Author: davidjo

Five volunteers continued receiving 40Hz stimulation for around two years after an early-stage MIT clinical study. Those who had late-onset Alzheimer’s performed significantly better on several assessments than comparable Alzheimer’s patients outside the trial

A new research paper documents the outcomes of five volunteers who continued to receive 40Hz light and sound stimulation for around two years after participating in an MIT early-stage clinical study of the potential Alzheimer’s disease therapy. The results show that for the three participants with late-onset Alzheimer’s disease, several measures of cognition remained significantly higher than comparable Alzheimer’s patients in national databases. Moreover, in the two late-onset volunteers who donated plasma samples, levels of Alzheimer’s biomarker tau proteins were significantly decreased.

The three volunteers who experienced these benefits were all female. The two other participants, each of whom were males with early-onset forms of the disease, did not exhibit significant benefits after two years. The dataset, while small, represents the longest-term test so far of the safe, non-invasive treatment method (called GENUS, for gamma entrainment using sensory stimuli), which is also being evaluated in a nationwide clinical trial run by MIT-spinoff company Cognito Therapeutics.

“This pilot study assessed the long-term effects of daily 40Hz multimodal GENUS in patients with mild AD,” the authors wrote in Alzheimer’s & Demetntia: The Journal of the Alzheimer’s Association. “We found that daily 40Hz audiovisual stimulation over 2 years is safe, feasible, and may slow cognitive decline and biomarker progression, especially in late-onset AD patients.”

Diane Chan, a former research scientist in The Picower Institute for Learning and Memory and a neurologist at Massachusetts General Hospital, is the study’s lead and co-corresponding author. Picower Professor Li-Huei Tsai, director of The Picower Institute and the Aging Brain Initiative at MIT, is the study’s senior and co-corresponding author.

An “open label” extension

In 2020, MIT enrolled 15 volunteers with mild Alzheimer’s disease in an early-stage trial to evaluate whether an hour a day of 40Hz light and sound stimulation, delivered via an LED panel and speaker in their homes, could deliver clinically meaningful benefits. Several studies in mice had shown that the sensory stimulation increases the power and synchrony of 40Hz gamma frequency brain waves, preserves neurons and their network connections, reduces Alzheimer’s proteins such as amyloid and tau, and sustains learning and memory. Several independent groups have also made similar findings over the years.

MIT’s trial, though cut short by the Covid-19 pandemic, found significant benefits after three months. The new study examines outcomes among five volunteers who continued to use their stimulation devices on an “open label” basis for two years. These volunteers came back to MIT for a series of tests 30 months after their initial enrollment. Because four participants started the original trial as controls (meaning they initially did not receive 40Hz stimulation), their open label usage was six to 9 months shorter than the 30-month period.

The testing at 0, 3 and 30 months of enrollment included measurements of their brain wave response to the stimulation, MRI scans of brain volume, measures of sleep quality and a series of five standard cognitive and behavioral tests. Two participants gave blood samples. For comparison to untreated controls, the researchers combed through three national databases of Alzheimer’s patients, matching thousands of them on criteria such as age, gender, initial cognitive scores, and retests at similar timepoints across a 30-month span.

Outcomes and outlook

The three female late-onset Alzheimer’s volunteers showed improvement or slower decline on most of the cognitive tests, including significantly positive differences compared to controls on three of them. These volunteers also showed increased brain-wave responsiveness to the stimulation at 30 months and showed improvement in measures of circadian rhythms. In the two late-onset volunteers who gave blood samples, there were significant declines in phosphorylated tau (47 percent for one and 19.4 percent for the other) on a test recently approved by the FDA as the first plasma biomarker for diagnosing Alzheimer’s.

“One of the most compelling findings from this study was the significant reduction of plasma pTau217, a biomarker strongly correlated with AD pathology, in the two late-onset patients in whom follow-up blood samples were available,” the authors wrote in the journal. “These results suggest that GENUS could have direct biological impacts on Alzheimer’s pathology, warranting further mechanistic exploration in larger randomized trials.”

