Posted on by John Ngai, PhD, NIH BRAIN Initiative
Ever wonder how you’re able to remember life events that happened days, months, or even years ago? You have your hippocampus to thank. This essential area in the brain relies on intense and highly synchronized patterns of activity that aren’t found anywhere else in the brain. They’re called “sharp-wave ripples.”
These dynamic ripples have been likened to the brain version of an instant replay, appearing most commonly during rest after a notable experience. And, now, the top video winner in this year’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative’s annual Show Us Your BRAINs! Photo and Video Contest allows you to witness the “chatter” that those ripples set off in other neurons. The details of this chatter determine just how durable a particular memory is in ways neuroscientists are still working hard to understand.
Neuroscientist Saman Abbaspoor in the lab of Kari Hoffman at Vanderbilt University, Nashville, sets the stage in the winning video by showing an electrode or probe implanted in the brain that can reach the hippocampus. This device allows the Hoffman team to wirelessly record neural activity in different layers of the hippocampus as the animal either rests or moves freely about.
In the scenes that follow, neurons (blue, cyan, and yellow) flash on and off. The colors highlight the fact that this brain area and the neurons within it aren’t all the same. Various types of neurons are found in the brain area’s different layers, some of which spark the activity you see, while others dampen it.
Hoffman explains that the specific shapes of individual cells pictured are realistic but also symbolic. While they didn’t trace the individual branches of neurons in the brain in their studies, they relied on information from previous anatomical studies, overlaying their intricate forms with flashing bursts of activity that come straight from their recorded data.
Tyler Sloan, Quorumetrix Studio, Montreal, Quebec, then added yet another layer of artistry to the experience with what he refers to as sonification, or the use of music to convey information about the dynamic and coordinated bursts of activity in those cells. At five seconds in, you hear the subtle flutter of a sharp-wave ripple. With each burst of active neural chatter that follows, you hear the dramatic plink of piano keys.
Together, their winning video creates a unique sensory experience that helps to explain what goes on during memory formation and recall in a way that words alone can’t adequately describe. Through their ongoing studies, Hoffman reports that they’ll continue delving even deeper into understanding these intricate dynamics and their implications for learning and memory. Ultimately, they also want to explore how brain ripples, and the neural chatter they set off, might be enhanced to make memory formation and recall even stronger.
S Abbaspoor & KL Hoffman. State-dependent circuit dynamics of superficial and deep CA1 pyramidal cells in macaques. BioRxiv DOI: 10.1101/2023.12.06.570369 (2023). Please note that this article is a pre-print and has not been peer-reviewed.
NIH Support: The NIH BRAIN Initiative
Posted on by John Ngai, PhD, NIH BRAIN Initiative
Silas Busch at the University of Chicago captured this slightly eerie scene, noting it reminded him of people shuffling through the dark of night. What you’re really seeing are some of the largest neurons in the mammalian brain, known as Purkinje cells. The photo won first place this year in the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative’s annual Show Us Your BRAINs! Photo and Video Contest.
While humans have them, too, the Purkinje cells pictured here are in the brain of a mouse. The head-like shapes you see in the image are the so-called soma, or the neurons’ cell bodies. Extending downwards are the heavily branched dendrites, which act like large antennae, receiving thousands of inputs from the rest of the body.
One reason this picture is such a standout, explains Busch, is because of what you don’t see. You’ll notice that only a few cells are fluorescently labeled and therefore lit up in green, leaving the rest in shadows. As a result, it’s possible to trace the detailed branches of individual Purkinje cells and make out their intricate forms. As it turns out, this ability to trace Purkinje cells so precisely led Busch, who is a graduate student in Christian Hansel’s lab focused on the neurobiology of learning and memory, to a surprising discovery, which the pair recently reported in Science.1
Purkinje cells connect to nerve fibers that “climb up” from the brain stem, which connects your brain and spinal cord to help control breathing, heart rate, balance and more. Scientists thought that each Purkinje cell received only one of these climbing fibers from the brain stem on its single primary branch.
However, after carefully tracing thousands of Purkinje cells in brain tissue from both mice and humans, the researchers have now shown that Purkinje cells and climbing fibers don’t always have a simple one-to-one relationship. In fact, Busch and Hansel found more than 95 percent of human Purkinje cells have multiple primary branches, not just one. In mice, that ratio is closer to 50 percent.
The researchers went on to show that mouse Purkinje cells with multiple primary branches often also receive multiple climbing fibers. The discovery rewrites the textbook idea of how Purkinje cells in the brain and climbing fibers from the brainstem are anatomically arranged.
