Taub Institute: Genomics Core


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Taub Institute news and events


2022 - 2020 | 2019 - 2011

  • Navigating Life with Dementia
    August 31, 2022

    Navigating Life with Dementia, written by Dr. James M. Noble, an associate professor of neurology and dementia specialist in the Division of Aging and Dementia, is the latest title in the American Academy of Neurology's Brain & Life® Book series, published with Oxford University Press. In an engaging interview now featured on the Brain & Life website, Dr. Noble explains that he wrote the book “to create something that patients and their families could read at their own pace for additional information and resources, other patients' experiences, and some sense of the road ahead."

  • Columbia Joins International Genetic Study of Alzheimer’s Disease in People of Hispanic and African Ancestry

    A team of investigators from the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at NewYork-Presbyterian/Columbia University Irving Medical Center (NYP/CUIMC) have joined a major international initiative, directed by the John P. Hussman Institute for Human Genomics (HIHG) at the University of Miami Miller School of Medicine, to build a resource that will expand Alzheimer’s disease genetic studies in the underrepresented African ancestry populations and Hispanic/Latinx groups. This five-year, multisite initiative also includes investigator teams from Case Western Reserve University, Wake Forest University, the University of Pennsylvania, and the University of Ibadan as the lead institution for the African Dementia Consortium (AfDC). [read more]

  • Missing Link Between Alzheimer’s and Vascular Disease Found?
    CUIMC Newsroom
    May 24, 2022

    For more than 20 years, scientists have known that people with hypertension, diabetes, high cholesterol, or obesity have a higher likelihood of developing Alzheimer’s disease.

    The conditions can all affect the brain, damaging blood vessels and leading to strokes. But the connection between vascular disease in the brain and Alzheimer’s has remained unexplained despite the intense efforts of researchers.

    Now, a study led by researchers at Columbia University's Vagelos College of Physicians and Surgeons has uncovered a possible mechanism. The study found a gene called FMNL2 links cerebrovascular disease and Alzheimer’s and suggests changes in FMNL2 activity caused by cerebrovascular disease prevent the efficient clearance of toxic proteins from the brain, eventually leading to Alzheimer’s disease.

    The finding could lead to a way to prevent Alzheimer’s in people with hypertension, diabetes, obesity, or heart disease.

    “Not only do we have a gene, but we have a potential mechanism,” says senior author Richard Mayeux, MD, chair of neurology at Columbia and NewYork-Presbyterian/Columbia University Irving Medical Center. “People have been trying to figure this out for a couple of decades, and I think we have our foot in the door now. We feel there must be other genes involved and that we've just scratched the surface.”

    Mayeux and his colleagues found FMNL2 in a genome-wide hunt designed to uncover genes associated with both vascular risk factors and Alzheimer’s disease. The search involved five groups of patients representing different ethnic groups. [read more]

  • Alzheimer’s Researchers Probe New Treatment Paths
    The Wall Street Journal
    By Dominique Mosbergen
    May 22, 2022

    The amyloid hypothesis, posited in the 1990s, proposes that amyloid-plaque formation leads to a cascade of negative effects including the accumulation of tau, inflammation, cell death and the loss of synapses, the junctions through which nerve cells known as neurons communicate with each other. “It was so compelling that it triggered the pharmaceutical industry to act,” said Scott Small, director of the Alzheimer’s Disease Research Center at Columbia University. [read more]
    Editor's Note: Accessing this article requires a WSJ subscription.

  • Brain Region’s Vulnerability to Alzheimer’s Tied to Recycling Problems Inside Cells
    December 28, 2021

    NEW YORK – When Alzheimer's disease first attacks the brain, it doesn't strike randomly. The damage tends to begin in the entorhinal cortex, a tiny hub especially connected to other parts of the brain. Why this area would be particularly vulnerable is a puzzle that scientists have been trying to work out for decades.

    Researchers at Columbia University may finally have a solution, one that backs a new approach to developing treatments for this devastating neurodegenerative disease. Seven years of step-by-step sleuthing has implicated retromers: microscopic mail carriers that help package, ship and recycle molecules inside of cells. The scientists report their findings December 28 in Cell Reports.

    “Efforts to treat Alzheimer’s disease have focused on what Dr. Alois Alzheimer observed more than a hundred years ago, but we have come a long way since then. Retromers offer a new direction and a new hope,” said Scott Small, MD, director of the Alzheimer’s Disease Research Center at Columbia University, the Boris and Rose Katz Professor of Neurology at Columbia University’s Taub Institute and Vagelos College of Physicians and Surgeons, and an affiliate member of Columbia’s Zuckerman Institute

    Starting with the Fundamentals

    Sabrina Simoes, PhD, wasn't thinking about Alzheimer's when she first began exploring retromers as an associate research scientist in Dr. Small's lab. She had been reading about how, in organisms ranging from yeast to humans, every cell contains the retromer VSP26a. But only neurons, a type of brain cell, possess a different paralog of this retromer, VSP26b. As a scientist fascinated by the fundamental biology of cells, she found her curiosity piqued.

    “I thought, 'This can't be a fluke, there must be some reason neurons need this second version of this retromer,'” said Dr. Simoes, who is now an Assistant Professor of Neurology at Columbia University’s Vagelos College of Physicians and Surgeons and Taub Institute. “So I took a closer look.”

    Dr. Simoes grew and stimulated neurons in a dish. Under a microscope, she saw that the 26b paralog tended to hang out in cellular compartments used to recycle molecules inside brain cells: that is, to move molecules to and from the surfaces of neurons to regulate the cells’ electrical activity. The researcher wondered what role 26b plays in different brain regions. So she started working with mice from the University of Science & Technology in Korea that had been genetically modified to disable the Vps26b gene. And she teamed up with Jia Guo, PhD, an expert in the brain scanning technology functional magnetic resonance imaging at Columbia’s Zuckerman Institute.

    A Surprising Scan

    Dr. Guo used fMRI machines specially made for small animals to noninvasively scan the brains of the modified lab mice. He noticed something peculiar: a lack of activity in one small, sharply defined area in their brains, as compared to the brains of normal mice.