Though the initial trial results showed preservation of brain volume at 3 months among those who received 40Hz stimulation, that was not significant at the 30-month timepoint. And the two male early-onset volunteers did not show significant improvements on cognitive test scores. Notably, the early onset patients showed significantly reduced brain-wave responsiveness to the stimulation.

Though the sample is small, the authors hypothesize that the difference between the two sets of patients is likely attributable to the difference in disease onset rather than the difference in gender.

“GENUS may be less effective in early onset Alzheimer’s disease patients, potentially owing to broad pathological differences from late-onset Alzheimer’s disease that could contribute to differential responses,” the authors wrote. “Future research should explore predictors of treatment response, such as genetic and pathological markers.”

Currently, the research team is studying whether GENUS may have a preventative effect when applied before disease onset. The new trial is recruiting participants aged 55+ with normal memory who have or had a close family member with Alzheimer’s disease, including early-onset.

In addition to Chan and Tsai, the paper’s other authors are Gabrielle de Weck, Brennan L. Jackson,, Ho-Jun Suk, Noah P. Milman, Erin Kitchener, Vanesa S. Fernandez Avalos, MJ Quay, Kenji Aoki, Erika Ruiz, Andrew Becker, Monica Zheng, Remi Philips, Rosalind Firenze, Ute Geigenmüller, Bruno Hammerschlag, Steven Arnold, Pia Kivisäkk, Michael Brickhouse, Alexandra Touroutoglou, Emery N. Brown, Edward S. Boyden, Bradford C. Dickerson and, Elizabeth B. Klerman.

Funding for the research came from the Freedom Together Foundation, the Robert A. and Renee E. Belfer Family Foundation, the Eleanor Schwartz Charitable Foundation, the Dolby Family, Che King Leo, Amy Wong and Calvin Chin, Kathleen and Miguel Octavio, the Degroof-VM Foundation, the Halis Family Foundation, Chijen Lee, Eduardo Eurnekian, Larry and Debora Hilibrand, Gary Hua and Li Chen, Ko Han Family, Lester Gimpelson, David B Emmes, Joseph P. DiSabato and Nancy E. Sakamoto, Donald A. and Glenda G. Mattes, the Carol and Gene Ludwig Family Foundation, Alex Hu and Anne Gao, Elizabeth K. and Russell L. Siegelman, the Marc Haas Foundation, Dave and Mary Wargo, James D. Cook, and the Nobert H. Hardner Foundation.

Cultured from induced pluripotent stem cells, ‘miBrains’ integrate all major brain cell types and model brain structures, cellular interactions, activity, and pathological features.

A new 3D human brain tissue platform developed by MIT researchers is the first to integrate all major brain cell types, including neurons, glial cells and the vasculature into a single culture. Grown from individual donors’ induced pluripotent stem cells, these models—dubbed Multicellular Integrated Brains (miBrains)—replicate key features and functions of human brain tissue, are readily customizable through gene editing, and can be produced in quantities that support large-scale research. 

Although each unit is smaller than a dime, miBrains may be worth a great deal to researchers and drug developers who need more complex living lab models to better understand brain biology and treat diseases. 

“The miBrain is the only in vitro system that contains all six major cell types that are present in the human brain,” said Li-Huei Tsai, Picower Professor, director of The Picower Institute for Learning and Memory, and senior author of the study describing miBrains, published Oct. 17 in the Proceedings of the National Academy of Sciences.

“In their first application, miBrains enabled us to discover how one of the most common genetic markers for Alzheimer’s disease alters cells’ interactions to produce pathology,” she added.

Tsai’s co-senior authors are Robert Langer, David H. Koch (1962) Institute Professor, and Joel Blanchard, associate professor in the Icahn School of Medicine at Mt. Sinai in New York and a former Tsai Laboratory postdoc. The study is led by Alice Stanton, former postdoc in the Langer and Tsai labs and now assistant professor at Harvard Medical School and Massachusetts General Hospital, and Adele Bubnys, a former Tsai lab postdoc and current senior scientist at Arbor Biotechnologies.

Cyan staining shows each of the six major cell types integrated in a miBrain culture.