Not surprisingly, those extra connections in the cerebellum (located in the back of the brain) also have important functional implications. When Purkinje cells have just one climbing fiber input, the new study shows, the whole cell receives each signal equally and responds accordingly. But, in cells with multiple climbing fiber inputs, the researchers could detect differences across a single cell depending on which primary branch received an input.
What this means is that Purkinje cells in the brain have much more computational power than had been appreciated. That extra brain power has important implications for understanding how brain circuits can adapt and respond to changes outside the body that now warrant further study. The new findings may have implications also for understanding the role of these Purkinje cell connections in some neurological and developmental disorders, including autism2 and a movement disorder known as cerebellar ataxia.
As they say, a picture is worth a thousand words. And this winning image comes as a reminder that we still have more to learn from careful study of basic brain anatomy, with important implications for human health and disease.
 SE Busch and C Hansel. Climbing fiber multi-innervation of mouse Purkinje dendrites with arborization common to human. Science. DOI: 10.1126/science.adi1024. (2023).
 DH Simmons et al. Sensory Over-responsivity and Aberrant Plasticity in Cerebellar Cortex in a Mouse Model of Syndromic Autism. Biological Psychiatry: Global Open Science. DOI: 10.1016/j.bpsgos.2021.09.004. (2021).
Posted on by Lawrence Tabak, D.D.S., Ph.D.
When NIH launched The BRAIN Initiative® a decade ago, one of many ambitious goals was to develop innovative technologies for profiling single cells to create an open-access reference atlas cataloguing the human brain’s many parts. The ultimate goal wasn’t to produce a single, static reference map, but rather to capture a dynamic view of how the brain’s many cells of varied types are wired to work together in the healthy brain and how this picture may shift in those with neurological and mental health disorders.
So I’m now thrilled to report the publication of an impressive collection of work from hundreds of scientists in the BRAIN Initiative Cell Census Network (BICCN), detailed in more than 20 papers in Science, Science Advances, and Science Translational Medicine.1 Among many revelations, this unprecedented, international effort has characterized more than 3,000 human brain cell types. To put this into some perspective, consider that the human lung contains 61 cell types.2 The work has also begun to uncover normal variation in the brains of individual people, some of the features that distinguish various disease states, and distinctions among key parts of the human brain and those of our closely related primate cousins.
Of course, it’s not possible to do justice to this remarkable body of work or its many implications in the space of a single blog post. But to give you an idea of what’s been accomplished, some of these studies detail the primary effort to produce a comprehensive brain atlas, including defining the brain’s many cell types along with their underlying gene activity and the chemical modifications that turn gene activity up or down.3,4,5
Other studies in this collection take a deep dive into more specific brain areas. For instance, to capture normal variations among people, a team including Nelson Johansen, University of California, Davis, profiled cells in the neocortex—the outermost portion of the brain that’s responsible for many complex human behaviors.6 Overall, the work revealed a highly consistent cellular makeup from one person to the next. But it also highlighted considerable variation in gene activity, some of which could be explained by differences in age, sex and health. However, much of the observed variation remains unexplained, opening the door to more investigations to understand the meaning behind such brain differences and their role in making each of us who we are.
Yang Li, now at Washington University in St. Louis, and his colleagues analyzed 1.1 million cells from 42 distinct brain areas in samples from three adults.4 They explored various cell types with potentially important roles in neuropsychiatric disorders and were able to pinpoint specific cell types, genes and genetic switches that may contribute to the development of certain traits and disorders, including bipolar disorder, depression and schizophrenia.
Yet another report by Nikolas Jorstad, Allen Institute, Seattle, and colleagues delves into essential questions about what makes us human as compared to other primates like chimpanzees.7 Their comparisons of gene activity at the single-cell level in a specific area of the brain show that humans and other primates have largely the same brain cell types, but genes are activated differently in specific cell types in humans as compared to other primates. Those differentially expressed genes in humans often were found in portions of the genome that show evidence of rapid change over evolutionary time, suggesting that they play important roles in human brain function in ways that have yet to be fully explained.
All the data represented in this work has been made publicly accessible online for further study. Meanwhile, the effort to build a more finely detailed picture of even more brain cell types and, with it, a more complete understanding of human brain circuitry and how it can go awry continues in the BRAIN Initiative Cell Atlas Network (BICAN). As impressive as this latest installment is—in our quest to understand the human brain, brain disorders, and their treatment—we have much to look forward to in the years ahead.
A list of all the papers part of the brain atlas research is available here: https://www.science.org/collections/brain-cell-census.
 M Maroso. A quest into the human brain. Science DOI: 10.1126/science.adl0913 (2023).
 L Sikkema, et al. An integrated cell atlas of the lung in health and disease. Nature Medicine DOI: 10.1038/s41591-023-02327-2 (2023).