    “I have never seen an fMRI imaging result in humans or other animals that was so striking, such a focused spot,” said Dr. Guo, an assistant professor in Columbia's Department of Psychiatry. “Normally, the differences in brain activity we see are fuzzy and diffuse.”

    That spot coincided with a sliver of the entorhinal cortex brain region. When the researchers then directly measured the electrical activity of neurons in that area using electrodes, they found deficits, confirming the fMRI results. The mice also had trouble completing memory-related tasks known to involve the entorhinal cortex. Reintroducing working copies of Vps26b into the mice completely fixed these problems.

    With all signs pointing to a link between the retromer and the entorhinal cortex, Simoes' fundamental cell biology work had been connected with Alzheimer's disease. That’s because neurological diseases have different hallmarks. Parkinson's starts in the substantia nigra, a brain region important for controlling the body. Huntington's first affects the striatum, related to rewards. And Alzheimer's, as has been known for decades, tends to set its sights on the entorhinal cortex.

    “The evidence built up that this retromer variant, linked to cellular recycling, was crucial for proper brain function in the entorhinal cortex,” said Dr. Simoes. “This brain region's role in Alzheimer's led us to investigate whether the paralog could be related to the disease.”

    Introducing SORL1

    While the researchers were hard on the retromer's trail, another clue emerged. In 2007, a team that included Columbia’s Richard Mayeux, MD, MSc, chair of neurology at Columbia University Vagelos College of Physicians and Surgeons, had found a new gene connected to Alzheimer's. Mutations in this SORL1 gene were associated with late-onset Alzheimer's, which afflicts people over the age of 65, and SORL1 has emerged as one of the most damaging genes in the disease. Dr. Small and colleagues first found that the SORL1 protein is part of the same molecular shipping system associated with retromers.

    Hoping to further connect this gene to their retromer variant, Dr. Small and his team checked their mice and found a deficiency of SORL1 in the entorhinal cortex. The scientists also examined brains donated by people diagnosed with Alzheimer’s and found a striking pattern: Tissues in the entorhinal cortex were depleted in both SORL1 and Vps26b.

    Putting all these pieces together suggests that Alzheimer’s might begin with problems with a neuron’s ability to move molecules around. Scientists know the entorhinal cortex, a hub in the brain, forms an unusually large number of connections with other parts of the brain. These connections and the activity they generate could stimulate a lot of molecular recycling, making the entorhinal cortex especially susceptible to disruptions in these processes. For Dr. Small, these results hold promise for developing new treatments.

    “Anchored in genetics and revealing that retromer dysfunction and SORL1 deficiency can explain the regional vulnerability we see in Alzheimer’s disease, this work validates the idea that retromer-enhancing drugs are worth pursuing for Alzheimer's disease therapeutics,” he said.


    “Alzheimer’s vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling” appeared on December 28 in Cell Reports. Authors are Sabrina Simoes, Jia Guo, Luna Buitrago, Yasir H. Qureshi, Xinyang Feng, Milankumar Kothiya, Etty Cortes, Vivek Patel, Suvarnambiga Kannan, Young-Hyun Kim, Kyu-Tae Chang, Alzheimer’s Disease Neuroimaging Initiative, S. Abid Hussaini, Herman Moreno, Gilbert Di Paolo, Olav M. Andersen, and Scott A. Small.

    The authors declare competing financial interests: Scott Small is a co-founder of Retromer Therapeutics, has equity in the company, and is a paid consultant to the company. In addition, Scott Small has equity in Imij Technologies, an MRI-based company. Gilbert Di Paolo is a full-time employee of Denali Therapeutics, Inc. Olav M. Andersen has commercial interests in Retromer Therapeutics. Lastly, Scott Small, Sabrina Simoes, and Yasir H. Qureshi are listed as co-inventors on Columbia University-owned patents that relate to retromer biomarkers and retromer drug discovery targets.

    This study was partly supported by NIH R01 grants AG034618, AG035015, and P30AG066462 to S.A.S., NS056049 to G.D.P. and AG051556 to H.M. Human MRI data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (NIH Grant U01 AG024904) and Department of Defense 409 ADNI (award number W81XWH-12-2-0012). Data collection and sharing for this project was partially funded by the ADNI (National Institutes of Health Grant U01 411 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-412 0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.;Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

    Source: Columbia Zuckerman Institute

  • Prevention
    By Marisa Cohen
    October 26, 2021
    How Is Alzheimer's Disease Treated?

    Whichever medication is prescribed, doctors will usually start the patient on a low dose and increase the amount based on how well they tolerate the drug (side effects may include nausea, fatigue, loss of appetite, constipation, and headache). “Sometimes there will be a mild improvement right away, in terms of being able to recall memories that the patient wasn’t remembering before,” says Elise Caccappolo, Ph.D., an associate professor of neuropsychology at Columbia University Irving Medical Center. “It’s a little bump that usually lasts around six months, and then they usually plateau,” she explains. [read more]

  • The Wall Street Journal
    By Emily Bobrow
    July 8, 2021
    ‘Forgetting’ Review: The Balm of Oblivion

    There is a robust market for books that praise our seemingly feeble habits of mind. Authors have lately offered empirical support for the benefits of everything from swearing to grumpiness. Now Scott Small, the director of the Alzheimer’s Disease Research Center at Columbia University, joins this merciful bunch with his own upbeat take on one of our more profound mental shortcomings: forgetfulness [read more (PDF)]

  • STAT
    June 4, 2021
    A landmark Alzheimer’s drug approval would likely deepen racial inequities in dementia care

    Other researchers are not convinced that these biomarkers vary by race, primarily because so little Alzheimer’s research has been conducted on Black and Latinx people. “We don’t know these differences exist and the reason we don’t know is we have an inequitable system,” said Jennifer Manly, a professor in the Columbia University neurology department who studies predictors of Alzheimer’s disease in Black and Hispanic populations. “Not only has research been occurring in clinics with mostly white people, the research is occurring on mostly well-educated and well-resourced white people.” [read more]

    March 30, 2021
    Dementia and COVID: What Families and Physicians Should Know

    Early in the pandemic, neurologists expressed concern that COVID-19 patients with dementia may be at higher risk for complications and mortality.