Benefits from two kinds of models 

The more closely a model recapitulates the brain’s complexity, the better suited it is for extrapolating how human biology works and how potential therapies may affect patients. In the brain, neurons interact with each other and with various helper cells, all of which are arranged in a three-dimensional tissue environment that includes blood vessels and other components. All of these interactions are necessary for health and any of them can contribute to disease. 

Simple cultures of just one or a few cell types can be created in quantity relatively easily and quickly, but they cannot tell researchers about the myriad interactions that are essential to understanding health or disease. Animal models embody the brain’s complexity, but can be difficult and expensive to maintain, slow to yield results, and different enough from humans to yield occasionally divergent results.

miBrains combine advantages from each type of model, retaining much of the accessibility and speed of lab-cultured cell lines while allowing researchers to obtain results that more closely reflect the complex biology of human brain tissue. Moreover, they are derived from individual patients, making them personalized to an individual’s genome. In the model, the six cell types self-assemble into functioning units, including blood vessels, immune defenses, and nerve signal conduction, among other features. Researchers ensured that miBrains also possess a blood-brain-barrier capable of gatekeeping which substances may enter the brain, including most traditional drugs. 

“The miBrain is very exciting as a scientific achievement,” said Langer. “Recent trends toward minimizing the use of animal models in drug development could make systems like this one increasingly important tools for discovering and developing new human drug targets.”

Two ideal blends for functional brain models

Designing a model integrating so many cell types presented challenges that required many years to overcome. Among the most crucial was identifying a substrate able to provide physical structure for cells and support their viability. The research team drew inspiration from the environment that surrounds cells in natural tissue, the extracellular matrix (ECM). The miBrain’s hydrogel-based “neuromatrix” mimics the brain’s ECM with a custom blend of polysaccharides, proteoglycans, and basement membrane that provide a scaffold for all the brain’s major cell types while promoting the development of functional neurons.

A second blend would also prove critical: the proportion of cells that would result in functional neurovascular units. The actual ratios of cell types have been a matter of debate for the last several decades, with even the more advanced methodologies providing only rough brushstrokes for guidance, for example 45-75% for oligodendroglia of all cells or 19-40% for astrocytes. 

The researchers developed the six cell types from patient-donated induced pluripotent stem cells, verifying that each cultured cell type closely recreated naturally-occurring brain cells. Then, the team experimentally iterated until they hit on a balance of cell types that resulted in functional, properly structured neurovascular units. This laborious process would turn out to be an advantageous feature of miBrains: because cell types are cultured separately, they can each be genetically edited so that the resulting model is tailored to replicate specific health and disease states. 

“Its highly modular design sets the miBrain apart, offering precise control over cellular inputs, genetic backgrounds, and sensors—useful features for applications such as disease modeling and drug testing,” said Stanton. 

Alzheimer’s discovery using miBrain

To test miBrain’s capabilities, the researchers embarked on a study of the gene variant APOE4, which is the strongest genetic predictor for the development of Alzheimer’s disease. Although one brain cell type, astrocytes, are known to be a primary producer of the APOE protein, the role that astrocytes carrying the APOE4 variant play in disease pathology is poorly understood.

miBrains were well-suited to the task for two reasons. First of all, they integrate astrocytes with the brain’s other cell types, so that their natural interactions with other cells can be mimicked. Second, because the platform allowed the team to integrate cell types individually, APOE4 astrocytes could be studied in cultures where all other cell types carried APOE3, a gene variant that does not increase Alzheimer’s risk. This enabled the researchers to isolate the contribution APOE4 astrocytes make to pathology.

In one experiment, the researchers examined APOE4 astrocytes cultured alone, vs. ones in APOE4 miBrains. They found that only in the miBrains did the astrocytes express many measures of immune reactivity associated with Alzheimer’s disease, suggesting the multicellular environment contributes to that state. 

The researchers also tracked the Alzheimer’s-associated proteins amyloid and phosphorylated tau, and found all-APOE4 miBrains accumulated them, whereas all-APOE3 miBrains did not, as expected. However, in APOE3 miBrains with APOE4 astrocytes, they found that APOE4 miBrains still exhibited amyloid and tau accumulation.