 K Siletti, et al. Transcriptomic diversity of cell types across the adult human brain. Science DOI: 10.1126/science.add7046 (2023).
 Y Li, et al. A comparative atlas of single-cell chromatin accessibility in the human brain. Science DOI: 10.1126/science.adf7044 (2023).
 W Tian, et al. Single-cell DNA methylation and 3D genome architecture in the human brain. Science DOI: 10.1126/science.adf5357 (2023).
 N Johansen, et al. Interindividual variation in human cortical cell type abundance and expression. Science DOI: 10.1126/science.adf2359 (2023).
 NL Jorstad, et al. Comparative transcriptomics reveals human-specific cortical features. Science DOI: 10.1126/science.ade9516 (2023).
Posted on by Lawrence Tabak, D.D.S., Ph.D.
People living with Alzheimer’s disease experience a gradual erosion of memory and thinking skills until they can no longer carry out daily activities. Hallmarks of the disease include the buildup of plaques that collect between neurons, accumulations of tau protein inside neurons and weakening of neural connections. However, there’s still much to learn about what precisely happens in the Alzheimer’s brain and how the disorder’s devastating march might be slowed or even stopped. Alzheimer’s affects more than six million people in the United States and is the seventh leading cause of death among adults in the U.S., according to the National Institute on Aging.
NIH-supported researchers recently published a trove of data in the journal Cell detailing the molecular drivers of Alzheimer’s disease and which cell types in the brain are most likely to be affected.1,2,3,4 The scientists, led by Li-Huei Tsai and Manolis Kellis, both at the Massachusetts Institute of Technology, Cambridge, MA, characterized gene activity at the single-cell level in more than two million cells from postmortem brain tissue. They also assessed DNA damage and surveyed epigenetic changes in cells, which refers to chemical modifications to DNA that alter gene expression in the cell. The findings could help researchers pinpoint new targets for Alzheimer’s disease treatments.
In the first of four studies, the researchers examined 54 brain cell types in 427 brain samples from a cohort of people with varying levels of cognitive impairment that has been followed since 1994.1 The MIT team generated an atlas of gene activity patterns within the brain’s prefrontal cortex, an important area for memory retrieval.
Their analyses in brain samples taken from people with Alzheimer’s dementia showed altered activity in genes involved in various functions. Additional findings showed that people with normal cognitive abilities with evidence of plaques in their brains had more neurons that inhibit or dampen activity in the prefrontal cortex compared to those with Alzheimer’s dementia. The finding suggests that the workings of inhibitory neurons may play an unexpectedly important role in maintaining cognitive resilience despite age-related changes, including the buildup of plaques. It’s one among many discoveries that now warrant further study.
In another report, the researchers compared brain tissues from 48 people without Alzheimer’s to 44 people with early- or late-stage Alzheimer’s.2 They developed a map of the various elements that regulate function within cells in the prefrontal cortex. By cross-referencing epigenomic and gene activity data, the researchers showed changes in many genes with known links to Alzheimer’s disease development and risk.
Their single-cell analysis also showed that these changes most often occur in microglia, which are immune cells that remove cellular waste products from the brain. At the same time, every cell type they studied showed a breakdown over time in the cells’ normal epigenomic patterning, a process that may cause a cell to behave differently as it loses essential aspects of its original identity and function.
In a third report, the researchers looked even deeper into gene activity within the brain’s waste-clearing microglia.3 Based on the activity of hundreds of genes, they were able to define a dozen distinct microglia “states.” They also showed that more microglia enter an inflammatory state in the Alzheimer’s brain compared to a healthy human brain. Fewer microglia in the Alzheimer’s brain were in a healthy, balanced state as well. The findings suggest that treatments that target microglia to reduce inflammation and promote balance may hold promise for treating Alzheimer’s disease.
The fourth and final report zeroed in on DNA damage, inspired in part by earlier findings suggesting greater damage within neurons even before Alzheimer’s symptoms appear.4 In fact, breaks in DNA occur as part of the normal process of forming new memories. But those breaks in the healthy brain are quickly repaired as the brain makes new connections.
The researchers studied postmortem brain tissue samples and found that, over time in the Alzheimer’s brain, the damage exceeds the brain’s ability to repair it. As a result, attempts to put the DNA back together leads to a patchwork of mistakes, including rearrangements in the DNA and fusions as separate genes are merged. Such changes appear to arise especially in genes that control neural connections, which may contribute to the signs and symptoms of Alzheimer’s.
The researchers say they now plan to apply artificial intelligence and other analytic tools to learn even more about Alzheimer’s disease from this trove of data. To speed progress even more, they’ve made all the data freely available online to the research community, where it promises to yield many more fundamentally important discoveries about the precise underpinnings of Alzheimer’s disease in the brain and new ways to intervene in Alzheimer’s dementia.
