Overview

The Neurodegeneration and Sleep Pathology Laboratory of Lea Grinberg, M.D., Ph.D., at Mayo Clinic is dedicated to understanding the causes and progression of neurodegenerative diseases, especially dementias such as Alzheimer's disease and frontotemporal dementia. Our team uses advanced techniques to study how changes in the brain's structure and chemistry lead to memory loss, behavior changes, and other symptoms that affect patients and their families.

We investigate how abnormal proteins, such as tau, build up in the brain and disrupt normal function. Our work explores why certain brain cells are more vulnerable to disease, and how genetic and environmental factors influence disease risk and progression.

We use cutting-edge tools to study human brain tissue, including single-cell RNA sequencing, digital pathology and spatial omics, an approach that combines gene and protein mapping with tissue structure. We also develop and validate new biomarkers — molecules in blood or spinal fluid that can help diagnose disease earlier and track its progression.

Areas of interest

Areas of particular interest in our lab include:

  • Early-onset and atypical Alzheimer's disease.
  • The role of tau protein and its different forms in dementia.
  • How sleep and circadian rhythms are affected in neurodegenerative diseases.
  • The impact of genetic differences, such as the 17q21.31 haplotype, on disease risk.
  • Refined and optimized correlation between high-resolution digital pathology and in vivo imaging techniques.
  • Development of ultrasensitive tests for early detection of Alzheimer's disease and related conditions.

Key findings

Dr. Grinberg leads research that has produced multiple important, novel findings on the relationship between sleep and neurodegeneration. These findings include:

  • Distinct tau pathology phases. Our lab identified that caspase-6–truncated tau (D13 tr-tau) is a major, previously under-recognized form of tau pathology in Alzheimer's disease, often present in neurons that do not show phospho-tau. This finding challenges the assumption that p-tau alone captures the full spectrum of tau pathology.
  • Ultrasensitive biomarkers. In collaboration with our partners, we created a highly sensitive cerebrospinal fluid assay for D13 tr-tau. Our validation of this assay will enable earlier and more accurate diagnosis of Alzheimer's disease and distinguish it from other tauopathies.
  • First-in-human mapping of sleep-regulating brain nuclei in dementia. We have demonstrated that specific sleep and circadian nuclei — for example, suprachiasmatic nucleus and orexinergic neurons — are differentially vulnerable in Alzheimer's disease and progressive supranuclear palsy. This finding provides a mechanistic link between sleep disruption and neurodegeneration.
  • Selective vulnerability of neuronal populations. Our team has shown that certain neuron types, such as RORB+ excitatory neurons and AVP+ neurons in the hypothalamus, are especially prone to tau pathology, explaining clinical differences in dementia syndromes and sleep and circadian symptoms.
  • Integration of multi-omics and spatial profiling. Dr. Grinberg's lab pioneered the use of single-cell RNA sequencing, spatial transcriptomics and proteomics to map disease mechanisms at cellular resolution in human brain tissue.
  • Genetic risk and mechanistic insights. The research team has used quantitative neuropathology and complex multiplex staining to validate findings from CRISPR screens and iPSC-derived models. These methods to dissect regulatory mechanisms advance the understanding of how the 17q21.31 haplotype (H1/H2) and MAPT mutations drive risk of tauopathies.

  • Novel imaging-pathology correlation. We study the human brain using advanced digital pathology and computer vision tools that let us turn high-resolution microscope images of brain tissue into detailed maps. By analyzing these images, we can connect what we see under the microscope with what brain scans show in living people, matching them voxel by voxel. ("Voxels" can be understood as tiny 3D pixels in an MRI.)

    This work helps us better understand how changes in brain scans relate to the actual biological processes happening in the brain, improving our ability to diagnose neurological diseases such as Alzheimer's disease earlier and monitor progression more closely.

  • Impact of traumatic brain injury. Our research showed that traumatic brain injury is associated with unique patterns of tau pathology in young-onset Alzheimer's disease. These findings provide a framework for understanding environmental modifiers of disease.
  • Microglial activation and neuroinflammation. We mapped how microglial activation patterns differ between typical and atypical Alzheimer's disease and how they relate to tau pathology and neuronal loss, thereby highlighting new therapeutic targets.

Driving improvements in dementia care

Dementia affects millions of people and their families. Many questions remain about why these diseases start, why they progress differently in different people, and how healthcare teams can best diagnose and treat them. By uncovering the root causes of dementia, our lab aims to:

  • Improve early diagnosis. Our work on new biomarkers and imaging techniques helps healthcare professionals detect disease before symptoms become severe, allowing for earlier intervention.
  • Guide new treatments. By understanding the molecular and cellular changes that drive disease, we identify new targets for drug development and test potential therapies in the lab.
  • Improve patient care. Our research directly informs clinical practice at Mayo Clinic and beyond, helping to personalize care and improve quality of life for patients and caregivers.

Our research directly improves care and quality of life for patients and their families by providing:

  • Better diagnostic tools. We are developing tests that can distinguish Alzheimer's from other forms of dementia and even detect disease in its earliest stages.
  • Personalized medicine. By studying genetic and molecular differences among patients, we help tailor treatments to individual needs.
  • Support for families. Our findings help explain symptoms and disease progression, empowering families with knowledge and resources.

Affiliations

Dr. Grinberg's lab is affiliated with Alzheimer's and dementia-related studies and research groups across Mayo Clinic.