Multiomics Characterization of Tau Pathology Onset and Its Relationship with Amyloid in the Human Hippocampus

In Alzheimer’s disease (AD), aggregates of tau in neurofibrillary tangles and amyloid beta in plaques interact with different neuronal and non-neuronal cell types, ultimately impacting memory and cognitive abilities. While we know that tau and amyloid beta are linked to the disease, we still are working to unravel how they interact at the cellular and molecular levels. This is crucial for understanding how AD progresses.

To delve deeper, we are studying the hippocampus of patients with AD and primary age-related tauopathy (PART). PART is a common condition in older individuals that demonstrates tau but not amyloid beta and typically progresses rather slowly. The hippocampus, which is central to memory formation, is significantly impacted in AD from the early stages. In AD, we see both tau and amyloid beta pathology in the hippocampus, often coinciding with the onset of memory problems and mild cognitive impairment. However, in PART, we primarily observe tau-related pathology.

To investigate these differences, we are using advanced research techniques to closely examine postmortem human brain tissue. This includes comparing gene expression in thousands of individual brain neurons with and without neurofibrillary tangles isolated from AD and PART brains. We also are using spatial multiomics, which allows us to map specific perturbations at the cellular and molecular levels in the tissue space in relation to tangles and plaques.

Our work aims to provide a clearer picture of the progression of tau-related pathology in the brain, pinpointing transitions from healthy states to early pre-tangles and further tangle formation. By examining how tau and amyloid beta influence each other during the course of the disease, our work may uncover the key alterations associated with neurodegeneration and disease progression, which may lead to identifying therapeutic entry points to slow down or halt AD.