 Mathys H, et al. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology. Cell. DOI: 10.1016/j.cell.2023.08.039. (2023).
 Xiong X, et al. Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion. Cell. DOI: 10.1016/j.cell.2023.08.040. (2023).
 Sun N, et al. Human microglial state dynamics in Alzheimer’s disease progression. Cell. DOIi: 10.1016/j.cell.2023.08.037. (2023).
 Dileep V, et al. Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration. Cell. 2023 DOI: 10.1016/j.cell.2023.08.038. (2023).
NIH Support: National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institute of General Medical Sciences
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Chronic pain is an often-debilitating health condition and serious public health concern, affecting more than 50 million Americans.1 The opioid and overdose crisis, which stems from inadequate pain treatment, continues to have a devastating impact on families and communities across the country. To combat both challenges, we urgently need new ways to treat acute and chronic pain effectively without the many downsides of opioids.
While there are already multiple classes of non-opioid pain medications and other approaches to manage pain, unfortunately none have proved as effective as opioids when it comes to pain relief. So, I’m encouraged to see that an NIH-funded team now has preclinical evidence of a promising alternative target for pain-relieving medicines in the brain.2
Rather than activating opioid receptors, the new approach targets receptors for a nerve messenger known as acetylcholine in a portion of the brain involved in pain control. Based on findings from animal models, it appears that treatments targeting acetylcholine could offer pain relief even in people who have reduced responsiveness to opioids. Their findings suggest that the treatment approach has the potential to remain effective in combatting pain long-term and with limited risk for withdrawal symptoms or addiction.
The researchers, led by Daniel McGehee, University of Chicago, focused their attention on non-opioid pathways in the ventrolateral periaqueductal gray (vlPAG), a brain area involved in pain control. They had previously shown that activating acetylcholine receptors, which are part of the vlPAG’s underlying circuitry, could relieve pain.3 However, they found that when the body is experiencing pain, it unexpectedly suppresses acetylcholine rather than releasing more.
To understand how and why this is happening, McGehee and Shivang Sullere, now a postdoctoral fellow at Harvard Medical School, conducted studies in mice to understand how acetylcholine is released under various pain states. They found that mice treated with a drug that stimulates an acetylcholine receptor known as alpha-7 (⍺7) initially led to more activity in the nervous system. But this activity quickly gave way to a prolonged inactive or quiet state that delivered pain relief. Interestingly, this unexpected inhibitory effect lasted for several hours.
Additional studies in mice that had developed a tolerance to opioids showed the same long-lasting pain relief. This encouraging finding was expected since opioids use a pathway separate from acetylcholine. In more good news, the animals didn’t show any signs of dependence or addiction either. For instance, in the absence of pain, they didn’t prefer spending time in environments where they’d receive the ⍺7-targeted drug.
Imaging studies measuring brain activity revealed greater activity in cells expressing ⍺7 with higher levels of pain. When that activity was blocked, pain levels dropped. The finding suggests to the researchers it may be possible to monitor pain levels through brain imaging. It’s also possible the acetylcholine circuitry in the brain may play a role in the process whereby acute or temporary pain becomes chronic.
Finding treatments to modify acetylcholine levels or target acetylcholine receptors may therefore offer a means to treat pain and prevent it from becoming chronic. Encouragingly, drugs acting on these receptors already have been tested for use in people for treating other health conditions. It will now be important to learn whether these existing therapeutics or others like them may act as highly effective, non-addictive painkillers, with important implications for alleviating chronic pain.
 NIH HEAL Initiative Research Plan. NIH HEAL Initiative.
 Sullere S et al. A cholinergic circuit that relieves pain despite opioid tolerance. Neuron. DOI: 10.1016/j.neuron.2023.08.017 (2023).
 Umana IC et al. Nicotinic modulation of descending pain control circuitry. Pain. PMID: 28817416; PMCID: PMC5873975 (2017).
Pain (National Institute of Neurological Disorders and Stroke/NIH)
Opioids (National Institute on Drug Abuse/NIH)
Daniel McGehee (University of Chicago, Illinois)
NIH Support: National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse
Recent scientific advances in the field of genome editing, which enables precise modifications to DNA, have greatly increased the potential to treat genetic diseases. Despite revolutionary progress in this area, treatment options remain limited. Several scientific challenges must be addressed before gene editing can be widely used in the clinic. For example, gene editing tools may cut in unintended areas in addition to the target site, and more research is necessary to understand how these errors affect patients.
