Summary: Researchers uncover how specific brain cells and circuits become vulnerable in Alzheimer’s disease and identify factors that may promote resilience to cognitive decline.
Analyzing gene expression in over 1.3 million cells across multiple brain regions, the study highlights the role of Reelin in neuron protection and choline metabolism in astrocytes for cognitive resilience. These findings pave the way for potential therapeutic targets to sustain cognition and memory amid Alzheimer’s pathology.
Key Facts:
- Reelin-producing neurons are linked to cognitive resilience in Alzheimer’s patients.
- Choline metabolism in astrocytes is associated with sustained cognition despite pathology.
- Gene expression analysis in 1.3 million cells revealed significant insights into Alzheimer’s.
An MIT study published today in Nature provides new evidence for how specific cells and circuits become vulnerable in Alzheimer’s disease, and hones in on other factors that may help some people show resilience to cognitive decline, even amid clear signs of disease pathology.
To highlight potential targets for interventions to sustain cognition and memory, the authors engaged in a novel comparison of gene expression across multiple brain regions in people with or without Alzheimer’s disease, and conducted lab experiments to test and validate their major findings.
Brain cells all have the same DNA but what makes them differ, both in their identity and their activity, are their patterns of how they express those genes. The new analysis measured gene expression differences in more than 1.3 million cells of more than 70 cell types in six brain regions from 48 tissue donors, 26 of whom died with an Alzheimer’s diagnosis and 22 of whom without.
As such, the study provides a uniquely large, far-ranging and yet detailed accounting of how brain cell activity differs amid Alzheimer’s disease by cell type, by brain region, by disease pathology, and by each person’s cognitive assessment while still alive.
“Specific brain regions are vulnerable in Alzheimer’s and there is an important need to understand how these regions or particular cell types are vulnerable,” said 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.
“And the brain is not just neurons. It’s many other cell types. How these cell types may respond differently, depending on where they are, is something fascinating we are only at the beginning of looking at.”
Co-senior author Manolis Kellis, professor of computer science and head of MIT’s Computational Biology Group, likened the technique used to measure gene expression comparisons, single cell RNA profiling, to being a much more advanced “microscope” than the ones that first allowed Alois Alzheimer to characterize the disease’s pathology more than a century ago.
“Where Alzheimer saw amyloid protein plaques and phosphorylated tau tangles in his microscope, our single-cell ‘microscope’ tells us, cell by cell and gene by gene, about thousands of subtle yet important biological changes in response to pathology,” said Kellis.
“Connecting this information with the cognitive state of patients reveals how cellular responses relate with cognitive loss or resilience, and can help propose new ways to treat cognitive loss.
“Pathology can precede cognitive symptoms by a decade or two before cognitive decline becomes diagnosed. If there’s not much we can do about the pathology at that stage, we can at least try to safeguard the cellular pathways that maintain cognitive function.”
Hansruedi Mathys, a former MIT postdoc in the Tsai Lab, who is now an assistant professor at the University of Pittsburgh, Carles Boix, a former graduate student in Kellis’s lab who is now a postdoc at Harvard Medical School, and Leyla Akay, a graduate student in Tsai’s lab, led the study analyzing the prefrontal cortex, entorhinal cortex, hippocampus, anterior thalamus, angular gyrus, and the midtemporal cortex.
The brain samples came from the Religious Order Study and the Rush Memory and Aging Project at Rush University.
Neural vulnerability and Reelin
Some of the earliest signs of amyloid pathology and neuron loss in Alzheimer’s occurs in memory-focused regions called the hippocampus and the entorhinal cortex. In those regions, and in other parts of the cerebral cortex, the researchers were able to pinpoint a potential reason why.
One type of excitatory neuron in the hippocampus and four in the entorhinal cortex were significantly less abundant in people with Alzheimer’s than in people without. Individuals with depletion of those cells performed significantly worse on cognitive assessments.
Moreover, many vulnerable neurons were interconnected in a common neuronal circuit. And just as importantly, several either directly expressed a protein called Reelin, or were directly affected by Reelin signaling.
In all, therefore, the findings distinctly highlight especially vulnerable neurons, whose loss is associated with reduced cognition, that share a neuronal circuit and a molecular pathway.
Tsai noted that Reelin has become prominent in Alzheimer’s research because of a recent study of a man in Colombia. He had a rare mutation in the Reelin gene that caused the protein to be more active, and was able to stay cognitively healthy at an advanced age despite having a strong family predisposition to early-onset Alzheimer’s.