    But those fears have not been realized, according to a new study of patients who were hospitalized with COVID-19 during the first wave of the pandemic in New York City. The study, led by James Noble, MD, MS, associate professor of neurology at Columbia University Vagelos College of Physicians and Surgeons and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Amro Harb, a Vagelos medical student, was published this month in the Journal of Alzheimer’s Disease [read more]

    February 18, 2021
    A New Way to Prevent Nerve Damage Caused by Chemotherapy?

    About 60% of cancer patients treated with chemotherapy develop painful nerve damage but no drugs exist to prevent this complication.

    Now a new study—that identifies how one agent causes nerve degeneration—may lead to the development of the first drugs to prevent peripheral neuropathy and identify people who may be at greatest risk of developing the condition. [read more]

    By Adam Piore
    December 7, 2020
    A 73-Year-Old-Woman Who Should Have Gotten Alzheimer's, Didn't—Revitalizing a Search for the Cure

    Dr. Eric Reiman can't reveal the identity of the 73-year-old woman from a rugged mountain town outside Medellin, Colombia, who arrived at Boston's Logan Airport a couple of years ago for tests at Harvard Medical School. But he will say this: Finding her may well be among the most surprising developments to emerge from a nearly three-decade-long study of Colombians cursed with a gene that usually dooms its victims to full-blown Alzheimer's disease by the age of 50.

    The Colombian woman is just the latest piece of evidence to emerge suggesting that the causes of Alzheimer's disease are far more complex and heterogeneous than previously understood. Despite a brain scan that revealed more amyloid-beta plaque deposition than many of her doctors had ever seen, her cognitive abilities were only mildly impaired. Which is why, even as the list of failed treatments continues to grow, many in the field have found cause for renewed optimism.

    This hope is fed by an explosion in technological innovations in gene sequencing, data analysis and molecular biology, which are allowing scientists to study the progression of the disease earlier and in far more detail than previously possible. It's also fed by money: the National Institutes of Health is expected to spend $2.8 billion on Alzheimer's research in 2020—a six-fold increase since 2011, when Congress passed legislation directing the NIH to come up with an aggressive and coordinated plan to accelerate research with the ambitious goal of coming up with a way to prevent and effectively treat Alzheimer's by 2025.

    That ambition reflects a growing urgency on the part of an aging public, their doctors and public health officials. By the year 2050, the number of Americans with the disease will double to 14 million, with a projected cost in treatment and care that, by some estimates, will top $2 trillion—10 percent of the present U.S. GDP. Scientists are racing to diffuse a ticking demographic time bomb. Although the field seems unlikely to meet the 2025 deadline, what researchers have learned in the past few years has given them a far more detailed and nuanced understanding of the disease. And it is raising hopes that we are finally getting closer to cracking Alzheimer's disease.

    What made the Colombian woman special was not just what doctors discovered when they first scanned her brain to measure the buildup of amyloid-beta, the sticky plaques long suspected of playing a key role in the devastating cognitive decline seen in advanced Alzheimer's disease. She had the highest levels they'd ever recorded. What made the woman so special was that—despite those plaques—she seemed almost normal for her age.

    "Nobody's at higher risk for Alzheimer's than she would have been," says Reiman, a neuroscientist at the Banner Alzheimer's Institute in Phoenix, who has spent the last three decades studying the loosely related, 6,000-person family cohort she belongs to in Colombia. "But she developed mild cognitive impairment about three decades after the average age in her family. And she still hasn't developed Alzheimer's dementia."

    The Colombian woman's case is a potent testament to both the tantalizing promise—and the enormous frustration—that have come to characterize the pursuit of drugs to treat Alzheimer's disease. In two decades, the pharmaceutical industry has spent $600 billion in pursuit of drugs, focusing with almost single-minded intensity on compounds designed to safely reduce or prevent the buildup of deadly plaques that are one of its primary hallmarks.

    Attacking plaque is precisely the point of the new Alzheimer's drug aducanumab, made by the drug maker Biogen, which was being tested in two separate clinical trials. High-ranking officials at the U.S. Food and Drug Administration have supported the drug and recently called preliminary trial results "highly persuasive." But in early November, a panel of independent experts, convened by the FDA to review data from ongoing trials, contradicted this assessment. They cited conflicting data—one trial showed a mild therapeutic effect, another trial showed none—and a lack of efficacy. "The totality of the data does not seem to provide sufficient evidence" of effectiveness, declared one of the FDA's own statisticians in a report. An FDA advisor, Dr. David Knopman of Mayo Clinic, called for a new clinical trial. "Contrary to the hope that aducanumab will help Alzheimer patients," he wrote in a report, "the evidence shows it will offer improvement to none, it will harm some of those exposed, and it will consume enormous resources."

    Even if the FDA were to contravene its own experts and approve aducanumab in March, the drug appears unlikely to live up to the early promise of the class of drugs that stave off Alzheimer's by interfering with the accumulation of plaque in the brain. With aducanumab, Biogen's approach reflects the dominance of a theory called the "amyloid cascade hypothesis," which argues that amyloid-beta plaques are the first step in the condition—the kindling that eventually ignites into the fire that causes the massive cell death and memory and thinking problems that make Alzheimer's such a devastating disease. But that theory has been losing steam for years, as the case of the Colombian woman suggests.

    Plaque Distraction

    From the beginning, there was good reason to suspect the thick plaques that characterize the disease might also be their cause. In 1901, a 50-year-old woman named Auguste Dieter was placed under the care of Dr. Alois Alzheimer at the Frankfurt Psychiatric Hospital with an inexplicable set of symptoms, which included memory loss, disorientation, hallucinations, aphasia and delusions. "I have lost myself," she lamented shortly before her passing in 1906, according to Alzheimer's meticulous notes.