Another key challenge is that many organs remain difficult to reach with gene therapies because we do not have adequate ways to deliver gene editing tools to all cells. While efficient delivery technologies exist for some targets, like liver cells, novel and specialized delivery methods designed for specific cell types and locations in the body are needed to ensure genome editing tools can reach sufficient numbers and types of somatic cells to modify DNA safely and effectively. Somatic cell gene therapies target non-reproductive cells, so the changes only affect the person who receives the gene therapy and are not passed down generation to generation.
To address these challenges, NIH launched the TARGETED (Targeted Genome Editor Delivery) Challenge, a multi-phase competition funded through the NIH Common Fund as part of the NIH Somatic Cell Genome Editing (SCGE) Program. SCGE was funded in 2018 to improve the efficacy and specificity of genome editing to help reduce the burden of common and rare diseases caused by genetic changes.
As part of the TARGETED Challenge, research teams will develop technologies for delivering genome editors to somatic cells. NIH will award up to $6 million in prize money across the challenge.
The Challenge is focused on finding delivery systems that can be programmed with biological or chemical tags that correspond to specific target cells and tissues. These tags would direct the delivery systems and the genome editing therapies to the target cells or tissues—like mail being delivered to different zip codes. Such programmable delivery systems would improve gene editing efficacy by targeting diseases at their source and would enhance safety by reducing undesired impacts on other tissues or cells. Ultimately, the development of safe and effective programmable delivery technologies for genome editors that are applicable to multiple diseases would help advance the application of gene editing therapies into the clinic.
The Challenge also is interested in gene editing delivery technologies that can cross the blood-brain barrier (BBB). The BBB protects the brain by blocking harmful substances from entering the fluid of the central nervous system. Unfortunately, it also blocks the uptake of many therapeutics, hindering treatments for brain diseases. While viruses are one of the few approaches that can be used as delivery systems to cross the BBB, they are expensive and difficult to make. Therefore, there is a pressing need for effective non-viral technologies to deliver genome editing machinery across the BBB to a substantial proportion of clinically relevant brain cell types. Such technologies could have broad implications for the treatment of many neurogenetic diseases.
Solutions to both target areas would not only provide proof-of-concept for the delivery of genome editing therapeutics, but they could be adapted to deliver other types of therapies to treat common and rare diseases in general.
The first phase of the Challenge began on May 15, 2023 and will run until October 5, 2023. More information about the Challenge is available on the TARGETED Genome Editor Delivery Challenge website.
“National Institutes of Health launch TARGETED Challenge,” NIH Common Fund, May 15, 2023
TARGETED Genome Editor Delivery Challenge (NIH Common Fund)
Somatic Cell Genome Editing Program (NIH Common Fund)
NIH Support: The SCGE program is led by the NIH Common Fund, the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS). The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the National Heart, Lung, and Blood Institute (NHLBI) are also contributors to this Challenge.
Posted on by Lawrence Tabak, D.D.S., Ph.D.
In people with Alzheimer’s disease, the underlying changes in the brain associated with dementia typically begin many years—or even decades—before a diagnosis. While pinpointing the exact causes of Alzheimer’s remains a major research challenge, they likely involve a combination of genetic, environmental, and lifestyle factors. Now an NIH-funded study elucidates the role of another likely culprit that you may not have considered: the human gut microbiome, the trillions of diverse bacteria and other microbes that live primarily in our intestines .
Earlier studies had showed that the gut microbiomes of people with symptomatic Alzheimer’s disease differ from those of healthy people with normal cognition . What this new work advances is that these differences arise early on in people who will develop Alzheimer’s, even before any obvious symptoms appear.
The science still has a ways to go before we’ll know if specific dietary changes can alter the gut microbiome and modify its influence on the brain in the right ways. But what’s exciting about this finding is it raises the possibility that doctors one day could test a patient’s stool sample to determine if what’s present from their gut microbiome correlates with greater early risk for Alzheimer’s dementia. Such a test would help doctors detect Alzheimer’s earlier and intervene sooner to slow or ideally even halt its advance.
The new findings, reported in the journal Science Translational Medicine, come from a research team led by Gautam Dantas and Beau Ances, Washington University School of Medicine, St. Louis. Ances is a clinician who treats and studies people with Alzheimer’s; Dantas is a basic researcher and expert on the gut microbiome.
The pair struck up a conversation one day about the possible connection between the gut microbiome and Alzheimer’s. While they knew about the earlier studies suggesting a link, they were surprised that nobody had looked at the gut microbiomes of people in the earliest, so-called preclinical, stages of the disease. That’s when dementia isn’t detectable, but the brain has formed amyloid-beta plaques, which are associated with Alzheimer’s.
