Preventing dementia

We are dedicated to preventing age-related cognitive decline, such as Alzheimer’s Disease.

Fulcrum Neuroscience provides health care providers with personalized risk assessment and preventive insights by generating digital twins from patient data using a proprietary mathematical model of brain metabolism developed by our founders.

Analysis of each digital twin provides tangible, explainable insights that help primary care physicians, and neurologists provide at-risk patients the chance for additional years of cognitive health, enhancing quality of life, reducing family caregiving burdens, and reducing total medical costs.

Our digital twin capabilities extend into research, generating deep insights into disease pathology and variability in diverse populations. This research is driving novel biomarker characterization and innovative strategies for stabilizing brain energy metabolism, including new drugs.

We won’t stop until we live in a world without cognitive decline.

Our founders

We are an interdisciplinary team committed to improving cognitive health and reducing medical costs by combining the state-of-the-art in systems biology with computational modeling, including artificial intelligence.

George Savage, MD

Chief Executive Officer

George has a successful track record founding and building first-in-category life science companies. He most recently was co-founder and CMO of Proteus Digital Health.

Tom Paterson

Chief Technology Officer

Tom is a pioneer of Computational Systems Physiology  modeling and the driving force behind Fulcrum’s Brain Homeostasis and Neurodegeneration model (BHN3). He most recently was CEO of Embody Bio.

Andrew Thompson

Chief Financial Officer

Andy is a serial entrepreneur with a track record of conceiving, growing and selling life science businesses. He most recently was co-founder and CEO of Proteus Digital Health.

Alex Bangs

Chief Product Officer

Alex is a life science and digital health product leader with experience designing and building software for physicians, patients, and researchers. He was previously CIO at Vir Biotechnology.

 

Cory Funk, PhD

Vice President, Biology

Cory is a scientist with a decade of experienced focused on Alzheimer’s Disease and other dementias. He is a senior research scientist at the Institute for Systems Biology and a key contributor to BHN3 model development

Jennifer Rohrs, PhD

Vice President, Platform Development

Jen is a modeling and simulation expert who has spent the past 4 years developing Fulcrum’s Brain Homeostasis and Degeneration model (BHN3). She was most recently co-founder and Director of Modeling at Embody Bio.

Don Breuner

Chief Software Architect

Don is a senior architect and developer with decades of experience building and maintaining complex software. He is responsible for back-end development of the BHN3 model.

Lee Hood, MD, PhD

Co-founder, Scientific Advisor

Lee is a world-renowned scientist, inventor, and entrepreneur; a pioneer in mapping the human genome and developing systems biology. He is currently CEO of Phenome Health.

Craig Mundie

Co-founder, Technical Advisor

Craig served as Microsoft’s Chief Research and Strategy Officer for 22 years. He is one of the world’s foremost experts on artificial intelligence and hyperscale computation.

Our approach

Preventing Dementia – Where is the leverage?

Like all chronic diseases of aging, clinical and observational studies clearly show that lifestyle choices (sleep, exercise, nutrition) have an impact on cognitive decline.  Likewise for some common medications taken for other chronic disorders (erectile dysfunction, gastric reflux, edema).  The effects observed, however, are highly variable.

  • What works for whom and why?
  • Are there synergies in combinations?
  • How long can you wait before these choices have little impact?

The answers are elusive . . . but the clues are there.

How all our brains stay healthy . . . and how they are each different

Answers to such questions are sought in larger and deeper data sets.  Massive investments have been made in genomic, proteomic, lipidomic, and metabolomic technologies with the promise of transforming health care.  While these technologies have been a boon for research, the health care benefits have yet to arrive.

  • Diverse biomarker signatures that stratify disease subtypes?  Yes
  • Intriguing observations from preclinical models? Yes
  • Deep causal understanding of how these multiomic pieces fit together in diverse human beings? No

Again, the clues are there, but health care is left with a handful of fragmented risk metrics, and with research insights out of reach for overworked clinicians.

Cumulative knowledge

To transform healthcare, all these clues, from risk factors to disease subtypes to preclinical model insights, need to be reconciled and synthesized into a transparent, validated, causal understanding of how our brains maintain homeostasis, and how we slowly lose that healthy balance as we age.  

That understanding needs to be personalized, based on individual medical data, continually updated over time with new test or log entries, with support for patients and their physicians for each new piece of data and how it brings this understanding into sharper focus.

Finally, that understanding must be put to work, exploring different lifestyle and therapeutic combinations to find those that best work both for the individual’s biology and preferences.

This is the Fulcrum Digital Twin. 

Fulcrum brings formidable technology and expertise to achieve our mission:

  • 30 years of experience building causal models of complex human diseases
  • 10 years building a robust technology platform for digital twins
  • 6 years focusing that expertise and technology on neurodegenerative diseases
  • 10 years of research experience in Alzheimer’s disease with a focus on multiomic systems biology
  • A rich research collaborator network spanning numerous NIH-funded consortia
  • Lee Hood’s legacy and pioneering vision for systems biology and P4 medicine

These resources are enabling Fulcrum to redefine age-driven cognitive decline.