    In an autopsy, Alzheimer noted the buildup of dark clumps of plaques formed by protein fragments known as amyloid-beta, along with the other two symptoms that are now considered the primary physical hallmarks of the disease that bears his name: the tangles of stringy protein molecules known as tau that clog up the space between brain cells and disrupt normal cell function, and massive cerebral atrophy caused by the death of the gray matter we rely upon to think, feel and live.

    Still, the modern age of Alzheimer's research wouldn't begin until decades later, when Robert Katzman, a prominent UCSD neurologist, penned an 1978 editorial arguing that the obscure condition known as "Alzheimer disease"—a term previously reserved for those developing dementia before age 65—was actually the primary cause of what was then known only as senility. By that measure, Katzman argued, Alzheimer's disease ranked as the fourth or fifth most common cause of death in the United States and thus constituted a vastly overlooked public health challenge. In the years that followed, the first patient interest groups began to mobilize and the newly established National Institute of Aging began pouring resources into research.

    Then came the discovery and study of families carrying rare mutations, like those seen in the mountains outside Medellin, Colombia, that caused them to develop the symptoms of full-blown Alzheimer's disease far earlier than elsewhere. Using the genetic tools available at the time, researchers throughout the 1990s homed in on specific mutations that appeared to be present only in family members who had developed early-onset Alzheimer's—mutations that were entirely absent in close relatives spared by the disease. Virtually all the genetic typos seemed to appear on genes that could be directly linked to the buildup of the amyloid-beta plaques in the brain.

    These discoveries were among the most compelling evidence for the amyloid hypothesis, which by the early 2000s had become the dominant model used to explain how and why Alzheimer's disease progresses. And with the advent of brain scanning technologies that allowed clinicians for the first time to measure the plaques in the brains of living people, it suddenly seemed possible to track this accumulation in real time.

    The implications were clear: if scientists could develop a drug capable of countering the accumulation of plaques, we could halt the progression of Alzheimer's, and the heartbreaking cognitive decline that came with it, in its tracks. "I was a student at the time—and they were heady times," recalls Scott Small, a neurologist who directs the Alzheimer's Disease Research Center at Columbia University. "We thought we had it figured it all out."

    Unfortunately, things have not proven that simple. Between 1998 and 2017, there were 146 unsuccessful attempts to develop medicines to treat and potentially prevent Alzheimer's, according to a 2018 report put out by the Pharmaceutical Research and Manufacturers of America (PhRMA), the vast majority focused on the amyloid hypothesis. (The last Alzheimer's medication to receive FDA approval was Namenda in 2003, a drug that aims to temporarily boost cognitive performance by boosting the chemical messengers in the brain known as neurotransmitters).

    The list of disappointing drugs that promised to cure or slow the progression of the disease is long. There was, for instance, Pfizer and Johnson & Johnson's bapineuzumab, a monoclonal antibody designed to bind to amyloid-beta. In 2012, the study's principal investor at Harvard declared human trials had produced "absolutely no evidence at all of a clinical benefit of treatment on either of the primary measures, one cognitive and one functional" in 1,100 patients with mild to moderate symptoms of the disease. Another widely anticipated drug, semagacestat, was halted after some recipients developed skin cancer and their cognition declined. In 2016, Eli Lilly & Co's solanezumab, "did nothing to improve cognition" in the phase 3, placebo-controlled trial of 2,129 patients with mild Alzheimer's disease who took the medication for more than a year.

    The latest shining hope has been aducanumab, a drug whose on-again, off-again journey toward approval seems to encapsulate the infuriating ambiguity of the present moment. In 2016, the drug, developed by Biogen and Eisai, made the cover of Nature Magazine after researchers announced it had slowed cognitive decline and reduced plaques in the brains of a small group of study participants. In 2018, massive phase 3 trials kicked off in clinics around the globe, slated to finish in 2021. In March 2019, Biogen announced that a preliminary look at the results, known as a "futility analysis," had shown the medicine wasn't working as it should on the more than 3,000 hopeful early stage Alzheimer's patients participating in the study. They shut the trial down two years early and declared it a failure.

    By Caroline Seydel
    November 10, 2020
    How Epigenetics Could Turn Things Around for Alzheimer’s Disease

    Last Friday, an FDA advisory panel voted unanimously against recommending the Alzheimer’s drug aducanumab. Based on evidence from two clinical trials, they found that the data did not show that the drug effectively treats Alzheimer’s disease. Remarkably, however, the panel agreed that the drug does appear to reduce the brain protein thought to cause the disease. What’s going on?

    Despite hundreds of clinical trials conducted, no new Alzheimer’s drugs have been approved in almost two decades. Many of these attempts have centered on reducing two Alzheimer’s-associated proteins in the brain, called beta amyloid plaques and tau tangles.

    Maybe these drugs aren’t working because something else causes the disease, besides beta amyloid and tau. Some researchers are working a different angle, called epigenetics, to try to find a way to stop the disease.

    Genetics considers a person’s DNA sequence, and epigenetics looks at how the cell turns genes on and off. By comparing the genes that are activated in healthy people versus those with Alzheimer’s, researchers hope to understand how healthy aging changes the brain — and how certain changes open the door to disease. Research teams around the world have identified significant epigenetic changes associated with Alzheimer’s disease, and these changes may be modifiable with medications.

    Epigenetics changes with age

    Shelley Berger is the founding director of the Epigenetics Institute at University of Pennsylvania. She’s studying how genes are turned on and off in the brain, and how different patterns of gene activation could be related to Alzheimer’s disease.

    Every single cell in your body has the same set of genes. For instance, the gene responsible for producing insulin is present in all your cells, but it’s only active in certain cells in the pancreas. That’s because cells have chemical signposts that they plant in the DNA, to mark which genes should be switched on. Epigenetics is the study of how cells use these chemical signposts.

    All sorts of things can change your epigenetic profile, including environmental exposures and aging. There’s a concept called an “epigenetic clock”: you can pretty closely guess a person’s age by looking at the epigenetic changes in their DNA.

    Berger and her team compared the epigenetics of brain cells from three populations: older people with Alzheimer’s disease, older people without Alzheimer’s disease, and healthy people younger than 65.