Then the team dug deeper into how APOE4 astrocytes’ interactions with other cell types might lead to their contribution to disease pathology. Prior studies have implicated molecular cross-talk with the brain’s microglia immune cells. Notably, when the researchers cultured APOE4 miBrains without microglia, their production of phosphorylated tau was significantly reduced. When the researchers dosed APOE4 miBrains with culture media from astrocytes and microglia combined, phosphorylated tau increased, whereas when they dosed them with media from cultures of astrocytes or microglia alone, the tau production did not increase. The results therefore provided new evidence that molecular cross-talk between microglia and astrocytes is indeed required for phosphorylated tau pathology.

In the future, the research team plans to add new features to miBrains to more closely model characteristics of working brains, such as leveraging microfluidics to add flow through blood vessels or single cell RNA sequencing methods to improve profiling of neurons. 

Researchers expect that miBrains could advance research discoveries and treatment modalities for Alzheimer’s disease and beyond. 

 “Given its sophistication and modularity, there are limitless future directions,” said Stanton. “Among them, we would like to harness it to gain new insights into disease targets, advanced readouts of therapeutic efficacy, and optimization of drug delivery vehicles.”

“I’m most excited by the possibility to create individualized miBrains for different individuals,” added Tsai. “This promises to pave the way for developing personalized medicine.”

Funding for the study came from the BT Charitable Foundation, Freedom Together Foundation, the Robert A. and Renee E. Belfer Family, Lester A. Gimpelson, Eduardo Eurnekian, Kathleen and Miguel Octavio, David B. Emmes, the Halis Family, The Picower Institute for Learning and Memory, and an anonymous donor.

–By David Orenstein, The Picower Institute for Learning and Memory, and Bendta Schroeder, MIT Koch Institute

Research Article

Lipid metabolism and cell membrane function can be disrupted in the neurons of people who carry rare variants of ABCA7.

A new study from MIT neuroscientists reveals how rare variants of a gene called ABCA7 may contribute to the development of Alzheimer’s in some of the people who carry it.

Dysfunctional versions of the ABCA7 gene, which are found in a very small proportion of the population, contribute strongly to Alzheimer’s risk. In the new study, the researchers discovered that these mutations can disrupt the metabolism of lipids that play an important role in cell membranes.

This disruption makes neurons hyperexcitable and leads them into a stressed state that can damage DNA and other cellular components. These effects, the researchers found, could be reversed by treating neurons with choline, an important building block precursor needed to make cell membranes.

“We found pretty strikingly that when we treated these cells with choline, a lot of the transcriptional defects were reversed. We also found that the hyperexcitability phenotype and elevated amyloid beta peptides that we observed in neurons that lost ABCA7 was reduced after treatment,” says Djuna von Maydell, an MIT graduate student and the lead author of the study.

Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and Aging Brain Initiative and the Picower Professor in the MIT Department of Brain and Cognitive Sciences, is the senior author of the paper, which appears today in Nature.

Membrane dysfunction

Genomic studies of Alzheimer’s patients have found that people who carry variants of ABCA7 that generate reduced levels of functional ABCA7 protein have about double the odds of developing Alzheimer’s as people who don’t have those variants.

ABCA7 encodes a protein that transports lipids across cell membranes. Lipid metabolism is also the primary target of a more common Alzheimer’s risk factor known as APOE4. In previous work, Tsai’s lab has shown that APOE4, which is found in about half of all Alzheimer’s patients, disrupts brain cells’ ability to metabolize lipids and respond to stress.

To explore how ABCA7 variants might contribute to Alzheimer’s risk, the researchers obtained tissue samples from the Religious Orders Study/Memory and Aging Project (ROSMAP), a longitudinal study that has tracked memory, motor, and other age-related changes in older people since 1994. Of about 1,200 samples in the dataset that had genetic information available, the researchers obtained 12 from people who carried a rare variant of ABCA7.