To take a look, they enrolled 164 healthy volunteers, age 68 to 94, who performed normally on standard tests of cognition. They also collected stool samples from each volunteer and thoroughly analyzed them all the microbes from their gut microbiome. Study participants also kept food diaries and underwent extensive testing, including two types of brain scans, to look for signs of amyloid-beta plaques and tau protein accumulation that precede the onset of Alzheimer’s symptoms.
Among the volunteers, about a third (49 individuals) unfortunately had signs of early Alzheimer’s disease. And, as it turned out, their microbiomes showed differences, too.
The researchers found that those with preclinical Alzheimer’s disease had markedly different assemblages of gut bacteria. Their microbiomes differed in many of the bacterial species present. Those species-level differences also point to differences in the way their microbiomes would be expected to function at a metabolic level. These microbiome changes were observed even though the individuals didn’t seem to have any apparent differences in their diets.
The team also found that the microbiome changes correlated with amyloid-beta and tau levels in the brain. But they did not find any relationship to degenerative changes in the brain, which tend to happen later in people with Alzheimer’s.
The team is now conducting a five-year study that will follow volunteers to get a better handle on whether the differences observed in the gut microbiome are a cause or a consequence of the brain changes seen in Alzheimer’s. If it’s a cause, this discovery would raise the tantalizing possibility that specially formulated probiotics or fecal transplants that promote the growth of “good” bacteria over “bad” bacteria in the gut might slow the development of Alzheimer’s and its most devastating symptoms. It’s an exciting area of research and definitely one worth following in the years ahead.
 Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease. Ferreiro AL, Choi J, Ryou J, Newcomer EP, Thompson R, Bollinger RM, Hall-Moore C, Ndao IM, Sax L, Benzinger TLS, Stark SL, Holtzman DM, Fagan AM, Schindler SE, Cruchaga C, Butt OH, Morris JC, Tarr PI, Ances BM, Dantas G. Sci Transl Med. 2023 Jun 14;15(700):eabo2984. doi: 10.1126/scitranslmed.abo2984. Epub 2023 Jun 14. PMID: 37315112.
 Gut microbiome alterations in Alzheimer’s disease. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Sci Rep. 2017 Oct 19;7(1):13537. doi: 10.1038/s41598-017-13601-y. PMID: 29051531; PMCID: PMC5648830.
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
Video: How Alzheimer’s Changes the Brain (NIA)
Dantas Lab (Washington University School of Medicine. St. Louis)
Ances Bioimaging Laboratory (Washington University School of Medicine, St. Louis)
NIH Support: National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Biomedical breakthroughs most often involve slow and steady research in studies involving large numbers of people. But sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications.
An NIH-funded case study published recently in the journal Nature Medicine falls into this far-reaching category . The report highlights the world’s second person known to have an extreme resilience to a rare genetic form of early onset Alzheimer’s disease. These latest findings in a single man follow a 2019 report of a woman with similar resilience to developing symptoms of Alzheimer’s despite having the same strong genetic predisposition for the disease .
The new findings raise important new ideas about the series of steps that may lead to Alzheimer’s and its dementia. They’re also pointing the way to key parts of the brain for cognitive resilience—and potentially new treatment targets—that may one day help to delay or even stop progression of Alzheimer’s.
The man in question is a member of a well-studied extended family from the country of Colombia. This group of related individuals, or kindred, is the largest in the world with a genetic variant called the “Paisa” mutation (or Presenilin-1 E280A). This Paisa variant follows an autosomal dominant pattern of inheritance, meaning that those with a single altered copy of the rare variant passed down from one parent usually develop mild cognitive impairment around the age of 44. They typically advance to full-blown dementia around the age of 50 and rarely live past the age of 60. This contrasts with the most common form of Alzheimer’s, which usually begins after age 65.
The new findings come from a team led by Yakeel Quiroz, Massachusetts General Hospital, Boston; Joseph Arboleda-Velasquez, Massachusetts Eye and Ear, Boston; Diego Sepulveda-Falla, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Francisco Lopera, University of Antioquia, Medellín, Colombia. Lopera first identified this family more than 30 years ago and has been studying them ever since.
In the new case report, the researchers identified a Colombian man who’d been married with two children and retired from his job as a mechanic in his early 60s. Despite carrying the Paisa mutation, his first cognitive assessment at age 67 showed he was cognitively intact, having limited difficulties with verbal learning skills or language. It wasn’t until he turned 70 that he was diagnosed with mild cognitive impairment—more than 20 years later than the expected age for this family—showing some decline in short-term memory and verbal fluency.
