Study finds factors that help some people resist cognitive decline in Alzheimer's

• A study from MIT reveals new insights into the cellular and circuit vulnerabilities in Alzheimer’s disease.
• The study also identified factors that might help some individuals 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 Nature , finds that certain cellular and circuit vulnerabilities might enable some individuals to resist cognitive decline , despite having a clear disease pathology.

For this study, researchers used a novel method to compare gene expression across various brain regions in individuals with and without Alzheimer’s.

While brain cells share the same DNA, their identity and activity differ based on gene expression patterns.

The researchers analyzed gene expression in over 1.3 million cells from more than 70 cell types across six brain regions in 48 tissue donors, 26 of whom had Alzheimer’s disease and 22 who did not.

Co-senior author Li-Huei Tsai , Picower professor of neuroscience and director of The Picower Institute for Learning and Memory and the Aging Brain Initiative at MIT, explained the key findings to Medical News Today , saying that the study “identified pathways related to cell vulnerability and cognitive resilience.”

“These findings provide new targets for therapeutic intervention,” Professor Tsai explained.

“The cell types that show the most extent of vulnerability (depletion from the brain) are in the brain regions most important for supporting learning and memory (entorhinal cortex and hippocampus) and these cells share a marker, Reelin. Also, metabolic pathway in a particular type of glial cells, namely astrocytes, is particularly disrupted in Alzheimer’s. Moreover, how astrocytes express genes in antioxidant, choline and polyamine biosynthesis appear to influence individual’s resilience to dementia.”

— Professor Li-Huei Tsai

Linking cellular changes to cognitive decline

The researchers analyzed brain samples from the prefrontal cortex, entorhinal cortex, hippocampus, anterior thalamus, angular gyrus, and midtemporal cortex.

They noted thousands of subtle yet important biological changes, cell by cell and gene by gene, in response to Alzheimer’s pathology.

By linking this information to the cognitive state of patients, they were able to understand how cellular responses correlate with cognitive decline or resilience, potentially suggesting new treatments for cognitive loss.

Since pathology can precede cognitive symptoms by a decade or more, even if it’s not possible to address the pathology at that stage, it may be possible to protect the cellular pathways that support cognitive function.

David Merrill , MD, PhD, geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, who was not involved in this research, said that “this study identifies 76 brain-region-specific cell types revealing the cellular vulnerability, response, and resilience to Alzheimer’s disease.”

“This work paves the way for early detection and targeted therapeutic interventions — the long-promised promise of precision medicine approaches,” he said.

Reelin and neural vulnerability in Alzheimer’s

Some of the earliest indications of amyloid pathology and neuron loss in Alzheimer’s disease appear in memory-centric regions like the hippocampus and the 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 compared to those without the disease.

Individuals with a depletion of these neurons scored significantly worse on cognitive assessments.

Many of these vulnerable neurons were part of a common neuronal circuit and were either directly expressing a protein called Reelin or were influenced by Reelin signaling.

These findings highlight particularly vulnerable neurons, whose loss is linked to reduced cognition, sharing both a neuronal circuit and a molecular pathway.

A recent study highlights the importance of Reelin in Alzheimer’s research, focusing on a man with a rare mutation that increased Reelin activity and kept him cognitively healthy despite a family history of early-onset Alzheimer’s.

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, emphasizing Reelin’s role in brain health and its potential loss in Alzheimer’s patients.

How brain cells and diet are linked to cognitive resilience

Researchers aimed to understand why some people maintain good cognitive function despite having Alzheimer’s-related brain changes.

They focused on genes, cells, and brain regions linked to this cognitive resilience.

They discovered that in several brain areas, 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 findings align with earlier research showing that dietary choline supplements help astrocytes manage issues caused by the APOE4 gene, a major Alzheimer’s risk factor.

In addition, the study highlighted spermidine, a dietary supplement with potential anti-inflammatory benefits, though 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 single-cell RNA analysis predictions.

New method simplifies complex data analysis

The researchers developed a new method to handle vast 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 helps make more reliable inferences by analyzing groups of functionally connected genes.

The researchers aim to use this method to uncover more discoveries and study the control mechanisms of these genes to find ways to reverse the progression of Alzheimer’s disease.

Dr. Merrill added that “this research highlights the complexity of Alzheimer’s and the importance of different cell types in the brain’s response to the disease. Increasing public awareness of these mechanisms supports better awareness and management of Alzheimer’s.”