The new study shows that loss of Reelin-producing neurons is associated with cognitive decline. Taken together it may mean that the brain benefits from Reelin, but that neurons that produce it may be lost in at least some Alzheimer’s patients.
“We can think of Reelin as having maybe some kind of protective or beneficial effect,” Akay said. “But we don’t yet know what it does or how it could confer resilience.”
In further analysis the researchers also found that specifically vulnerable inhibitory neuron subtypes identified in a previously study from this group in the prefrontal cortex also were involved in reelin signaling, further reinforcing the significance of the molecule and its signaling pathway.
To further check their results, the team directly examined the human brain tissue samples and the brains of two kinds of Alzheimer’s model mice. Sure enough, those experiments also showed a reduction in Reelin-positive neurons in the human and mouse entorhinal cortex.
Resilience associated with choline metabolism in astrocytes
To find factors that might preserve cognition, even amid pathology, the team examined which genes, in which cells, and in which regions, were most closely associated with cognitive resilience, which they defined as residual cognitive function, above the typical cognitive loss expected given the observed pathology.
Their analysis yielded a surprising and specific answer: across several brain regions astrocytes that expressed genes associated with antioxidant activity and with choline metabolism and polyamine biosynthesis were significantly associated with sustained cognition, even amid high levels of tau and amyloid.
The results reinforced previous research findings led by Tsai and Susan Lundqvist in which they showed that dietary supplement of choline helped astrocytes cope with the dysregulation of lipids caused by the most significant Alzheimer’s risk gene, the APOE4 variant.
The antioxidant findings also pointed to a molecule that can be found as a dietary supplement, spermidine, which may have anti-inflammatory properties, although such an association would need further work to be established causally.
As before, the team went beyond the predictions from the single-cell RNA expression analysis to make direct observations in the brain tissue of samples. Those that came from cognitively resilient individuals indeed showed increased expression of several of the astrocyte-expressed genes predicted to be associated with cognitive resilience.
New analysis method, open dataset
To analyze the mountains of single-cell data, the researchers developed a new robust methodology based on groups of coordinately-expressed genes (known as “gene modules”), thus exploiting the expression correlation patterns between functionally-related genes in the same module.
“In principle, the 1.3 million cells we surveyed could use their 20,000 genes in an astronomical number of different combinations,” explain Kellis.
“In practice, however, we observe a much smaller subset of coordinated changes. Recognizing these coordinated patterns allow us to infer much more robust changes, because they are based on multiple genes in the same functionally-connected module.”
He offered this analogy: With many joints in their bodies, people could move in all kinds of crazy ways, but in practice they engage in many fewer coordinated movements like walking, running, or dancing. The new method enables scientists to identify such coordinated gene expression programs as a group.
While Kellis and Tsai’s labs already reported several noteworthy findings from the dataset, the researchers expect that many more possibly significant discoveries still wait to be found in the trove of data. To facilitate such discovery the team posted handy analytical and visualization tools along with the data on Kellis’s website at: https://compbio.mit.edu/ad_multiregion.
“The dataset is so immensely rich. We focused on only a few aspects that are salient that we believe are very, very interesting, but by no means have we exhausted what can be learned with this dataset,” Kellis said. “We expect many more discoveries ahead, and we hope that young researchers (of all ages) will dive right in and surprise us with many more insights.”
Going forward, Kellis said, the researchers are studying the control circuitry associated with the differentially expressed genes, to understand the genetic variants, the regulators, and other driver factors that can be modulated to reverse disease circuitry across brain regions, cell types, and different stages of the disease.
Additional authors of the study include Ziting Xia, Jose Davila Velderrain, Ayesha P. Ng, Xueqiao Jiang, Ghada Abdelhady, Kyriaki Galani, Julio Mantero, Neil Band, Benjamin T. James, Sudhagar Babu, Fabiola Galiana-Melendez, Kate Louderback, Dmitry Prokopenko, Rudolph E. Tanzi, and David A. Bennett.
Funding: Support for the research came from the National Institutes of Health, The Picower Institute for Learning and Memory, The JPB Foundation, the Cure Alzheimer’s Fund, The Robert A. and Renee E. Belfer Family Foundation, Eduardo Eurnekian, and Joseph DiSabato.