    “Most people in the field of Alzheimer’s disease compare cognitively normal, age-matched samples to Alzheimer’s disease samples,” she said. “That’s interesting, that tells you what kind of changes happen in disease.” By also looking at gene expression in young brains, Berger and her colleagues singled out changes that happen naturally with healthy aging.

    “We find that there are some changes that happen in the cognitively normal aged brain that are protective, that actually help to maintain healthy aging,” Berger said. The study also discovered that those protective changes do not occur in people with Alzheimer’s disease.

    How the signposts work

    If the cell’s DNA was laid out full-length, it would stretch from your head to your toes. To cram all that into the cell, and keep it organized, the DNA is tightly wrapped around proteins called histones. Adding molecules called acetyl groups to the histones can loosen up the package, allowing the cell’s DNA-reading tools to get in there and activate the gene.

    By looking at where these acetyl group signposts were added at different stages, Berger found clues to how genes are activated differently in Alzheimer’s disease than in healthy aging. She found acetyl groups improperly placed at two very interesting spots: they were directing the cell to make more of a molecule, called an enzyme, that adds the acetyl groups to the histones.

    “There are different enzymes that put the acetyl group on the packing material,” said Berger. In this case, she said, “It’s kind of a feed-forward mechanism, where the enzyme is leading to more activation of its own gene.”

    It may be possible to develop drugs to stop that self-activating pathway, as there are compounds known to inhibit the enzyme doing the work. But that would be a long way down the road, Berger said.

    Two paths to the same endpoint

    New findings in epigenetics will more than likely tie into what’s already been learned about the disease genetics. Jonathan Mill, an epigeneticist at the University of Exeter, UK, led a similar study, looking for epigenetic signals in Alzheimer’s patients.

    Researchers know Alzheimer’s disease has a genetic component, but it’s still not well understood. People who inherit certain genetic mutations, such as in the ApoE gene, develop Alzheimer’s at a young age. This is called familial or early-onset Alzheimer’s, and it’s fairly rare. Far more often, the genetic cause of the disease is more subtle and distributed among many genes that each exert a tiny effect. This is called sporadic Alzheimer’s, and it usually comes on a little later, with symptoms arising after age 65 or so.

    In patients with sporadic Alzheimer’s, Mill detected a curious pattern. Comparing the differences in the acetyl groups in the DNA from healthy and Alzheimer’s brains, he found the changes were congregating around genes that are known to be damaged in early-onset familial Alzheimer’s.

    “The endpoint is similar, and there’s many ways you can get there,” he explained. Mutations in the gene itself can cause it to no longer function: that’s what happens in early-onset cases. “The other way is altering the way the genes are expressed,” Mill said. “That’s probably by disruptions in the epigenetic signatures.”

    Unlike genetic mutations, changes in the epigenetic signature can come and go over the course of a lifetime. Just as healthy aging causes natural epigenetic changes, environmental factors can alter epigenetic signals.

    “It’s really clear that lots of things in the environment probably have effects on gene expression via epigenetic changes,” Mill said. One major contributor? Smoking. “It’s pretty amazing—I could pretty accurately work out who was a smoker and who wasn’t, based on their epigenetic profile.”

    This fluidity is good, because it means we could potentially change our epigenetics with medication. And indeed, drugs already exist that can rearrange the epigenetic signposts in our genome. Whether this can effectively treat disease, however, depends on whether the epigenetic changes are causing the disease — or are a result of it.

    "What we don’t know is whether the signature that we’re seeing is something to do with the onset, or a consequence of the pathology,” as Mill puts it.

    Tau protein influences epigenetics

    One distinctive feature of Alzheimer’s disease is long strings of protein, called tau tangles, that gather like dust bunnies inside neurons. Brain cells do normally contain tau, but in Alzheimer’s disease, it stops doing its job and instead forms tangled masses that eventually kill the cell.

    It turns out that tau tangles can alter the epigenome. Philip De Jager, a neurologist at Columbia University in New York, investigated what epigenetic changes occurred in the presence of tau tangles.

    De Jager and his team found that the tau tangles cause the tightly packed DNA to become disorganized — in a predictable, reproducible way. The researchers were able to induce the epigenetic changes in lab-grown neurons by adding tau tangles to the cells.

    “By increasing expression of tau, we were able to generate some of the same changes in the epigenome in the lab that we saw in the actual brain,” De Jager said.

    What’s exciting is that De Jager and his team were also able to stop tau from effecting these changes, using a drug candidate that inhibits a protein called Hsp90. Hsp90 may play a role in helping tau form those long tangles that build up in the cell, so blocking it with a drug could prevent tangle formation and thus stave off the epigenetic changes.

    Tau may influence epigenetics, but epigenetics may also contribute to tau buildup. In a preprint earlier this year, De Jager’s group proposed another way that epigenetic changes could influence brain health: via the immune system. Immune cells called microglia help support neurons, cleaning up cellular debris, helping the brain recover after a stroke, and stopping beta amyloid plaques from forming. “In Alzheimer’s disease, with relation to amyloid, they seem to not be working quite as well as they should,” said De Jager. “Later, when tau begins to accumulate, it appears that the problem is that they’re overactive.” At that stage, the microglia begin releasing chemicals that may accelerate the buildup of tau.

    Remember the genetic mutation in the ApoE gene, the one that causes early-onset, familial Alzheimer’s disease? It turns out that not everyone with that mutation ends up getting the disease. De Jager’s group tested people who had two damaged copies of ApoE but remained dementia-free in their 80s. Those people carried epigenetic factors that somehow make up for that mutation, reducing the risk of the disease. These factors influenced the activation of genes in the microglia, suggesting that they may restrain the microglia from promoting tau accumulation.

    Because the brain is uniquely difficult to study, advances in Alzheimer’s disease have been a long time coming. With the power of modern genetic and epigenetic technology, some of the mysteries surrounding this devastating disease are beginning to open up. New understanding of how the complex tapestry of epigenetic changes impacts brain health will, hopefully, bring new insights into ways to slow or stop the disease.

