ALZHEIMER’S DISEASE
2025: THE SALK INSTITUTE’S YEAR OF ALZHEIMER’S DISEASE RESEARCH
Salk scientists are redefining Alzheimer’s research by exploring a largely overlooked driver of the disease—chronic inflammation—rather than focusing solely on traditional hallmarks like amyloid plaques. By investigating this underlying factor across all brain cell types, not just neurons, we are uncovering new avenues for early detection and treatment.
The Challenge
Alzheimer’s disease is one of the most significant public health crises of our time. Despite more than $30 billion in research funding since 1984, no cure, prevention, or effective long-term treatment exists.
Tunnel vision. It’s no secret that Alzheimer’s research hasn’t progressed as quickly as we—and the many families affected— would like. That’s in part due to the overemphasis on amyloid plaques and tau tangles. These abnormal clumps of proteins in the brain were first observed by Alois Alzheimer himself in 1906 and thus became the defining biomarkers of the disease. For decades, these proteins were the focus of nearly all Alzheimer’s research and more than 400 failed clinical trials. There are two recently approved monoclonal antibody therapies that reduce amyloid plaques, but the benefit to patients is modest at best.
Furthermore, most research on brain function and cognitive decline is focused exclusively on neurons. Yet, in reality, neurons make up only half of the brain’s total cell count. The other half are glial cells, which support and protect neurons and undoubtedly play an underappreciated role in maintaining brain health.
Variable disease. To further complicate the matter, not all Alzheimer’s cases are alike. First, there are two main types: 1) familial Alzheimer’s disease, which is a rare, early-onset form caused by inherited gene mutations; and 2) sporadic Alzheimer’s, which is the most common form of the disease, making up more than 90% of cases. Yet even for sporadic Alzheimer’s, the disease can be influenced by combinations of genetic and environmental factors. That means that among sporadic Alzheimer’s patients, disease progression is highly heterogeneous, requiring individualized prevention and treatment strategies.
The need for a transformative approach has never been more urgent.
What drives Alzheimer’s disease?
What contributes to harmful chronic inflammation in the brain?
The Salk Approach
The Salk Institute is rewriting the narrative of Alzheimer’s disease research. Led by a team of world-renowned scientists, our approach centers on applying what we’ve learned from nearly a decade of research on the biology of aging. Compared to other age-associated diseases, such as cancer and heart disease, progress on Alzheimer’s has been too slow and needs a new approach.
Salk scientists have long been investigating the many molecular hallmarks of aging, with support from the American Heart Association and Allen Frontiers Group Initiative. From this experience, the team has homed in on chronic inflammation as a critical driver of Alzheimer’s disease.
Chronic inflammation is a sustained immune response in the brain over an individual’s lifetime, and that long-term damage can ultimately manifest as Alzheimer’s disease. The Salk team also identified two key factors as key contributors to this harmful inflammation: genome instability and dysregulated energy metabolism.
Salk scientists believe that inflammation, genome stability, and energy metabolism are directly connected and influence one another.
Even at baseline, human brains require enormous amounts of energy—approximately 20% of the body’s total energy consumption, about twice that of other primates. Our brains are already running in energetic hyperdrive. So, when life throws an added stress on top of that, such as the need for extra DNA repair, or as mitochondria naturally decline with age, inflammation increases. Ultimately, this stress makes the brain more susceptible to Alzheimer’s.
Unlike traditional research focused solely on pathological markers such as amyloid plaques and tau tangles, Salk’s approach pulls back the lens and takes into account the primary risk factor for Alzheimer’s—aging—not only in neurons, but the whole brain.
This approach will allow researchers to identify biomarkers for early signs of the disease and new opportunities for intervention with next-generation therapeutics.
See the Salk
Approach at Work
Here are just a few examples of Salk studies that demonstrate our expertise in neuroscience, immunobiology, genomics, and metabolism, as well as our strengths in thinking creatively and collaboratively to find what few others are even looking for:
Chromosomes, mitochondria, and inflammation are interconnected: As we age, the end caps of our chromosomes, called telomeres, gradually shorten. By collaborating across disciplines, Salk scientists discovered that when telomeres become very short, they communicate with mitochondria. This communication triggers a complex set of signaling pathways and initiates an inflammatory response. The team is now determining how this crosstalk between genomes, mitochondria, and inflammation plays a role in Alzheimer’s disease.
