- MIT study reveals new insights into cellular and circuit vulnerabilities in Alzheimer’s disease.
- The study also identified factors that might help some people resist cognitive decline, such as key brain cells and diet.
- This analysis highlights the relationship between cellular responses and cognitive resilience, offering new avenues for treatment strategies..
New research, published in
For this study, the researchers used a new method to compare gene expression in different brain regions in individuals with and without Alzheimer’s disease.
Although brain cells share the same DNA, their identity and activity differ based on patterns of gene expression.
The researchers analyzed gene expression in more than 1.3 million cells from more than 70 cell types in six brain regions from 48 tissue donors, 26 of whom had Alzheimer’s disease and 22 of whom did not.
Li-Huei Tsai, co-senior author, Picower Professor of Neuroscience and director of the Picower Institute for Learning and Memory and the Brain Aging Initiative at MIT, explained the key findings to Today’s Medical Newssaying the study “identified pathways linked to cellular vulnerability and cognitive resilience.”
“These results provide new targets for therapeutic intervention,” Professor Tsai said.
“The most vulnerable cell types (brain exhaustion) are found in the brain regions most important for supporting learning and memory (entorhinal cortex and hippocampus) and these cells share a marker, Reelin. Furthermore, the metabolic pathway of a particular type of glial cell, namely astrocytes, is particularly disrupted in Alzheimer’s disease. Furthermore, the way astrocytes express genes for the biosynthesis of antioxidants, choline and polyamines appears to influence the individual’s resilience to dementia.”
— Professor Li-Huei Tsai
The researchers analyzed brain samples from the prefrontal cortex, entorhinal cortex, hippocampus, anterior thalamus, angular gyrus, and mediotemporal cortex.
They noted thousands of subtle but important biological changes, cell by cell and gene by gene, in response to Alzheimer’s pathology.
By linking this information to the patients’ cognitive status, they were able to understand how cellular responses correlate with cognitive decline or resilience, potentially suggesting new treatments for cognitive loss.
Because the pathology may precede cognitive symptoms by a decade or more, even if it is not possible to treat the pathology at this stage, it may be possible to protect the cellular pathways that support cognitive function.
David Merrill, MD, PhD, a geriatric psychiatrist and director of the Pacific Brain Health Center at the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, Calif., who was not involved in the research, said, “This study identifies 76 brain region-specific cell types that reveal cellular vulnerability, response, and resilience to Alzheimer’s disease.”
“This work paves the way for early detection and targeted therapeutic interventions, the long-awaited promise of precision medicine approaches,” he said.
Some of the earliest indications of amyloid pathology and neuronal loss in Alzheimer’s disease appear in memory-centric regions such as the hippocampus and entorhinal cortex.
The researchers identified a potential reason for this: a significant reduction in one type of excitatory neuron in the hippocampus and four types in the entorhinal cortex in people with Alzheimer’s disease compared to those without the disease.
Individuals with a decrease in these neurons performed significantly worse on cognitive assessments.
Many of these vulnerable neurons were part of a common neural circuit and directly expressed a protein called
These results highlight particularly vulnerable neurons, the loss of which is linked to reduced cognition, sharing both a neuronal circuit and a molecular pathway.
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The study found that cognitive decline is linked to the loss of Reelin-producing neurons.
Analysis of human brain tissue and Alzheimer’s model mice confirmed a reduction in Reelin-positive neurons, highlighting the role of Reelin in brain health and its potential loss in Alzheimer’s patients.
Researchers sought to understand why some people retain good cognitive function despite brain changes linked to Alzheimer’s disease.
They focused on the genes, cells and brain regions linked to this cognitive resilience.
They found that in several areas of the brain, a type of brain cell called astrocytes – which are involved in antioxidant activity, choline metabolism and polyamine biosynthesis – were essential for maintaining cognitive function even with high levels of harmful tau and amyloid proteins.
The results are consistent with
Additionally, the study highlighted spermidine, a dietary supplement with potential anti-inflammatory properties, although more research is needed.
By examining brain tissue samples, the team confirmed that individuals with better cognitive resilience had higher levels of certain genes in astrocytes, supporting their predictions from single-cell RNA analysis.
Researchers have developed a new method for processing large single-cell data by grouping related genes into “gene modules.”
This approach uses patterns of coordinated gene expression, similar to how human movement involves coordinated joint actions.
This method allows more reliable inferences to be made by analyzing groups of functionally connected genes.
The researchers hope to use this method to make further discoveries and study the mechanisms that control these genes in order to find ways to reverse the progression of Alzheimer’s disease.
Dr. Merrill added, “This research highlights the complexity of Alzheimer’s disease and the importance of different cell types in the brain’s response to the disease. Increasing public awareness of these mechanisms will help to improve understanding and management of Alzheimer’s disease.”