At age 73, he enrolled in the Colombia-Boston biomarker research study (COLBOS). This study is a collaborative project between the University of Antioquia and Massachusetts General Hospital involving approximately 6,000 individuals from the Paisa kindred. About 1,500 of those in the study carry the mutation that sets them up for early Alzheimer’s. As a member of the COLBOS study, the man underwent thorough neuroimaging tests to look for amyloid plaques and tau tangles, both of which are hallmarks of Alzheimer’s.
While this man died at age 74 with Alzheimer’s, the big question is: how did he stave off dementia for so long despite his poor genetic odds? The COLBOS study earlier identified a woman with a similar resilience to Alzheimer’s, which they traced to two copies of a rare, protective genetic variant called Christchurch. This variant affects a gene called apolipoprotein E (APOE3), which is well known for its influence on Alzheimer’s risk. However, the man didn’t carry this same protective variant.
The researchers still thought they’d find an answer in his genome and kept looking. While they found several variants of possible interest, they zeroed in on a single gene variant that they’ve named Reelin-COLBOS. What helped them to narrow it down to this variant is the man also had a sister with the Paisa mutation who only progressed to advanced dementia at age 72. It turned out, in addition to the Paisa variant, the siblings also shared an altered copy of the newly discovered Reelin-COLBOS variant.
This Reelin-COLBOS gene is known to encode a protein that controls signals to chemically modify tau proteins, which form tangles that build up over time in the Alzheimer’s brain and have been linked to memory loss. Reelin is also functionally related to APOE, the gene that was altered in the woman with extreme Alzheimer’s protection. Reelin and APOE both interact with common protein receptors in neurons. Together, the findings add to evidence that signaling pathways influencing tau play an important role in Alzheimer’s pathology and protection.
The neuroimaging exams conducted when the man was age 73 have offered further intriguing clues. They showed that his brain had extensive amyloid plaques. He also had tau tangles in some parts of his brain. But one brain region, called the entorhinal cortex, was notable for having a very minimal amount of those hallmark tau tangles.
The entorhinal cortex is a hub for memory, navigation, and the perception of time. Its degeneration also leads to cognitive impairment and dementia. Studies of the newly identified Reelin-COLBOS variant in Alzheimer’s mouse models also help to confirm that the variant offers its protection by diminishing the pathological modifications of tau.
Overall, the findings in this one individual and his sister highlight the Reelin pathway and brain region as promising targets for future study and development of Alzheimer’s treatments. Quiroz and her colleagues report that they are actively exploring treatment approaches inspired by the Christchurch and Reelin-COLBOS discoveries.
Of course, there’s surely more to discover from continued study of these few individuals and others like them. Other as yet undescribed genetic and environmental factors are likely at play. But the current findings certainly offer some encouraging news for those at risk for Alzheimer’s disease—and a reminder of how much can be learned from careful study of remarkable individuals.
 Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Lopera F, Marino C, Chandrahas AS, O’Hare M, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT, et al. Nat Med. 2023 May;29(5):1243-1252.
 Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Tariot PN, Johnson KA, Reiman EM, Quiroz YT et al. Nat Med. 2019 Nov;25(11):1680-1683.
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
“NIH Support Spurs Alzheimer’s Research in Colombia,” Global Health Matters, January/February 2014, Fogarty International Center/NIS
“COLBOS Study Reveals Mysteries of Alzheimer’s Disease,” NIH Record, August 19, 2022.
Yakeel Quiroz (Massachusetts General Hospital, Harvard Medical School, Boston)
Joseph Arboleda-Velasquez (Massachusetts Eye and Ear, Harvard Medical School, Boston)
Diego Sepulveda-Falla Lab (University Medical Center Hamburg-Eppendorf, Hamburg, Germany)
Francisco Lopera (University of Antioquia, Medellín, Colombia)
NIH Support: National Institute on Aging; National Eye Institute; National Institute of Neurological Disorders and Stroke; Office of the Director
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Anyone who has ever had a bad habit knows how vexingly difficult breaking it can be. The reason is the repeated action, initially linked to some type of real or perceived reward, over time changes the way our very brains are wired to work. The bad habit becomes automatic, even when the action does us harm or we no longer wish to do it.
Now an intriguing new study shows that the same bundled nerve fibers, or brain circuits, involved in habit formation also can go awry in people with eating disorders. The findings may help to explain why eating disorders are so often resistant to will power alone. They also may help to point the way to improved approaches to treating eating disorders, suggesting strategies that adjust the actual brain circuitry in helpful ways.
These latest findings, published in the journal Science Translational Medicine, come from the NIH-supported Casey Halpern, University of Pennsylvania’s Perelman School of Medicine, Philadelphia, and Cara Bohon, Stanford University School of Medicine, Stanford, CA .
