While amyloid beta accumulates in the brain for decades before Alzheimer’s disease (AD) symptoms appear, it is the subsequent spread of tau tangles from the hippocampus and the loss of synaptic connections that best correlate with cognitive decline. However, some people remain cognitively intact despite having high levels of amyloid and even tau pathologies. These resilient individuals offer a valuable opportunity to identify protective factors that can be translated into novel therapeutics.
Dr. Gomez-Isla and her team have been leading research into cognitive resilience for many years. As part of previous CureAlz-funded projects, they curated and extensively characterized a cohort of more than 200 human brain autopsy samples from three groups: 1) cognitively resilient despite having AD-related pathology, 2) cognitively impaired with AD-pathology levels similar to the resilient group, and 3) control, cognitively intact individuals without AD-pathology. Comparing these sets of valuable tissue, they discovered that resilient brains have fewer tau oligomers—an early-stage, toxic form of tau—in the synapses. They also found differences in the inflammatory responses of microglia and astrocytes. During early disease stages, microglia and astrocytes released inflammatory signals before mature tau tangles formed. These activated glial cells are found near synapses, and in cognitively impaired AD patients, they engulf more synapses than in resilient individuals. The team also showed that activated glia preferentially removed synapses with tau oligomers. Recent studies have increasingly implicated peripheral immune cells in the pathogenesis of AD, particularly in relation to tau pathology. In light of that growing body of evidence and her previous findings, Dr. Gomez-Isla now aims to expand her investigation of resilience to include T cells and other peripheral immune cell populations. She has refined her hypothesis and now proposes that cognitive resilience arises from the suppression of a coordinated peripheral-brain-immune response triggered by tau oligomers in synapses.
They proposed three experimental aims to test this hypothesis. For the first aim, they want to define the changes in peripheral and central immune cell transcription patterns in resilient and AD cases. By doing so, they hope to characterize the immune crosstalk between these cell populations that might predispose someone to resilience and discover protective signaling pathways for therapeutic targeting in the future. They are comparing patterns of gene expression in blood-derived immune cells from 612 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with amyloid PET, MRI, and cognitive test scores available across disease stages. They are also utilizing a large single-cell gene sequencing dataset from another cohort, the Religious Orders Study and Memory and Aging Project (ROSMAP), to investigate how changes in other immune cell types, such as dendritic cells, basophils, and neutrophils, are related to cognitive resilience.
The immune system is complex and consists of several cell types; some of these are known to contribute to AD, while the role of others remains unclear. By casting a wide net, Dr. Gomez-Isla is generating valuable data on the role that understudied immune cells may play in AD and/or resilience. As part of this aim, they are validating changes in gene levels or cell types of interest with histological staining and imaging in brain tissue from their original cohort of resilient and AD patient brain samples. In the second aim, they are exploring whether tau oligomers in the synapse may attract peripheral immune cells that interact with and amplify the immune responses of microglia and astrocytes. They are focusing on the complement cascade signaling pathway, which is known to cause synapse removal. To visualize the proximity of infiltrating immune cells, microglia, astrocytes, neuroimmune proteins, and toxic tau forms in and around synapses in human tissue, they are using expansion microscopy, a technique that physically enlarges brain tissue by embedding it in a special gel that swells. This stretching spreads out tiny structures—like synapses—that are normally packed too closely together to see clearly. By expanding the tissue, researchers can use regular microscopes to view details that would otherwise be too small or close to one another for traditional imaging methods to be possible. The team is then examining whether these cell and protein changes correspond to greater synapse loss and worse cognitive scores in control, resilient, and typical AD brains across early to late disease stages. In the third aim, they are initiating an exploratory search for plasma biomarkers of resilience. They have access to a large publicly available dataset that contains nearly 3,000 different proteins recorded from 54,000 participants in the UK Biobank. They are analyzing these data to identify novel plasma markers associated with AD resilience.
Dr. Gomez-Isla’s team made substantial progress during the first funding period. They completed much of the proposed investigation of peripheral and brain immune crosstalk in resilient and AD brains. Using data from the ADNI cohort, they defined initial transcriptomic signatures associated with amyloid beta accumulation and resilience. Furthermore, they determined the relative abundance of 40 different immune cells. Specific populations of immune cells, like monocytes and neutrophils, were significantly lower in resilient cases compared to AD. They also observed an increase in complement-dependent synaptic pruning in AD cases, suggesting that this pathway may trigger microglia to engulf synapses, leading to cognitive impairment, and that suppressing this pathway may preserve synaptic function and contribute to resilience. Dr. Gomez-Isla’s team plans to publish their findings in the coming months, with another manuscript submission planned during the second funding period. Work in the second year will focus on completing data analyses for the first two aims and advancing the third aim. This project continues to further our understanding of not only resilience, but also the mechanisms connecting peripheral immune cells to changes in synaptic function and abundance, and, ultimately, cognitive decline and disease progression.
