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The Promise in a Preventative View of Alzheimer’s

Through my work in Alzheimer’s research over the past decade, I have heard from patients who are battling the disease firsthand, along with their loved ones and caregivers. Many have told me they initially shrugged off the forgotten names, the misplaced car keys, and repetitive questions. After all, they thought, isn’t forgetfulness a natural part of growing older? Even after receiving a diagnosis, they might avoid saying it out loud and hold off telling loved ones (and understandably so). Ultimately, many believe they are left with no choice but to sit by and wait as their world is becomes increasingly unrecognizable. 

The reality is that our current health-care model doesn’t address Alzheimer’s until it’s too late. Since the early 2000s, U.S. researchers have conducted more than 500 clinical trials seeking a drug that can slow, stop, or reverse the course of Alzheimer’s – and none have succeeded (source). In 2021, although the U.S. Government poured nearly $3.2 billion in funding into the National Institutes of Health to study the disease, the majority of these dollars continue to be directed toward late-stage treatment interventions (source).

It is becoming increasingly clear that we are chasing the cause of Alzheimer’s in the wrong place and at the wrong point in time within its disease trajectory. This November, for Alzheimer’s Disease Awareness Month, we should come together to radically shift our understanding of and approach toward this dreaded disease. This can start with moving away from the failed amyloid hypothesis and instead affirming the fundamental metabolic basis of the disease, stemming from diverse systematic failures to meet the high energy requirements needed to keep our neurons alive. From there, we can use this framework to prioritize prevention over traditional, late-stage treatment, and, in doing so, unlock groundbreaking and effective interventions. Indeed, the only clinical trial effort to show significant beneficial effects for dementia so far is the FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial, and its derivatives, which used an approach focused on prevention, lifestyle interventions, and nutrition (source).

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The stakes are incredibly high. With more than six million individuals in the United States living with Alzheimer’s, diagnoses continue to climb and economic implications magnify (source). The cost of caring for Alzheimer’s sufferers and other dementias is estimated to be $355 billion annually (source). Medicare just recently announced that it was raising the monthly premiums for its Part B plan, in part because of the expected spending on the Alzheimer’s drug aducanumab – despite the fact that this therapy has shown no significant impact on improving cognitive function (source). These consequences are further exacerbated by the cost of late-stage and chronic disease management, which is estimated to make up 75 percent of federal health-care spending (source). We must urgently change course and introduce a new paradigm for Alzheimer’s and chronic disease intervention – one that is driven by the promise of prevention and a different understanding of the driving mechanisms.

Reframing the root cause of Alzheimer’s

For decades, Alzheimer’s research has focused on the prevailing theory that the disease is caused by the buildup of amyloid plaques in the brain (source). But recently, an investigative report found that some of the most influential papers on this theory contained fraudulent results –paving  the way for a paradigm shift in how we think about the pathology of Alzheimer’s (source). We are now seeing growing support for the notion that amyloid, rather than being the cause, is instead part of a compensatory response triggered by the brain as it tries to recover from synapse loss and cell death. Given this misattribution of causality, amyloid serves as an excellent biomarker, but a faulty drug target.

That’s why many researchers are shifting their attention to a new theory that Alzheimer’s is fundamentally a metabolic disease that results in energy deficits in the brain (source). This theory is predicated on the idea that the body’s most vulnerable neurons become metabolically exhausted due to aging, resulting in an inability to satisfy neuronal energy requirements as oxygenation to the brain declines with age. This is exacerbated by effects on cholesterol metabolism, associated with the largest genetic risk factor for late-stage Alzheimer’s, APOE4. As more neurons die, this results in even greater metabolic demands on the remaining neurons to maintain cognitive function, and thus pushing the next most vulnerable into failure, creating a cascade of degeneration. 

Prioritizing prevention with digital twins

When we fundamentally reframe Alzheimer’s as a metabolic disease, it becomes clear that a preventative approach gets us much farther than traditional late-stage treatment. After the neurons are dead and the synapses lost, we can’t put them back together. But we can push off this decline and keep our brains functioning.

Of course, introducing this new paradigm and turning the tide on public sentiment around Alzheimer’s won’t come without challenges. For decades, some experts have advised against testing for high-genetic risk, perpetuated by the narrative that because there is no successful drug, there is nothing that can be done to reverse its trajectory. However, research shows this is simply not true (source). Through a preventative approach, we can vigilantly screen for wellness-to-disease transitions and identify treatments that can reverse disease at the earliest transition point, long before it is traditionally symptomatic. I cover this in detail in my new book co-authored with biotechnology pioneer Lee Hood, The Age of Scientific Wellness (source).

In turn, this will open up myriad potential lifestyle interventions, emboldening the field to move beyond a singular focus on late-stage drug development. One tool that can tailor multi-modal approaches to the individual are “digital twins.” At their core, digital twins enable us to simulate an individual’s unique physiology and biochemistry in a computer. Leveraging this technology, together with our partners at EmbodyBio, Thorne HealthTech can now build computational, multi-omics models of brain health that incorporate data from hundreds of scientific publications and combine them to simulate brain health and dementias for more than 10 million digital twins across the adult lifespan (source). When contextualized with phenomics data, such as genetics, blood measures, and from digital devices, we can then identify contributors to and subtypes of Alzheimer’s and predict the most beneficial multimodal intervention strategies at a personalized level.

Moving forward with a multimodal model

The multimodal model for prevention and early detection has shown far-reaching promise beyond Alzheimer’s. Research indicates that other neurodegenerative diseases – such as ALS, frontotemporal dementia, and at least one form of Parkinson’s disease – might also respond to this approach. 

We must come together to initiate more convincing clinical trials that support a multimodal approach for prevention and early detection. Hospital systems can also play an instrumental role by working with private health companies and research institutions to pilot brain health programs among their patients. From there, we can collect more deep phenotyping data, assess the efficacy of these programs, and identify the most effective and economical intervention strategies based on real patient feedback. 

Together, we can step into the future of Alzheimer’s and chronic disease research with a sense of renewed hope, better data, and stronger treatment strategies for the decades ahead. 

Dr. Nathan Price is Chief Science Officer of Thorne HealthTech and author of The Age of Scientific Wellness.

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