the parts of the brain where they are needed.
- Waste clearance. Gene therapies will allow more efficient or better targeted disposal of amyloid plaques, tau tangles, and other waste products or malformations. Such treatments may be useful even if AD is not the result of the waste products, but is, rather, the cause.
- New formulations and delivery vehicles. Treatments that cross the blood-brain barrier more easily will be more useful for treating diseases of the central nervous system.
- Immunomodulation. Immuno-oncology drugs are being repurposed to modify the course of neurodegenerative diseases, and a new class of immuno-neurology drugs is being created.
- Gut-brain axis. We are just beginning to understand the gut-brain axis, but it appears to present targets for AD drugs.
From small steps to giant leaps
In addition to pursuing the discovery projects mentioned earlier in this article, drug developers will explore possibilities that haven’t even been imagined yet. It’s impossible to say which advances will finally enable us to defeat AD. But certainly, it would be better to know sooner than later. Let’s launch the Alzheimer’s moonshot right away.
Sungho Han, PhD, is founder and CEO of Genuv, a clinical-stage biopharma company in Seoul, South Korea, that develops treatments for cancer and degenerative neurological diseases. Allan I. Levey, MD, PhD, is a neurologist and neuroscientist at the Emory University School of Medicine who advises Genuv.
1. Thomas KR, Bangen KJ, Weigand AJ, et al. Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration. Neurology 2020; 94(4): e397–e406.
2. McGinley L. The controversial approval of an Alzheimer’s drug reignites the battle over the underlying cause of the disease. Washington Post. Published: July 16, 2021. Accessed: March 29, 2022.
3. Sachs R. The FDA’s Approval Of Aduhelm: Potential Implications Across A Wide Range Of Health Policy Issues And Stakeholders. Health Affairs. Published: June 10, 2021. Accessed: March 29, 2022.
4. Kapadia R. The Other Pandemic: What to Do About the Coming Alzheimer’s Crisis. Barron’s. Published: February 5, 2021. Updated: February 7, 2021. Accessed: March 29, 2022.
5. Suneson G, Byrnes H. Alzheimer’s disease to affect 7.1 million Americans by 2025. Here’s the expected increase by state. USA Today. Published: August 10, 2020. Accessed: March 29, 2022.