Amyotrophic lateral sclerosis (ALS) Feldman's research on
amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease, has led to groundbreaking discoveries in disease mechanisms, risk factors, and potential treatments. She was instrumental in developing the first FDA-approved human clinical trial for a
stem cell therapy for ALS. The Phase 1 and 2 trials demonstrated the safety and feasibility of transplanting up to 16 million stem cells into the spinal cord of individuals with ALS, laying the foundation for future cell-based treatments. Feldman has also made national headlines for her work uncovering links between ALS risk and the
exposome – the totality of environmental exposures across a person's lifetime – including pesticides, metals, air pollution, and residential and occupational exposures. Her work, supported by an NIH Director's Transformative Award she received in October 2021, integrates cutting-edge multi-omics approaches, including
genomics,
epigenomics,
transcriptomics, and
metabolomics, to better understand how environmental factors contribute to ALS. As part of this effort, her team is also developing polygenic and environmental risk scores to predict an individual's likelihood of developing ALS and how the disease may progress. These predictive models aim to enable earlier diagnosis and intervention, ultimately working towards the goal of making ALS a preventable disease. Her laboratory has also made considerable strides investigating the relationship between the immune system and ALS. In 2018, she and her team secured a method-of-use patent to repurpose
Jakinibs, a family of Janus kinase inhibitors, for ALS treatment. This patent was based on her research identifying a novel immune-driven mechanism contributing to disease progression, offering a promising avenue for targeted therapies. Her laboratory is also analyzing immune cells in patients with ALS to develop immune profiles that help predict how the disease will progress. This research aims to uncover an immune signature that could guide personalized treatment approaches and improve patient outcomes. To accelerate discoveries, Feldman founded the University of Michigan ALS Consortium in 2010, establishing a comprehensive repository containing biospecimens, clinical data, lifestyle and toxin exposure history, and postmortem tissues (brain, spinal cord, teeth) from over 1,300 ALS patients and age- and sex-matched healthy individuals. This resource has enabled the identification of
epigenetic,
transcriptomic,
metabolomic, and
immunological signatures associated with ALS, leading to the discovery of potential biomarkers and new therapeutic targets.
Neuropathy and diabetes complications Feldman is also internationally known for her groundbreaking work on
diabetes complications, particularly
peripheral neuropathy. Her early work led to the development of the Michigan Neuropathy Screening Instrument (MNSI), a standardized, validated, and easy-to-use screening tool designed for the early detection of
diabetic neuropathy. The MNSI provides a reliable and consistent method for diagnosing neuropathy across diverse clinical and research settings, helping to identify patients at risk before significant nerve damage occurs. Due to its efficacy and accessibility, the MNSI has been widely adopted in major clinical trials and epidemiological studies, where it has played a key role in advancing the understanding of diabetic neuropathy and shaping global diabetes management. Her pioneering discoveries also include identifying obesity as a risk factor for peripheral neuropathy and establishing the
metabolic syndrome as a composite risk factor across multiple large and diverse clinical cohorts. Feldman combined data from patient studies and lab models to show that diabetic peripheral neuropathy is not just caused by
high blood sugar. Instead, it results from altered energy production in nerves due to abnormal processing of fat. This insight explains the classic stocking-glove presentation of diabetic peripheral neuropathy, where nerve damage progresses from distal (hands and feet) to proximal regions. These findings expanded the focus of research and clinical care from
blood sugar control alone to a broader, multi-targeted metabolic approach. This led to NIH-funded interventional trials examining the effects of diet, exercise, and
bariatric surgery, which have demonstrated that these strategies can stabilize or even improve neuropathy. As a result, the
American Diabetes Association (ADA) now advocates diet and exercise as first-line therapy for diabetic peripheral neuropathy. Feldman's current research interests focus on understanding the underlying causes of neuropathy and how it progresses over time, with a particular emphasis on the role of
extracellular vesicles and
Schwann cells in the pathogenesis of neuropathy. She is identifying key clinical risk factors that play a critical role in the development and worsening of neuropathy in patients with diabetes. She is developing risk assessment tools to guide the care of patients with diabetes and COVID-19, while also studying the neurological implications of
long COVID in affected individuals.
Brain health and Alzheimer's disease Feldman's research has also demonstrated critical connections between
metabolic dysfunction and
cognitive impairment. Her laboratory was among the first to show that brain neurons can become nonresponsive to
insulin, a molecule essential for sugar metabolism and memory formation. Using preclinical models of diabetes, her team demonstrated that these models develop hallmarks of
Alzheimer's disease pathology, including changes in
tau protein, which is associated with neurodegeneration. Feldman has reported that cognitive performance is impaired in individuals with
severe obesity compared to lean controls, and that waist circumference is a key metabolic risk factor for cognitive impairment, emphasizing the impact of metabolic health on brain function. Feldman's current research focuses on uncovering the underlying causes and drivers of neurodegenerative conditions like
dementia to develop targeted treatments. A key area of her work examines the complex interplay between aging,
metabolic dysfunction, and
neuroinflammation, particularly how these factors contribute to cognitive impairment and Alzheimer's disease. Using advanced omics techniques, her team is investigating how obesity alters brain
microglia – the immune cells responsible for clearing debris and regulating inflammation in the brain. Similar to her work on nerve health, she has also highlighted the potential benefits of diet and exercise for brain health. Drawing from insights gained from her pioneering ALS clinical trials, Feldman is developing stem cell therapies as a potential treatment for Alzheimer's disease and dementia. Her recent studies have demonstrated that transplanting stem cells into the brains of preclinical models with Alzheimer's disease improves cognitive outcomes and reduces disease pathology. Currently, her team is investigating the role of
interneurons – specialized brain cells that connect sensory and motor neurons – in Alzheimer's disease progression and their potential as a therapeutic target for stem cell-based treatments. ==Sources==