News
3D-printed implant offers a potential new route to repair spinal cord injuries
A research team at RCSI University of Medicine and Health Sciences has developed a 3-D printed implant to deliver electrical stimulation to injured areas of the spinal cord, offering a potential new route to [...]
Nanocrystals Carrying Radioisotopes Offer New Hope for Cancer Treatment
The Science Scientists have developed tiny nanocrystal particles made up of isotopes of the elements lanthanum, vanadium, and oxygen for use in treating cancer. These crystals are smaller than many microbes and can carry isotopes of [...]
New Once-a-Week Shot Promises Life-Changing Relief for Parkinson’s Patients
A once-a-week shot from Australian scientists could spare people with Parkinson’s the grind of taking pills several times a day. The tiny, biodegradable gel sits under the skin and releases steady doses of two [...]
Weekly injectable drug offers hope for Parkinson’s patients
A new weekly injectable drug could transform the lives of more than eight million people living with Parkinson's disease, potentially replacing the need for multiple daily tablets. Scientists from the University of South Australia [...]
Most Plastic in the Ocean Is Invisible—And Deadly
Nanoplastics—particles smaller than a human hair—can pass through cell walls and enter the food web. New research suggest 27 million metric tons of nanoplastics are spread across just the top layer of the North [...]
Repurposed drugs could calm the immune system’s response to nanomedicine
An international study led by researchers at the University of Colorado Anschutz Medical Campus has identified a promising strategy to enhance the safety of nanomedicines, advanced therapies often used in cancer and vaccine treatments, [...]
Nano-Enhanced Hydrogel Strategies for Cartilage Repair
A recent article in Engineering describes the development of a protein-based nanocomposite hydrogel designed to deliver two therapeutic agents—dexamethasone (Dex) and kartogenin (KGN)—to support cartilage repair. The hydrogel is engineered to modulate immune responses and promote [...]
New Cancer Drug Blocks Tumors Without Debilitating Side Effects
A new drug targets RAS-PI3Kα pathways without harmful side effects. It was developed using high-performance computing and AI. A new cancer drug candidate, developed through a collaboration between Lawrence Livermore National Laboratory (LLNL), BridgeBio Oncology [...]
Scientists Are Pretty Close to Replicating the First Thing That Ever Lived
For 400 million years, a leading hypothesis claims, Earth was an “RNA World,” meaning that life must’ve first replicated from RNA before the arrival of proteins and DNA. Unfortunately, scientists have failed to find [...]
Why ‘Peniaphobia’ Is Exploding Among Young People (And Why We Should Be Concerned)
An insidious illness is taking hold among a growing proportion of young people. Little known to the general public, peniaphobia—the fear of becoming poor—is gaining ground among teens and young adults. Discover the causes [...]
Team finds flawed data in recent study relevant to coronavirus antiviral development
The COVID pandemic illustrated how urgently we need antiviral medications capable of treating coronavirus infections. To aid this effort, researchers quickly homed in on part of SARS-CoV-2's molecular structure known as the NiRAN domain—an [...]
Drug-Coated Neural Implants Reduce Immune Rejection
Summary: A new study shows that coating neural prosthetic implants with the anti-inflammatory drug dexamethasone helps reduce the body’s immune response and scar tissue formation. This strategy enhances the long-term performance and stability of electrodes [...]
Scientists discover cancer-fighting bacteria that ‘soak up’ forever chemicals in the body
A family of healthy bacteria may help 'soak up' toxic forever chemicals in the body, warding off their cancerous effects. Forever chemicals, also known as PFAS (per- and polyfluoroalkyl substances), are toxic chemicals that [...]
Johns Hopkins Researchers Uncover a New Way To Kill Cancer Cells
A new study reveals that blocking ribosomal RNA production rewires cancer cell behavior and could help treat genetically unstable tumors. Researchers at the Johns Hopkins Kimmel Cancer Center and the Department of Radiation Oncology and Molecular [...]
AI matches doctors in mapping lung tumors for radiation therapy
In radiation therapy, precision can save lives. Oncologists must carefully map the size and location of a tumor before delivering high-dose radiation to destroy cancer cells while sparing healthy tissue. But this process, called [...]
Scientists Finally “See” Key Protein That Controls Inflammation
Researchers used advanced microscopy to uncover important protein structures. For the first time, two important protein structures in the human body are being visualized, thanks in part to cutting-edge technology at the University of [...]