The researchers performed single-cell RNA sequencing of neurons from these ABCA7 carriers, allowing them to determine which other genes are affected when ABCA7 is missing. They found that the most significantly affected genes fell into three clusters related to lipid metabolism, DNA damage, and oxidative phosphorylation (the metabolic process that cells use to capture energy as ATP).

To investigate how those alterations could affect neuron function, the researchers introduced ABCA7 variants into neurons derived from induced pluripotent stem cells.

These cells showed many of the same gene expression changes as the cells from the patient samples, especially among genes linked to oxidative phosphorylation. Further experiments showed that the “safety valve” that normally lets mitochondria limit excess build-up of electrical charge was less active. This can lead to oxidative stress, a state that occurs when too many cell-damaging free radicals build up in tissues.

Using these engineered cells, the researchers also analyzed the effects of ABCA7 variants on lipid metabolism. Cells with the variants altered metabolism of a molecule called phosphatidylcholine, which could lead to membrane stiffness and may explain why the mitochondrial membranes of the cells were unable to function normally.

A boost in choline

Those findings raised the possibility that intervening in phosphatidylcholine metabolism might reverse some of the cellular effects of ABCA7 loss. To test that idea, the researchers treated neurons with ABCA7 mutations with a molecule called CDP-choline, a precursor of phosphatidylcholine.

As these cells began producing new phosphatidylcholine (both saturated and unsaturated forms), their mitochondrial membrane potentials also returned to normal, and their oxidative stress levels went down.

The researchers then used induced pluripotent stem cells to generate 3D tissue organoids made of neurons with the ABCA7 variant. These organoids developed higher levels of amyloid beta proteins, which form the plaques seen in the brains of Alzheimer’s patients. However, those levels returned to normal when the organoids were treated with CDP-choline. The treatment also reduced neurons’ hyperexcitability.

In a 2021 paper, Tsai’s lab found that CDP-choline treatment could also reverse many of the effects of another Alzheimer’s-linked gene variant, APOE4, in mice. She is now working with researchers at the University of Texas and MD Anderson Cancer Center on a clinical trial exploring how choline supplements affect people who carry the APOE4 gene.

Choline is naturally found in foods such as eggs, meat, fish, and some beans and nuts. Boosting choline intake with supplements may offer a way for many people to reduce their risk of Alzheimer’s disease, Tsai says.

“From APOE4 to ABCA7 loss of function, my lab demonstrates that disruption of lipid homeostasis leads to the development of Alzheimer’s-related pathology, and that restoring lipid homeostasis, such as through choline supplementation, can ameliorate these pathological phenotypes,” she says.

In addition to the rare variants of ABCA7 that the researchers studied in this paper, there is also a more common variant that is found at a frequency of about 18 percent in the population. This variant was thought to be harmless, but the MIT team showed that cells with this variant exhibited many of the same gene alterations in lipid metabolism that they found in cells with the rare ABCA7 variants.

“There’s more work to be done in this direction, but this suggests that ABCA7 dysfunction might play an important role in a much larger part of the population than just people who carry the rare variants,” von Maydell says.

The research was funded, in part, by the Cure Alzheimer’s Fund, the Freedom Together Foundation, the Carol and Gene Ludwig Family Foundation, James D. Cook, and the National Institutes of Health.

–FROM MIT NEWS

Research Article

Study of 3.5 million cells from more than 100 human brains finds that Alzheimer’s progression—but also resilience to disease—depends on preserving epigenomic stability.

Most people recognize Alzheimer’s from its devastating symptoms such as memory loss, while new drugs target pathological aspects of disease manifestations, such as plaques of amyloid proteins. Now a sweeping new study in the Sept. 4 edition of Cell by MIT researchers shows the importance of understanding the disease as a battle over how well brain cells control the expression of their genes. The study paints a high-resolution picture of a desperate struggle to maintain healthy gene expression and gene regulation where the consequences of failure or success are nothing less than the loss or preservation of cell function and cognition.

The study presents a first-of-its-kind, multimodal atlas of combined gene expression and gene regulation spanning 3.5 million cells from six brain regions, obtained by profiling 384 post-mortem brain samples across 111 donors. The researchers profiled both the “transcriptome,” showing which genes are expressed into RNA, and the “epigenome,” the set of chromosomal modifications that establish which DNA regions are accessible and thus utilized between different cell types.