What We’ve Learned

Brain Energy and Lipid Metabolism

In humans, the brain is an exceptionally energy-demanding organ despite its relatively small size in comparison to the rest of the body. Although the human brain represents only ~2% of the body’s total weight, it accounts for 20% of the body’s total energy consumption. That’s roughly 12x the energy utilization density compared to the rest of the body.

Supporting this enormous energy demand is a tightly-orchestrated network of metabolic storage, transport, recycling, energy-extraction, and signaling pathways that traverse multiple cell types (e.g., neurons, astrocytes, microglia, and endothelial cells).

While the complexity of these brain systems enables stability across a wide range of conditions, it also means that variations due to genetics, aging, and lifestyle choices create diverse boundaries for the edges of that stability.

Another one of the most regulated quantities in the human body is cholesterol.  An essential component of cell membranes and the myelin sheaths that insulate axons, the brain accounts for 25% of whole body cholesterol (16x higher cholesterol density than the rest of the body).  Neuronal membranes (30% cholesterol) are highly dynamic structures, capable of rapid expansion and contraction in response to various physiological needs, including the formation of new synapses and the pruning of existing ones.  As a result, cholesterol homeostasis in the brain requires tight and dynamic regulation of cholesterol levels.

APOE is the central protein in cholesterol and other lipid transport in the brain, and is integral to this tight regulation of cholesterol homeostasis.  The variant, APOE4, is the highest known genetic risk factor for late-onset Alzheimer’s disease.  Variants from numerous other cholesterol-related genes (e.g., TREM2, BIN1, ABCA7) are also implicated in Alzheimer’s etiology.

When we map out the feedback loops that provide the tight regulation of both energy metabolism and cholesterol/lipid homeostasis in the brain, we see how these pathways are highly interwoven

By understanding these complex relationships of brain homeostasis we are better able to mechanistically understand previously reported risk factors as well as devise parallel therapeutic strategies.

Getting Nudged Down the Slippery Slope

The reduction in cerebral blood flow we experience as we age ultimately results in diminished metabolic capacity in the poorly vascularized regions of our brains, resulting in regional metabolic deficits.  The hippocampus, the short-term memory center of our brains and a key region in early cognitive decline, is more poorly vascularized than the cortex and is more vulnerable to these metabolic deficits.

We believe these metabolic deficits drive early waves of neuronal death and provide the nudge down the slippery slope of age-driven cognitive decline.

The slippery slope (or destabilizing positive feedback loops that accelerate the process of neurodegeneration and cognitive decline) is a result of the brain’s limited capacity to handle the cellular debris from dead neurons:

  • The high cholesterol/lipid content of neuronal debris needs to be processed and removed from the brain.
  • That removal process utilizes the same cholesterol/lipid transport system that is critical for maintaining healthy neurons
  • As the transport system becomes overloaded, excess cholesterol/lipids across multiple cell types disrupts and lowers neuron metabolic capacity

More neurons die, generating more debris, and the cycle accelerates

  • Cholesterol dyshomeostasis is well-documented in Alzheimer’s disease (Luo 2020), and our own analysis of clinical data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (AAIC 2023 poster, manuscript in preparation), shows evidence of this process.  These data also show clear variability between individuals.  Recent high-profile publications (TCW 2022, Nugent 2022, Haney 2024,) provide additional evidence for this limited capacity to handle neuronal debris.

What about Amyloid and Tau?

Amyloid is a contributing factor in disease progression, and is highly correlated with its pathology.  However, the clinical failures of drugs targeting different steps in the amyloid life cycle demonstrate the complexity of its role.  What is not often highlighted are the upstream mechanisms that drive an increase in amyloid synthesis:  elevated cholesterol levels in the neuron cell membrane (Wang 2020).

We see amyloid, and particularly its effect on cerebral blood flow (Cerebral Amyloid Angiopathy or CAA, Greenberg 2020) as a contributor, but that the defining dysfunctions of age-driven cognitive decline lie upstream in cholesterol/lipid dysregulation.  This is aligned with a growing number of Alzheimer’s researchers who see AD as primarily metabolic in nature.

Like amyloid, we see tau dysregulation to be a downstream contributor to disease progression, and a valuable biomarker.

Delaying the Nudge, and Making Your Slope Less Slippery

The cumulative knowledge that Fulcrum has assembled in our platform encompasses the core biology described here, and much more.  The broad regulatory networks for energy and cholesterol/lipid metabolism create a wealth of touch-points for genetic variants, lifestyle factors, and existing/novel drug targets that can impact:

  • The inherent stability of these systems
  • The factors that can de-stabilize them
  • The interventions that can re-stabilize or compensate for destabilizing factors, or slow the rate of progression

Fulcrum Digital Twins provide a scalable framework for efficiently and flexibly learning how an individual’s brain metabolism is balanced, and suggest intervention strategies to maintain cognitive function as long as possible.

© 2024 Fulcrum Neuroscience, inc.