Alzheimer’s disease, the sixth leading cause of death in the United States, has defied our best efforts to find a cure or even a treatment that can substantially slow its devastating degradation of the brain. The now decades-long sequence of high-profile setbacks in Alzheimer’s drug discovery and development underscores the unique challenge this disease presents.
For the sake not only of tens of millions of patients and families worldwide, but also the sustainability of the US health care system and economy, the Alzheimer’s research community must acknowledge the gaps in the current approach to curing the disease and make significant changes in how science, technology, and industry work together to meet this challenge.
The brain’s complexity is evident not only when its processes are humming along smoothly but also when problems crop up. Alzheimer’s is the epitome of such a profoundly complex problem. Confounding early hopes for a straightforward solution, it has not turned out to be a disease attributable to just one runaway protein or just one gene. In fact, although Alzheimer’s is referred to as a single name, we in the Alzheimer’s research community don’t yet know how many different types of Alzheimer’s there may be and, therefore, how many different treatments might ultimately prove necessary across the population.
Over the past several years, we have continued to identify more genes (and lifestyle factors such as healthy diet and exercise) that convey some degree of protection against Alzheimer’s or, conversely, risk — both individually and, more vexingly, in combination. Often they affect multiple cellular and molecular processes, or pathways. For instance, some risk genes affect how certain cells handle fat molecules like cholesterol. Others seem to warp the brain’s immune response. Understanding how these pathways go awry, and whether these dysfunctions are distinct or derive from common underlying mechanisms, is a largely unexplored question for determining which therapies need to be developed and whom they will help.
Traditionally we’ve pursued small-molecule pharmaceuticals and immunotherapy that target a single protein, known as amyloid, but if we think about Alzheimer’s as a broader systemic breakdown, we need to turn to other molecular targets and explore alternate strategies, including gene therapies, or even digital therapies.
In my lab, we’ve been pursuing several novel approaches to Alzheimer’s. One involves increasing the power of a brain wave frequency that is flagging in Alzheimer’s patients, 40Hz, by stimulating the senses with light and sound flickering and clicking at that frequency. It’s an unconventional idea, but we and other groups are finding not only in Alzheimer’s mice but also in patients with Alzheimer’s that this systems neuroscience approach safely produces several therapeutically meaningful benefits, including reduced brain atrophy and preservation of cognitive function.
Notably, the development of this potential digital therapeutic has required the collaboration of a wide gamut of actors: MIT scientists and engineers, hospital physicians, philanthropists, investors, and volunteers from the community, whom we’ve marshaled via a collaboration called the Aging Brain Initiative.
Still, a more expansive scientific search is not enough. A huge innovation gap for many diseases, Alzheimer’s included, results from the so-called valley of death, in which novel discoveries, though promising, are nevertheless seen as too new for companies or investors to assume the risk of developing further. One collaborative opportunity for Greater Boston’s universities, hospitals, and biotech firms would involve creating a public-private “de-risking” consortium. Such an effort would combine resources both to pool the most promising intellectual property coming out of academic labs and conduct the testing needed to make worthy advances ready for commercial development. Success or failure would ride on the whole team, not just on a lone player. And with a broad coalition of stakeholders, it would also spread the financial risks associated with early-stage commercialization.
Moreover, innovations that would benefit from broader collaboration and de-risking are not limited to therapies. Clinicians, patients, engineers, businesspeople, and scientists could all advance a parallel ecosystem of technology development. Imagine how artificial intelligence and robotics could be harnessed to create assistive technologies for people with Alzheimer’s and the loved ones charged with their care. Technology can also accelerate the scientific and medical enterprise. For instance, as we grapple with immense data sets emanating from genomic, epigenomic, proteomic, and metabolomic research, AI can help us find new patterns and pathways.
The need for big change in how we think about Alzheimer’s is also an opportunity for Greater Boston to become a global leader. The region has all the scientific, educational, technological, medical, financial, and industrial infrastructure necessary to foster a more collaborative “hub-like” approach. With a more expansive mode of thinking, we can bridge the old innovation gaps and cross new valleys of discovery to deliver meaningful progress toward the end of Alzheimer’s.
Li-Huei Tsai is a professor in the department of brain and cognitive sciences and director of the Picower Institute for Learning and Memory at MIT.
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