    October 7, 2020
    Spotlight on Miguel Arce Rentería, PhD

    Columbia University Irving Medical Center believes that excellence, diversity, and inclusivity are inextricably linked and that different experiences, perspectives, and values are essential elements that enrich every dimension of our work. A diverse faculty facilitates culturally competent medical education and clinical care and also brings important and different perspectives to the research agenda.

    In recognition of Hispanic Heritage Month, CUIMC News will feature profiles of faculty members who are helping the medical center achieve excellence in research, education, and patient care.

    Miguel Arce Rentería, PhD, is an associate research scientist and clinical neuropsychologist at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Department of Neurology at the Vagelos College of Physicians and Surgeons. He grew up in Tijuana, Mexico, and was the first in his family to immigrate to the United States.

    Arce trained as a neuropsychologist at Fordham University before joining Columbia as a postdoctoral fellow in the laboratory of Jennifer Manly, PhD, professor of neuropsychology in the Department of Neurology.

    His research investigates the sociocultural and environmental determinants of disparities in cognitive aging and Alzheimer’s disease and related dementias (ADRD). His current focus has been on determining factors of reserve and resilience to ADRD among racial/ethnic minorities, such as understanding the role of bilingualism, literacy, and quality of education.

    In 2019, his study published in Neurology revealed a connection between illiteracy and dementia and was covered in multiple media outlets including the New York Times, CNN, and Scientific American.

    The interview below has been edited for brevity.

    What is it about neuropsychology that you fell in love with?

    While in high school in Tijuana, I got interested in psychology and I knew I wanted to do research in psychology, though I didn't know what kind of research exactly. In college, I had a wide range of different research experiences and in my last year, I was introduced to a neuropsychologist and neuroAIDS disparities research. And I was blown away; it just seemed so cool.

    Neuropsychologists specialize in understanding the relationship between brain and behavior. For instance, we evaluate how neurological conditions like Alzheimer’s disease affect behavior. Most anything that impacts the brain will have some kind of cognitive or behavioral consequence, and so we help evaluate patients and provide their referring physicians with guidance on potential etiologies, treatment recommendations, and information on their psychosocial functioning. As neuropsychologists, we can also provide cognitive remediation therapy, among other clinical interventions, to help patients learn to adapt to cognitive changes related to brain injury or surgical resection as their lives move forward.

    In our role as scientists, we provide expertise into the measurement of cognition and behavior and how health and sociocultural factors influence performance.

    I liked how it’s a multidisciplinary approach. Both clinical practice and research in neuropsychology allow you to work with a diverse medical and academic team of neurologists, geneticists, social workers, epidemiologists, etc.

    How did you become interested in disparities research?

    My interest in disparities in cognitive aging research comes from recognizing that certain groups are more vulnerable to developing Alzheimer’s disease and related dementias. Blacks and Latinos, for example, tend to have higher rates compared with non-Hispanic whites, and I find that fascinating. What's driving these differences?

    Being part of the Latinx community, I want to help figure out what's causing this and what can we do about it, if there's anything we can do to effect change.

    A lot of the work we do is trying to understand early life experiences and how that influences development of these diseases.

    What do you hope comes out of your recent work showing illiteracy increases the chance of developing dementia?

    A big take-home message for me on our work with literacy and dementia risk is to highlight the importance of early life experiences and their impact on late-life health. Educational opportunities are largely policy and socially determined and may provide a potential source of intervention to narrow disparities in cognition and brain health.

    The next step, at least for me, is to understand other potential factors of reserve and resilience, specifically among Latinx adults. I’m currently funded through an NIA K99/R00 grant to explore whether bilingualism can provide some form of resilience to cognitive aging among Latinx. My approach involves characterizing different aspects of bilingualism, such as frequency of dual language use and code-switching, among others. The preliminary results seem exciting.

    What recommendations do you have for institutions like VP&S and CUIMC that are working to strengthen their diversity?

    I think it would be really helpful to see diversity represented in leadership positions. Currently, most leadership positions across VP&S and CUIMC do not seem to be held by individuals from diverse racial/ethnic backgrounds, so I do not feel myself represented and do not feel that those opportunities are for me. That doesn’t stop me from striving and working hard to eventually obtain such a position, but I am not sure if that’s a goal of the institutions.

    A way that CUIMC could strengthen diversity is by hiring faculty from diverse backgrounds, providing them with leadership opportunities, and further supporting disparities research. A critical thing to keep in mind when hiring diverse faculty is to be willing to accommodate the needs of potential diverse faculty. For instance, for me as a first generation individual in the U.S., with little to no financial support from family, my entire academic career has been extremely expensive, and I had to incur debt beyond that of my peers. I am barely at a place now where I’m not living paycheck to paycheck and can begin to consider something like a savings account. Hopefully at the time of hire, if the institution is interested in hiring diverse faculty with a focus on disparities research, then they may consider the unique needs of potential candidates.

    Lastly, the focus on supporting health disparities research is a no-brainer. What better way to strengthen diversity than helping scientists understand the causes and ways to reduce health disparities that largely impact diverse communities?

    Bringing diverse faculty on board will help bring awareness to issues that may not be easily apparent unless you’re from and interact with communities disproportionately impacted by health disparities. Similarly, given that we’re an academic medical center, we should be able to meet the needs of the surrounding community. For instance, I recently had to bring my wife to the medical center, and I was shocked to see that several of the COVID-related messages I saw were not translated correctly to Spanish. The Spanish messages had grammatical errors and were somewhat confusing. That was incredibly disappointing to see, especially keeping in mind that we’re in the Heights where there's a Spanish-speaking majority.

    What do you like to do outside of work?

    I love live music. Although I love all kinds of genres, I’m especially into heavy metal and hard rock, the heavier the better. There are so many music venues and so many artists from all kinds of genres that come to New York City; that was one of the best things about living here. I'm a musician myself: I play guitar and I'll play with friends, although I can’t right now because of the pandemic.

    I’m also very into comic books and graphic novels; I’m a huge comic book geek. Obviously, the pandemic has gotten in the way of seeing live bands and delaying the next big movies from Marvel and DC. It’s a bummer, but at least I can still read comic books digitally and blast music at home.

    If I’m not listening to or playing music, then I’m hiking. There's a lot of parks here in New York City and within about 20 minutes of the city. I like just being outdoors, and luckily we can still do that.

    June 24, 2020
    By Meghan Rabbitt
    Researchers Explain Why Black Americans Are At Higher Risk For Alzheimer's
    The Alzheimer’s epidemic no one is talking about.

    Six years ago, Veronica Shanklin showed up at her childhood home in DeSoto, Texas, expecting a typical visit. Shanklin’s grandmother, who’d been diagnosed with Alzheimer’s disease at age 82, had moved in with Shanklin’s mom a few years earlier. Shanklin, a marketing executive in Chicago, wanted to spend some time with them and was also eager to help with caretaking for a few days; she was sure her mom, then 66, could use a break.

    Yet mere minutes after walking in the door, Shanklin’s heart sank. Both her grandmother and mother had lost weight. The usually tidy home was a mess, with dirty laundry piling up and overdue bills scattered across a bed.

    “My mom was the manager of the credit union at her church,” Shanklin says. “If she couldn’t pay her own bills or keep up with cooking and cleaning, I knew something was wrong.” Then Shanklin noticed that her mother kept forgetting what day it was. She’d seen her grandmother—and grandfather, who also had Alzheimer’s—deal with similar issues. Worried, Shanklin took her mom to the doctor. The diagnosis confirmed her fear: Alzheimer’s disease.

    Shanklin quit her job and moved to Texas. She took over caregiving for her mother and grandmother—preparing meals, keeping house, helping them get to doctor’s visits—all while making sure they didn’t wander out of the house or otherwise endanger themselves. “This disease has turned my life upside down,” Shanklin says. “And the fact that it’s touched two of my grandparents and my mom almost seems unfair.”

    Unfair, yes, but unfortunately not unusual. Shanklin’s family history is in line with some staggering statistics: Older African Americans are about twice as likely as older non-Hispanic white people to develop Alzheimer’s or other dementias, according to the Alzheimer’s Association. On top of that, less than 5 percent of participants in U.S. health studies are black, making it difficult to identify factors driving the disparity and find ways to address them.

    Scientists have tried to ascertain whether African Americans naturally make more beta-amyloid and tau proteins, two of the signature causes of Alzheimer’s. Beta-amyloid forms clumps in the brain that interfere with cell-to-cell communication, and tau creates so-called tangles inside brain cells. Both result in forgetfulness, confusion, difficulty concentrating, delusions, and other telltale symptoms of the disease. So far, there’s no evidence that African Americans have higher levels of beta-amyloid or tau, says Reisa A. Sperling, MD, a Harvard Medical School neurology professor and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital.

    “We have other theories, though,” says Lisa L. Barnes, PhD, a professor of gerontology and geriatric medicine at the Rush Alzheimer’s Disease Center at Rush University Medical Center and a trailblazer in researching the Alzheimer’s racial imbalance. Barnes and other experts point to the fact that Black Americans have higher rates of diabetes, hypertension, stroke, elevated cholesterol, and heart disease—all of which are correlated with Alzheimer’s dementia. These conditions also affect blood vessels and can impair blood flow, which can then damage the brain and may also contribute to beta-amyloid and tau protein buildup, thereby raising Alzheimer’s risk, explains Barnes.

    On top of that, “diabetic brains have difficulty utilizing and managing glucose and have more difficulty making new brain cells,” says Goldie S. Byrd, PhD, professor and director of the Maya Angelou Center for Health Equity at Wake Forest School of Medicine. All of these issues can lead to memory impairment, cognitive and behavioral changes, and other signs of Alzheimer’s, she says.

    In a 2015 study, Barnes and colleagues compared brain autopsies of black and white Alzheimer’s patients who had similar backgrounds (age, sex, education level, and cognitive ability). They found that the Black patients were more likely to have “mixed brain pathologies”—meaning that in addition to the expected signs of Alzheimer’s (beta-amyloid and tau proteins), they had conditions like arteriosclerosis and atherosclerosis, two forms of vascular disease.

    Even when scientists control for cardiovascular and related factors, however, Black Americans are still more susceptible to Alzheimer’s and other dementias. A 2017 JAMA Neurology study found that those born in states with high stroke death rates (Alabama, Alaska, Arkansas, Louisiana, Mississippi, Oklahoma, South Carolina, Tennessee, and West Virginia) had a 67 percent higher risk for dementia compared with non-Black participants born elsewhere, while non-Black subjects born in those states faced a 46 percent increased risk. “A theory holds that older African Americans who were exposed to segregation, which was prevalent in many of these states, experienced significant long-term stress, which could possibly contribute to a decline in cognitive function later in life,” says Rachel Whitmer, PhD, a principal investigator on the study and professor and associate director of the Alzheimer’s Disease Research Center at UC Davis School of Medicine.

    A growing body of research is exploring the links between long-term stress and racial discrepancies in dementia. Among other things, chronic stress contributes to inflammation and vascular disease, and can even directly damage the brain’s neurons. “This can lead to a slew of health issues, including atrophy in areas of the brain that are key for memory and cognition,” says Megan Zuelsdorff, PhD, an assistant professor at the University of Wisconsin-Madison School of Nursing investigating the mechanisms underlying cognitive health and dementia disparities.

    A recent study coauthored by Zuelsdorff found that stressful life events (financial insecurity, legal issues, divorce, being fired from a job, the death of a child) took a greater toll on the memory function of African Americans. For white participants, each stressful event was equivalent to about six additional months of normal aging; in Black participants, each of the same stressors added an additional year and a half. The study also found that African Americans reported 84 percent more stressful life events than their white counterparts.

    Stressful events not only have residual effects but can also add up over time. “When you’re dealing with a stressor or a challenging life situation, your physical, social, and financial resources can become depleted, making you more vulnerable to the next hit,” says Zuelsdorff. “Since disadvantage—economic, educational, societal—can be cumulative, we think it could be one reason for theAlzheimer’s disparity.” One of Barnes’s studies shows a direct link between the specific stress of discrimination and poor cognitive function, particularly memory. “We need more research in this area,” says Barnes.

    That’s where the work of Jennifer J. Manly, PhD, a professor of neuropsychology at Columbia University Irving Medical Center, comes in. When Manly and colleagues compared results of memory tests of African Americans and white Americans who had received the same quality of childhood education, they found no difference in the rate of cognitive decline over time. In other research, they found a decreasing trend of dementia among African Americans who benefited from access to more schooling and better education. There is hope that widespread legal and cultural intolerance for discrimination will eventually help even out risk levels. “Thanks to increasing educational equality, we believe there’s a good chance that we won’t see this disparity in the future,” says Whitmer.

    Shanklin, too, is looking toward then future—hers and that of other Black people. Her grandmother died in 2017, and her mother’s short-term memory has worsened. To try to avoid a similar fate, Shanklin eats healthfully and exercises regularly, habits that research has shown may help delay cognitive decline. She started a nonprofit, Dementia Care Warriors, that offers support to caregivers and signed up with the Alzheimer’s Association to be considered for related studies (see “Get Involved”). “Watching someone you love battle Alzheimer’s can make you feel helpless—and mad, considering African Americans are so much more affected,” she says.“I want to do whatever I can to help experts find the answers we need.”

    June 29, 2020
    New Eye Drops May Prevent a Common Cause of Blindness

    Researchers at Columbia University Irving Medical Center have developed eye drops that could prevent vision loss after retinal vein occlusion, a major cause of blindness for millions of adults worldwide.

    A study, in mice, suggests that the experimental therapy—which targets a common cause of neurodegeneration and vascular leakage in the eye—could have broader therapeutic effects than existing drugs.

    The study was published in Nature Communications.

    What is Retinal Vein Occlusion?

    Retinal vein occlusion occurs when a major vein that drains blood from the retina is blocked, usually due to a blood clot. As a result, blood and other fluids leak into the retina, damaging specialized light-sensing neurons called photoreceptors.

    Standard treatment for the condition currently relies on drugs that reduce fluid leakage from blood vessels and abnormal blood vessel growth. But there are significant drawbacks. These therapies require repeated injections directly into the eye, and for the patients who brave this daunting prospect, the treatment ultimately fails to prevent vision loss in the majority of cases.

    The new treatment targets an enzyme called caspase-9, says Carol M. Troy, MD, PhD, professor of pathology & cell biology and of neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Vagelos College of Physicians and Surgeons, who led the studies. Under normal conditions, caspase-9 is believed to be primarily involved in programmed cell death, a tightly regulated mechanism for naturally eliminating damaged or excess cells.

    In studies of mice, the Troy lab discovered that when blood vessels are injured by retinal vein occlusion, caspase-9 becomes uncontrollably activated, triggering processes that can damage the retina.

    Eye Drops Prevent Retinal Injury

    The Troy lab found that a highly selective caspase-9 inhibitor, delivered in the form of eye drops, improved a variety of clinical measures of retinal function in a mouse model of the condition. Most importantly, the treatment reduced swelling, improved blood flow, and decreased neuronal damage in the retina.

    “We believe these eye drops may offer several advantages over existing therapies,” says Troy. “Patients could administer the drug themselves and wouldn’t have to get a series of injections. Also, our eye drops target a different pathway of retinal injury and thus may help patients who do not respond to the current therapy.”

    Next Steps

    The researchers are preparing to test the eye drops in people with retinal vein occlusion during a phase I clinical trial.

    Moving forward, the Troy lab will also study whether caspase-9 inhibitors can be used to treat other vascular injuries caused by overactivation of the enzyme, including diabetic macular edema (another common cause of blindness) and stroke.

    “Vascular dysfunction is at the heart of many chronic neurological and retinal disorders, because high energy demands in the brain and eye render these tissues exceptionally vulnerable to disruption in blood supply,” says the study’s first author, Maria Avrutsky, PhD, postdoctoral research scientist in pathology & cell biology at Columbia University Vagelos College of Physicians and Surgeons.

    May 8, 2020
    Dr. Ted Huey Provides Guidance on FTD Care During COVID Pandemic

    As a member of the Association for Frontotemporal Degeneration (AFTD) Medical Advisory Council, Dr. Ted Huey addressed the national FTD community to outline the unique challenges of FTD care during the COVID-19 pandemic and provide guidance to FTD patients, families, and caregivers.

    March 31, 2020
    New COVID-19 Biobank at Columbia Opens for Researchers

    Columbia University Vagelos College of Physicians and Surgeons, in partnership with NewYork-Presbyterian Hospital, has established a COVID-19 Biobank as a centralized resource to collect, store, and disseminate biological specimens and clinical data for researchers at Columbia University and elsewhere.

    “Our vibrant research community is one of our strengths,” says Michael Shelanski, MD, PhD, senior vice dean for research at VP&S. “We’re coming together in this moment of uncertainty to improve our understanding of COVID-19 and use that understanding to improve how to diagnose, treat, and prevent it.”

    The COVID-19 Biobank at Columbia started collecting clinical samples in March from patients who have permitted use of their samples for research related to COVID-19. The Department of Pathology & Cell Biology has established a COVID-19 clinical pathological laboratory and will facilitate access to residual clinical samples.

    Researchers who wish to receive samples must submit an application that will be reviewed by the biobank’s governance committee.

    An executive committee convened by Shelanski and Muredach Reilly, MBBCh, director of the Irving Institute for Clinical and Translational Research and associate dean for clinical and translational research at VP&S, will establish procedures that ensure the COVID-19 Biobank will be a robust resource and data generated from these samples are shared broadly.

    More information for researchers and patients is available at the Columbia University Biobank website.

    Congratulations to Drs. Jennifer J. Manly, Olajide Williams, and Richard Mayeux, who were among the inaugural inductees into the Vagelos College of Physicians and Surgeons (VP&S) Academy of Community and Public Service. Modeled after the VP&S Virginia Apgar and Clinical Excellence academies, this latest program stems from the new Office of Community Service Programs, led by Dr. Rafael Lantigua, and recognizes medical school faculty who make substantial contributions to community and public health.

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