- Genomic stability requires a lot of energy: Neurons lack the ability to replicate their DNA, so they’re constantly working to repair damage to their genomes. Salk scientists found that these repairs are not random but instead focus on protecting certain genetic “hot spots” that appear to play a critical role in neural identity and function. As cellular energy production declines as we age, neurons struggle to repair their genomes. Accordingly, the team is now unraveling the interplay between genomes and energy metabolism to determine its role in Alzheimer’s disease.
- Non-neuronal brain cells as therapeutic targets. Salk scientists discovered that astrocytes, the most common type of glial cell, are crucial for shaping communication across the brain. They also found that in Alzheimer’s patients, astrocytes are less able to create or strengthen synapses ultimately disrupting brain communication. The scientists are now testing whether boosting astrocyte function in the Alzheimer’s brain can restore synaptic function and delay disease progression.
- Past infections inform the immune system for a lifetime. Our immune system defends us against infections and deadly pathogens, but does a lifetime of repeated infections and chronic inflammation take a toll on our cells and tissues? How does this impact brain health as we age? Salk scientists are investigating how lifelong exposure to infections and other foreign agents influences immune cell infiltration and brain inflammation, potentially contributing to the development of Alzheimer’s disease.
- Cooperative defense system. Salk researchers have revealed that the body has evolved mechanisms to tolerate infections by maintaining physiological function and repairing tissue damage—both of which are necessary for survival. Beyond infections, this approach reshapes our perception of health—not merely as the absence of disease but as an active, mechanistic process of maintaining resilience and endurance. Cooperative defenses hold promise for treating non-infectious diseases such as Alzheimer’s disease and other inflammatory disorders, metabolic syndromes, and cancer, and hold secrets for regenerative medicine.
These research examples demonstrate the types of cross-disciplinary explorations that can only happen at a place like Salk.
Why Salk?
For 65 years, the Salk Institute has pursued founder Jonas Salk’s vision of fearless, interdisciplinary science tackling some of the biggest challenges facing humankind. This unique beginning, together with our exceptional people, collaborative culture, freedom to explore, and distinguished scientific legacy set Salk apart—even among the most elite research institutions.
Cross-disciplinary “think tanks.” At Salk, experts in diverse disciplines relevant to inflammation and the aging process interact regularly, influencing each other’s thinking and elevating each other’s research with their respective expertise. By design, the physical structure of Salk labs—open, not organized by research field—promotes this cross-disciplinary synergy.
Leading-edge tools and technologies. Numerous tools and technologies have already been developed at Salk to study aging and Alzheimer’s disease. These include personalized human brain organoids (3D brain-like structures that include multiple brain cell types) from both healthy people and those with Alzheimer’s, biocomputation methods such as artificial intelligence, real-time cell and tissue imaging, and comprehensive metabolite profiling. In addition, Salk scientists have created an open-access cell atlas of the entire mouse brain and a draft cell atlas of the human brain, the first of their kind. These atlases bring researchers closer to understanding the brain’s makeup at the cellular level, providing a highly valuable resource for investigating the causes, progression, and treatment of many brain disorders, including Alzheimer’s.
Salk scientists have also adopted many of the leading-edge technologies that have emerged in the scientific community over the past decade, including next-generation gene sequencing, single-cell sequencing, and super-resolution microscopy. One of the benefits of Salk’s culture and size is the ability to be nimble—to adapt as science changes and swiftly take advantage of new opportunities.
Track record of success. Since 2018, initial funding from the American Heart Association-Allen Initiative in Brain Health and Cognitive Impairment has allowed an interdisciplinary team of Salk scientists to begin investigating mechanisms underlying Alzheimer’s disease and aging-related cognitive decline, pointing toward potential new diagnostics and therapies.
The team’s track record speaks volumes. Over the first six years of AHA-Allen funding, the team published 51 peer-reviewed articles in leading journals. Moreover, these projects have laid the foundation for the collaborations and technologies needed to take a significant leap in our understanding of Alzheimer’s disease and how to identify, prevent, and treat it.