The resulting atlas revealed many insights showing that the progression of Alzheimer’s is characterized by two major epigenomic trends. The first is that vulnerable cells in key brain regions suffer a breakdown of the rigorous nuclear “compartments” they normally maintain to ensure some parts of the genome are open for expression but others remain locked away. The second major finding is that susceptible cells experience a loss of “epigenomic information,” meaning they lose their grip on the unique pattern of gene regulation and expression that gives them their specific identity and enables their healthy function.

Accompanying the evidence of compromised compartmentalization and the erosion of epigenomic information are many specific findings pinpointing molecular circuitry that breaks down by cell type, by region, and gene network. They found, for instance, that when epigenomic conditions deteriorate, that opens the door to expression of many genes associated with disease, whereas if cells manage to keep their epigenomic house in order, they can keep disease-associated genes in check. Moreover, the researchers clearly saw that when the epigenomic breakdowns were occurring people lost cognitive ability but where epigenomic stability remained, so did cognition.

“To understand the circuitry, the logic responsible for gene expression changes in Alzheimer’s disease, we needed to understand the regulation and upstream control of all the changes that are happening, and that’s where the epigenome comes in,” said senior author Manolis Kellis, a professor in the Computer Science and Artificial Intelligence Lab and head of MIT’s Computational Biology Group. “This is the first large-scale single-cell multi-region gene-regulatory atlas of AD, systematically dissecting the dynamics of epigenomic and transcriptomic programs across disease progression and resilience.”

By providing that detailed examination of the epigenomic mechanisms of Alzheimer’s progression, the study provides a blueprint for devising new Alzheimer’s treatments that can target factors underlying the broad erosion of epigenomic control or the specific manifestations that affect key cell types such as neurons and supporting glial cells.

“The key to developing new and more effective treatments for Alzheimer’s disease depends on deepening our understanding of the mechanisms that contribute to the breakdowns of cellular and network function in the brain,” said Picower Professor and co-corresponding author Li-Huei Tsai, director of The Picower Institute for Learning and Memory and a founding member of MIT’s Aging Brain Initiative, along with Kellis. “This new data advances our understanding of how epigenomic factors drive disease.”

Kellis Lab members Zunpeng Liu and Shanshan Zhang are the study’s co-lead authors.

Compromised compartments and eroded information

Among the post-mortem brain samples in the study, 57 came from donors to the Religious Orders Study or the Rush Memory and Aging Project (collectively known as “ROSMAP”) who did not have AD pathology or symptoms, while 33 came from donors with early-stage pathology and 21 came from donors at a late stage. The samples therefore provided rich information about the symptoms and pathology each donor was experiencing before death.

In the new study, Liu and Zhang combined analyses of single cell RNA sequencing of the samples, which measures which genes are being expressed in each cell, and ATACseq, which measures whether chromosomal regions are accessible for gene expression. Considered together, these transcriptomic and epigenomic measures enabled the researchers to understand the molecular details of how gene expression is regulated across seven broad classes of brain cells (e.g. neurons or other glial cell types) and 67 subtypes of cells types (e.g. 17 kinds of excitatory neurons or 6 kinds of inhibitory ones).

The researchers annotated more than 1 million gene-regulatory control regions that different cells employ to establish their specific identities and functionality using epigenomic marking. Then, by comparing the cells from Alzheimer’s brains to the ones without, and accounting for stage of pathology and cognitive symptoms, they could produce rigorous associations between the erosion of these epigenomic markings and ultimately loss of function.

For instance, they saw that among people who advanced to late-stage AD, normally repressive compartments opened up for more expression and compartments that were normally more open during health became more repressed. Worryingly, when the normally repressive compartments of brain cells opened up, they became more afflicted with disease.

“For Alzheimer’s patients, repressive compartments opened up, and gene expression levels increased, which was associated with decreased cognitive function,” explained Liu.

But when cells managed to keep their compartments in order such that they expressed the genes they were supposed to, people remained cognitively intact.