Halpern, Bohon, and colleagues were interested in a growing body of evidence linking habitual behaviors to mental health conditions, most notably substance use disorders and addictions. But what especially intrigued them was recent evidence also suggesting a possible role for habitual behaviors in the emergence of eating disorders.
To look deeper into the complex circuitry underlying habit formation and any changes there that might be associated with eating disorders, they took advantage of a vast collection of data from the NIH-funded Human Connectome Project (HCP). It was completed several years ago and now serves as a valuable online resource for researchers.
The HCP offers a detailed wiring map of a normal human brain. It describes all the structural and functional neural connections based on careful analyses of hundreds of high-resolution brain scans. These connections are then layered with genetic, behavioral, and other types of data. This incredible map now allows researchers to explore and sometimes uncover the roots of neurological and mental health conditions within the brain’s many trillions of connections.
In the new study, Halpern, Bohon, and colleagues did just that. First, they used sophisticated mapping methods in 178 brain scans from the HCP data to locate key portions of a brain region called the striatum, which is thought to be involved in habit formation. What they really wanted to know was whether circuits operating within the striatum were altered in some way in people with binge eating disorder or bulimia nervosa.
To find out, the researchers recruited 34 women who have an eating disorder and, with their consent, imaged their brains using a variety of techniques. Twenty-one participants were diagnosed with binge eating disorder, and 13 had bulimia nervosa. For comparison purposes, the researchers looked at the same brain circuits in 19 healthy volunteers.
The two groups were otherwise similar in terms of their ages, weights, and other features. But the researchers suspected they might find differences between the healthy group and those with an eating disorder in brain circuits known to have links to habitual behaviors. And, indeed, they did.
In comparison to a “typical” brain, those from people with an eating disorder showed striking changes in the connectivity of a portion of the striatum known as the putamen. That’s especially notable because the putamen is known for its role in learning and movement control, including reward, thinking, and addiction. What’s more, those observed changes in the brain’s connections and circuitry in this key brain area were more evident in people whose eating disorder symptoms and emotional eating were more frequent and severe.
Using other brain imaging methods in 10 of the volunteers (eight with binge eating disorder and two healthy controls), the researchers also connected those changes in the habit-forming brain circuits to high levels of a protein receptor that responds to dopamine. Dopamine is an important chemical messenger in the brain involved in pleasure, motivation, and learning. They also observed in those with eating disorders structural changes in the architecture of the densely folded, outer layer of the brain known as grey matter.
While there’s much more to learn, the researchers note the findings may lead to future treatments aimed to modify the brain circuitry in beneficial ways. Indeed, Halpern already has encouraging early results from a small NIH-funded clinical trial testing the ability of deep brain stimulation (DBS) in people with binge eating disorder to disrupt signals that drive food cravings in another portion of the brain associated with reward and motivation, known as the nucleus accumbens, . In DBS, doctors implant a pacemaker-like device capable of delivering harmless therapeutic electrical impulses deep into the brain, aiming for the spot where they can reset the abnormal circuitry that’s driving eating disorders or other troubling symptoms or behaviors.
But the latest findings published in Science Translational Medicine now suggest other mapped brain circuits as potentially beneficial DBS targets for tackling binge eating, bulimia nervosa, or other life-altering, hard-to-treat eating disorders. They also may ultimately have implications for treating other conditions involving various other forms of compulsive behavior.
These findings should come as a source of hope for the family and friends of the millions of Americans—many of them young people—who struggle with eating disorders. The findings also serve as an important reminder for the rest of us that, despite common misconceptions that disordered eating is a lifestyle choice, these conditions are in fact complex and serious mental health problems driven by fundamental changes in the brain’s underlying circuitry.
Finding new and more effective ways to treat serious eating disorders and other compulsive behaviors is a must. It will require equally serious ongoing efforts to unravel their underlying causes and find ways to alter their course—and this new study is an encouraging step in that direction.
 Human habit neural circuitry may be perturbed in eating disorders. Wang AR, Kuijper FM, Barbosa DAN, Hagan KE, Lee E, Tong E, Choi EY, McNab JA, Bohon C, Halpern CH. Sci Transl Med. 2023 Mar 29;15(689):eabo4919.
 Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating. Shivacharan RS, Rolle CE, Barbosa DAN, Cunningham TN, Feng A, Johnson ND, Safer DL, Bohon C, Keller C, Buch VP, Parker JJ, Azagury DE, Tass PA, Bhati MT, Malenka RC, Lock JD, Halpern CH. Nat Med. 2022 Sep;28(9):1791-1796.
Eating Disorders (National Institute of Mental Health/NIH)
Casey Halpern (Penn Medicine, Philadelphia)
Cara Bohon (Stanford University, Stanford, CA)
NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke