Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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Featured Research

Taub Institute Grants:
New in 2020


National Institutes of Health (NIH) Grants 2020


Factors of Resilience to Alzheimer's Disease and Related Dementias among Latinx: The Role of Bilingualism
Miguel Arce, MD, PhD
1K99AG066932-01

Latinx are at increased risk for Alzheimer's disease and related dementias (ADRD) compared with non-Hispanic whites. Bilingualism may reduce ADRD risk but prior studies lack detailed characterization of within-group differences among bilinguals, such as age of second language (L2) acquisition, L2 proficiency, and frequency of dual language use and its relationship to cognition in the presence of neuropathology. The current study will elucidate mechanisms underlying the relationship among bilingualism, neuroimaging markers of pathology, and cognitive function, which has the potential to inform novel interventions to preserve cognitive function and reduce ADRD disparities.


Discovery and validation of genetic variants affecting microglial activation in Alzheimer's disease
Philip L. De Jager, MD, PhD & William Kreisl, MD
1RF1AG070438-01

Determining how genetic regulation of microglia relates to neuroinflammatory changes seen in Alzheimer's disease is expected to inform future strategies to predict and prevent cognitive decline and progression to dementia. In this innovative proposal, Drs. De Jager and Kreisl will combine autopsy, PET, and human cell measures of microglial activation to create a multimodal investigation into the genetic architecture of microglial responses. Mapping the variants that regulate microglial activation and determining their functional consequences will provide key insights into prioritizing potential therapeutic targets for drug development and creating novel outcome measures with which to guide clinical trial design.


Microglia antigen presentation in the CNS of Alzheimer's Diseasee
Wassim Elyaman, PhD & Elizabeth Bradshaw, PhD
1R01AG067581-01

The finding of the human leukocyte antigen (HLA) region of the innate immune system being genetically associated with late-onset Alzheimer's disease (LOAD) further emphasizes the question of how microglia, the antigen-presenting cells of the central nervous system (CNS), interact with infiltrating T cells, which have been observed in the hippocampus of AD patients. In this proposal, Drs. Elyaman and Bradshaw propose to study isolated immune populations from the CNS of individuals with AD, to examine the phenotype, antigens being presented, and antigen reactivity of individual single-immune cells. Further, they will examine the interaction of the pathogen hypothesis and the CNS immune cells in the human system, to determine if these neuroinvasive pathogens are neurovirulent in AD.


Diet and Cognition within a Reserve Framework
Yian Gu, PhD
1R01AG061008-01A1

Mediterranean-type diet has been increasingly identified as playing an important role in preventing Alzheimer’s disease and cognitive decline in the elderly, but the mechanisms remain unclear. Several reserve concepts, including brain reserve, brain maintenance, and cognitive reserve, collectively explain individual differences in cognition, function, or clinical status relative to aging and brain disease. In this proposal, using data from two well-established imaging cohorts, Dr. Gu will examine the respective roles of brain reserve, brain maintenance, and cognitive reserve in relation to cognitive benefits of the Mediterranean-type diet.


Electrophysiological Evaluation of Brain Regions Vulnerable to Alzheimer’s Disease
Syed Abid Hussaini, PhD
1R01AG064066-01A1

This project will investigate which among the two brain regions—the entorhinal cortex or the locus coeruleus—is more vulnerable to amyloid beta and tau pathologies in Alzheimer’s disease mice. The project will utilize in vivo electrophysiology and optogenetic techniques combined with computational data analytics to identify and restore neuronal dysfunction.


Understanding How Activity Drives Diverse Spine Structural Interactions
Inbal Israely, PhD
1R01NS112485-01A1

Information is believed to be encoded at the cellular level through alterations in synaptic weights, and changes in connections between neurons are correlated with structural modifications of spines, such as growth or elimination. Additional forms of plasticity also impinge on these structures, such as homeostatic modulation of synaptic strength. With this first R01 for Dr. Israely, her lab will use two-photon imaging and glutamate uncaging to test a variety of plasticity mechanisms at individual spines and between groups of spines, to understand with high precision how information is physically stored in the brain.


Microglial TREM2 Interactome in Alzheimer's Disease
Tae-Wan Kim, PhD
1R01AG067606-01

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune modulatory receptor expressed in microglia, the brain's immune cells. Coding variants in TREM2 have been identified as risk factors for Alzheimer's disease (AD). The current proposal is to study how TREM2 protein interacts with other proteins in microglial cells. Dr. Kim aims to establish a protein-protein interaction map of TREM2 in microglial cells and to discover novel TREM2-interacting proteins that are critical for TREM2-mediated microglial functions relevant to AD.


Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer's disease
 William C. Kreisl, MD
1R01AG063888-01A1

While neuroinflammation is a proposed contributor to Alzheimer's disease (AD), the spatial and temporal relationship among inflammation, tau pathology, and neurodegeneration remains unclear. With this first R01, Dr. Kreisl aims to determine how microglial activation, measured with PET imaging, is spatially and temporally related to tau pathology and neurodegeneration in AD.



Understanding the Mechanisms Linking Small Vessel Cerebrovascular Disease and Alzheimer's disease Pathophysiology with Neurodegeneration and Cognition During Midlife
Patrick Lao, PhD
1K99AG065506-01

With this Pathway to Independence Award, Dr. Lao proposes to use advanced multimodal neuroimaging and statistical techniques to elucidate the extent to which small vessel cerebrovascular disease (svCBVD) and Alzheimer’s disease (AD) pathophysiology are additive or synergistic in their effects on neurodegeneration and cognition in a community-based, middle-aged, multiethnic cohort. Outcomes from this proposal will provide key information about the mechanisms by which svCBVD and AD pathophysiology interact at the earliest stage of their development to affect neurodegeneration and cognition, and inform clinical trials on the relevant target(s) in dementia with mixed pathology that can be generalized to racially/ethnically diverse populations.


Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order
Richard Mayeux, MD, MSc
1R01AG067501-01

For the past 25 years, Dr. Richard Mayeux and his Laboratory for Genetic Epidemiology team have investigated the genetic bases of familial and sporadic Alzheimer’s disease (AD) in Caribbean Hispanics. Despite identifying many genetic variants, the function of only a fraction of the relevant genes is fully understood. In this new proposal, Dr. Mayeux and team intend to conduct a genetically driven, epidemiological inclusive integration of AD in Caribbean Hispanics using deep molecular phenotyping--epigenomics, transcriptomics, proteomics, and metabolomics--to investigate genetic variants that perturb pathways leading to disease.


Elucidating Changes in Astrocyte Subpopulations Associated with Resistance to Alzheimer's Disease Pathology in Multiethnic Cohorts
Vilas Menon, PhD
1R01AG066831-01

Whereas Alzheimer's Disease (AD) generally manifests in cognitive decline and brain pathology in the form of plaques and tangles, a subset of aged individuals show AD-like pathology without the corresponding cognitive decline. Initial post-mortem analysis of brain tissue from these “resistant” individuals has highlighted changes in the composition of a specific class of non-neuronal cells called astrocytes, suggesting that distributions of these cells may confer protection against AD pathology. This proposal aims to shed light on astrocytes and coordinated changes in their composition with other cells at the molecular level, thus furthering our understanding of the disease, and potentially identifying sets of therapeutic avenues to counter cell type- dysregulation in AD.


Impaired Spatial Decoding and Neural Population Code Rescaling in AD Mice
Gustavo Rodriguez, PhD
1K01AG068598-01

Considerable evidence exists to support the notion that amyloid beta (Aβ) and tau pathology impair neuronal circuit integrity and function in Alzheimer’s disease (AD). Unfortunately, few studies have tested the direct influence of AD pathology on spatial computation within affected neuronal populations, resulting in an information gap at the neuronal network level. With this K01 Mentored Research Scientist Development Award, Dr. Rodriguez will test the overarching hypothesis that Aβ and tau associated neuronal network dysfunction impairs task-relevant, spatial information encoding in large populations of neurons within the EC-HIPP circuit, and that combating this aberrant activity can restore order and improve spatial information processing in AD mice.


Targeting Caspase-2 in Alzheimer's Disease
Michael Shelanski MD, PhD
1R21AG063012-01A1

Research published over the past 15 years has pointed to a critical role of the enzyme Caspase 2 in Alzheimer's disease (AD). Transgenic animals carrying human Amyloid Precursor Protein (APP) genes develop extensive amyloid plaques and show increasing memory impairment and synaptic loss. When Caspase 2 is removed from these animals, the amyloid plaques develop but the synaptic loss and memory impairment do not occur. Cell culture work has demonstrated that Caspase 2 is necessary for Aβ induced synaptic dysfunction and cell death. These results, taken together with the observation that Caspase 2 activity is increased in human AD, suggest that Caspase 2 is a potential therapeutic target for AD treatment. In this proposal, the laboratory of Dr. Michael Shelanski will examine two highly specific methods of inhibiting Caspase 2. The first uses a cell permeable form of siRNA to diminish the amount of Caspase 2 in the brain, while the second uses a newly developed agent, RAIDDpep, which blocks the activation of Caspase 2. These agents will be tested for their ability to block the cognitive and synaptic effects of Aβ in the J20 APP transgenic mouse and in mice where Aβ is introduced acutely by stereotaxic injection. The results of this work have the potential to open a new avenue for AD therapy.


Alzheimer’s Disease Research Center
Scott Small, MD (PI)
1P30AG066462-01

Since its inception 30 years ago, the ADRC at Columbia has established an elaborate infrastructure for research, fostered interdisciplinary collaborations, established a rich training environment, and promoted outreach and patient recruitment. At the same time the Center has become an active participant in a more global network comprised of other institutions, national consortia, and community organizations. This proposal for a new P30 ADRC will build off of these prior accomplishments, and will be motivated by two general goals. The first goal is to continue, as in previous cycles, to foster all research on AD and related disorders. The second goal is to support a theme focusing on ‘biological pathways’ implicated in AD pathogenesis. We propose to achieve these goals through our well-integrated cores, which collectively establish an infrastructure that generates a rich array of resources, biospecimens, and expertise.


Characterizing the Computational and Neural Basis of Deficits in Decision Making in Alzheimer’s
 Scott Small, MD
1R21AG067108-01

In this proposal, Dr. Small, together with mutual PI Dr. Michael N. Shadlen (Zuckerman Institute), will combine psychophysics and computational modeling to characterize the neural computations affected in decision making in patients with Alzheimer's disease (AD). They will mimic the behavioral deficits seen in AD by disrupting persistent activity in parietal cortex of the macaque monkey while they perform the same decision making task. The project will provide invaluable insight into the relationship between neural activity, neural computations, and behavioral deficits in AD.


Changing Lives, Changing Brains: How Modern Family and Work Life Influences ADRD Risks
 Yaakov Stern, PhD
1R01AG069109-01

Current changes in modern family life and work are likely to have important effects on the risk of Alzheimer's disease and related dementias (ADRD), yet work and family trajectories as pathways and moderators of ADRD risk are understudied. In this proposal, Dr. Stern's lab will study life-course effects of and interactions between family and work in adulthood for risk of ADRD and cognitive impairment in older adults. This will be done by exploiting the exceptional Norwegian HUNT (Nord-Trondelag Health Study) dataset, a large ongoing prospective population that includes cohorts born 1900 – 1960, combined with Norwegian national registry data. The results will help to identify "sensitive periods" over the life course and how they mediate genetic risks of cognitive decline and ADRD.



Genetic and Environmental Risk Factors in Mestizos and Indigenous Populations of Peru: The Role of Native Component in Alzheimer's Disease
 Giuseppe Tosto, MD, PhD
1R56AG069118-01

In this proposal, Dr. Tosto aims to investigate the role of Native American ancestry on late-onset Alzheimer's disease (LOAD) by studying the genetics of indigenous populations of the Peruvian Andes, not yet represented in genetic studies. Dr. Tosto will collect demographics, extensive cognitive testing, lifestyle metrics and blood for DNA extraction and biomarkers from ~1,000 Aymara and Quechua individuals, age 60 or older, located in Arequipa and Puno along with additional 1,000 mestizos from an ongoing cohort in Lima, Peru. These populations will provide valuable information because of their specific genetic background (predominant Amerindian ancestry, low frequency of APOE-e4 allele) and their low prevalence of cardiovascular risk factors and diseases (which, in turn, impact cognitive impairment and dementia). In addition to elucidating the role of Native American ancestry in LOAD, this project will expand the diversity of cohorts with available genetic data for the scientific community.



Characterizing Complex Structural Variation in Alzheimer's Disease
 Badri Vardarajan, PhD
1U01AG068028-01

Structural Variants (SVs) could contribute to some of the missing heritability of Late-Onset Alzheimer’s Disease (LOAD). However, SVs have been not been accurately and thoroughly characterized in sequencing studies due to challenges in detection and validation of structural rearrangements. To address this gap in knowledge, Dr. Vardarajan and co-PI Dr. Michael C. Zody (New York Genome Center) propose to comprehensively characterize SVs in LOAD using whole-genome sequencing data generated as part of the Alzheimer’s Disease Sequencing Project (ADSP), as well as additional long-read sequencing available through collaborators, which could identify novel locus disease relationships leading to putatively novel therapies.



Gene Discovery in Multiethnic Late Onset Alzheimer's Disease Families
 Badri Vardarajan, PhD
1U01AG066752-01

In this proposal, Dr. Vardarajan and co-PI Dr. Suzanne Leal (Sergievsky Center for Statistical Genetics) propose a powerful approach to study rare variants (RVs) in extended families with large numbers of affected individuals, where they are likely to aggregate and have stronger effect sizes. The major goal of this proposal is to analyze sequencing data from ~1000 families of non-Hispanic white, Hispanic, and African American ancestry to identify variants and genes that confer risk of late-onset Alzheimer’s Disease (LOAD). Drs. Vardarajan and Leal will apply existing and novel family-based analytics to identify LOAD susceptibility genes that can be tested as therapeutic targets.



Preclinical Markers of Alzheimer's Disease Using Psycholinguistic Semantic Measures
 Jet Vonk, PhD
1K99AG066934-01

The number of individuals with clinical Alzheimer's disease (AD) is rapidly increasing worldwide due to aging of the population, but current cognitive measures lack sufficient sensitivity and specificity to detect subtle decline within the preclinical phase. There is a critical need for tools that are sensitive to AD neuropathology during the preclinical phase that are low-cost, high-access, and fast to administer that can be used across educationally, linguistically, and culturally diverse older individuals. The goal of this project is to identify metrics for semantic impairment in diverse individuals that correlate with AD neuropathology and predict clinical decline.



Uncovering Stress-Induced Mechanisms of Tau Pathology in Alzheimer's Disease
 Clarissa Waites, PhD
1RF1AG069941-01

Clinical and epidemiological studies show that chronic psychological stress and elevated levels of glucocorticoids (GCs), the major stress hormones, are associated with increased risk of developing AD. However, very little is known about how stress triggers or exacerbates AD pathomechanisms. In this innovative and interdisciplinary proposal, the laboratory of Dr. Waites aims to elucidate the cellular and molecular mechanisms of stress/GC-induced Tau accumulation and secretion. Using various cell biological approaches, Dr. Waites and team hope to reveal whether there are robust markers of stress that can be detected in exosomes across sex, AD model, and tissue type. Overall, these studies will illuminate cellular mechanisms by which stress/GCs induce Tau-related neurotoxicity, and lead to novel therapeutic targets and biomarkers for AD diagnosis and treatment.


Foundation Awards 2020


A SUMO2 Mimetic to Modify the Progression of Alzheimer’s Disease
Ottavio Arancio, MD, PhD
Weston Foundation via University of Toronto

The goal of this project is to investigate safety and PK of a peptidomimetic SUMO2 molecule, PLB002, as well as its efficacy against amyloid elevation.


A Computational Approach to Predict Early Symptoms of AD
Syed Abid Hussaini, PhD
Alzheimer's Association

The goal of this project is to probe the Lateral Entorhinal Cortex (LEC)--one of the most vulnerable regions affected by Alzheimer's disease--and apply a computational approach to identify dysfunction earlier than currently possible.


Understanding How Blood-Borne Factors improve the Function of the Aging Brain
Scott Small, MD
Simon’s Foundation

The purpose of the proposed study is to elucidate the cellular and molecular mechanisms underlying the rejuvenating effects of BBB-permeable and impermeable systemic factors on the aged brain.


Human Tissue Banking for the Huntington’s Disease Research Community
Jean Paul Vonsattel, MD
Hereditary Disease Foundation

The New York Brain Bank at Columbia University has a long tradition of providing families with diagnoses of neurodegenerative diseases of their loved ones and supplying carefully characterized human tissues for research. This project expands the autopsy service for Huntington's disease (HD) individuals and will provide additional research tissues, including other organs implicated in HD, such as cardiac and skeletal muscle, to help provide better insight into disease mechanisms and therapies for HD patients.


ADRC Development Project Awards 2020


High Throughput Identification of Regulators of Neuroinflammatory Processes in Alzheimer's disease
Alejandro Chavez, MD, PhD (PI), with Taub Collaborators Andrew Sproul, MD, PhD and Gunnar Hargus, MD, PhD

The goal of this proposal is to use CRISPR-Cas9 based gene modulation coupled with a series of high-throughput in vitro and in vivo assays to assess the role of >100 genes predicted through genome-wide association studies as associated with AD, focusing on those associated with neuroinflammatory responses and susceptibility to cell death.


Neurodegeneration Associated with COVID-19 Infection, and the Role of Neuroinflammation
Anna Nordvig, MD, MS Candidate (PI), with Taub Faculty Mentor Karen Marder, MS, MPH

The goal of this proposal is to investigate blood biomarkers of neurodegeneration (neurofilament light chain and phosphorylated tau) in acute COVID-19 patients and compare these to normal controls and controls with dementia, collected in the same time period. Dr. Nordvig hopes that her findings will contribute to our understanding of how an acute inflammatory "hit" may associate with unmasking or predisposition to neurodegeneration.


Examining SORL1 as a new biomarker of endosomal trafficking for Alzheimer’s Disease
Sabrina Simoes, PhD (PI)

Endosomal pathway dysfunction is a well-accepted event in Alzheimer’s disease cellular pathophysiology. Lacking and urgently needed are biomarkers of this pathway that can detect endosomal dysfunction in living patients. This proposal is designed to develop such biomarkers.




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