Meanwhile, based on the cells’ expression of their regulatory elements, the researchers created an epigenomic information score for each cell. Generally, information declined as pathology progressed but that was particularly notable among cells in the two brain regions affected earliest in Alzheimer’s: the entorhinal cortex and the hippocampus. The analyses also highlighted specific cell types that were especially vulnerable including microglia that play immune and other roles, oligodendrocytes that produce myelin insulation for neurons, and particular kinds of excitatory neurons.

Risk genes and ‘chromatin guardians’

Detailed analyses in the paper highlighted how epigenomic regulation tracked with disease-related problems, Liu noted. The e4 variant of the APOE gene, for instance, is widely understood to be the single biggest genetic risk factor for Alzheimer’s. In APOE4 brains, microglia initially responded to the emerging disease pathology with an increase in their epigenomic information, suggesting that they were stepping up to their unique responsibility to fight off disease. But as the disease progressed the cells exhibited a sharp drop off in information, a sign of deterioration and degeneration. This turnabout was strongest in people who had two copies of APOE4, rather than just one. The findings, Kellis said, suggest that APOE4 might destabilize the genome of microglia, causing them to burn out.

Another example is the fate of neurons expressing the gene RELN and its protein Reelin. Prior studies, including by Kellis and Tsai, have shown that RELN- expressing neurons in the entorhinal cortex and hippocampus are especially vulnerable in Alzheimer’s, but promote resilience if they survive. The new study sheds new light on their fate by demonstrating that they exhibit early and severe epigenomic information loss as disease advances, but that in people who remained cognitively resilient the neurons maintained epigenomic information.

In yet another example, the researchers tracked what they colloquially call “chromatin guardians” because their expression sustains and regulates cells’ epigenomic programs. For instance, cells with greater epigenomic erosion and advanced AD progression displayed increased chromatin accessibility in areas that were supposed to be locked down by Polycomb repression genes or other gene expression silencers. While resilient cells expressed genes promoting neural connectivity, epigenomically eroded cells expressed genes linked to inflammation and oxidative stress.

“The message is clear: Alzheimer’s is not only about plaques and tangles, but about the erosion of nuclear order itself,” Kellis said. “Cognitive decline emerges when chromatin guardians lose ground to the forces of erosion, switching from resilience to vulnerability at the most fundamental level of genome regulation.

“And when our brain cells lose their epigenomic memory marks and epigenomic information at the lowest level deep inside our neurons and microglia, it seems that Alheimer’s patients also lose their memory and cognition at the highest level.”

Other authors of the paper are Benjamin T. James, Kyriaki Galani, Riley J. Mangan, Stuart Benjamin Fass, Chuqian Liang, Manoj M. Wagle, Carles A. Boix, Yosuke Tanigawa, Sukwon Yun, Yena Sung, Xushen Xiong, Na Sun, Lei Hou, Martin Wohlwend, Mufan Qiu, Xikun Han, Lei Xiong, Efthalia Preka, Lei Huang, William F. Li, Li-Lun Ho, Amy Grayson, Julio Mantero, Alexey Kozlenkov, Hansruedi Mathys, Tianlong Chen, Stella Dracheva, and David A. Bennett.

Funding for the research came from The National Institutes of Health, The National Science Foundation, the Cure Alzheimer’s Fund, the Freedom Together Foundation, the Robert A. and Renee E. Belfer Family Foundation, Eduardo Eurnekian, and Joseph P. DiSabato.

Research Article

Graduate student Mingus Rae Zoller has been named to the Howard Hughes Medical Institute’s highly selective Gilliam Fellows Program.

Read the full story on The Picower Institute website: https://picower.mit.edu/news/fellowship-supports-students-work-advance-alzheimers-research-and-equity

Postdoc Rebecca Pinals is among 28 around the world to have been named this year to a competitive Schmidt Science Fellowship, an award created in 2017 to advance interdisciplinary studies among early career researchers.

Read the full story on The Picower Institute website: https://picower.mit.edu/news/postdocs-earn-interdisciplinary-schmidt-science-fellowships