Research

Research in our laboratory focuses on dementia (Alzheimer’s disease & frontotemporal dementia) and addiction (alcohol use disorder (AUD)). In each of these projects our goal is to understand the molecular basis of disease in order to identify novel targets for therapeutic development.

Alzheimer’s disease (AD): We use genetic and genomic approaches to identify susceptibility alleles, this work includes genome wide association studies (GWAS) and whole genome/exome sequencing in families multiply affected by disease and in case control cohorts. Since 2013 and the discovery of TREM2 as an AD risk factor (Guerreiro et al., 2013: PMID 2315094) we have focused on the role of myeloid cells in the genetics of AD. Using an integrative genomic approach we have identified a network of AD risk genes regulated by SPI1 another AD risk gene (Huang et al., 2017: PMID: 28628103) and demonstrated that these gene are enriched in microglial pathways connected to efferocytosis (the uptake and clearance of lipid rich debris) (Novikova et al., 2021:PMID: 33712570). We are using similar approaches to identify other gene regulatory networks important in regulating microglial transcriptional states. To validate these genetic findings we are using primary microglia and induced pluripotent stem cells (iPSCs) to model the effects of disease-associated variants in disease relevant cell types. We currently have ongoing projects to study SPI1 (Pimenova et al., 2021:PMID: 33301878); APOE (Machlovi et al., 2022: PMID: 35031484; TCW et al., Cell in press: biorxiv, MS4A4A/MS4A6A and EED. To complement these in vitro studies we are using a xenotransplantation model to introduce human induced microglia into the mouse brain as well as studies to knock-down or increase expression of the cognate mouse genes in collaboration with Dr. Anne Schaefer. Finally, we are using this genetic knowledge to identify novel pathways and targets for the development of therapeutics for AD. We have ongoing projects to develop therapeutics mimicking knock-down of SPI1 and MS4A4A/MS4A6A.

Frontotemporal Dementia (FTD): We use stem cell and genomic approaches to study autosomal dominant causes of tauopathy such as mutations within the MAPT gene. Using crispr genome editing and differentiation of isogenic lines into forebrain organoids we have developed a system that shows age dependent neurodegeneration and recapitulates the selective neuronal vulnerability seen in people with FTD (Bowles et al., 2021:PMID: 34314701). Single cell and bulk RNAseq have identified key pathways that become progressively dysregulated as the organoids age. A second project focused on tauopathies uses an integrative genomics approach to understand the differential risks for sporadic tauopathies associated with the H1/H2 haplotypes. These haplotypes differ from one another by a 1Mb inversion of chromosome 17q21.31. We are using brain tissue and iPSC cultures to determine how this inversion influences chromatin structure and gene expression/regulation to understand how these differences lead to changes in disease risk.

Alcoholism: Interestingly, our GWAS in alcoholism have identified shared genetic risk with neurodegenerative disease including SPI1 and the MAPT locus (Kapoor et al., 2021: PMID: 34417470). Our functional analyses are aimed at validating these and other genes identified in the genetic studies. One ongoing collaboration with the Slesinger lab seeks to understand how the potassium channel GIRK2, encoded by KCNJ6 influences alcoholism risk using iPSC-derived neurons.

Contact us

Goate Laboratory
Alison M Goate, DPhil
Jean C. & James W. Crystal Professor and Chair
Director, Ronald M. Loeb Center for Alzheimer’s disease
Dept. of Genetics & Genomic Sciences,
Icahn Genomics Institute
Icahn School of Medicine at Mount Sinai

Location
Lab: ICAHN 10-52
Office: ICAHN 10-70C
Phone
Office: 212-659-5672
Email:alison.goate@mssm.edu

Current Projects

Therapeutic effects of APOE regulation via LNP-RNA formulations in Alzheimer's disease

Goal: The project objective is to develop novel therapeutics targeting APOE to treat Alzheimer’s disease.

Collaborators: Edoardo Marcora and Yizhou Dong

NIH award: R01AG092823

Biology and Pathobiology of ApoE in Aging and Alzheimer’s Disease

Goals: This interdisciplinary U19 is a collaborative project with Washington University and Mayo Clinic. The project uses a multi-omic approach in human tissues, induced pluripotent stem cells and mouse models to determine the mechanisms underlying APOE risk for Alzheimer’s disease. The goal of protect is to identify and characterize genetic modifiers of APOE risk for Alzheimer’s disease using human populations and to model the impact of these modifiers in human cells using induced pluritpotent stem cells.

Collaborators: Edoardo Marcora, Alan Renton, Celeste Karch, David Holtzman and Takahisa Kanekiyo

https://epaad.org/about-apoe-u19

NIH award: U19AG069701

Uncovering the Genetic Mechanisms of the Chromosome 17q21.31 Tau haplotype on Neurodegeneration Risk in FTD and PSP

Goals: The goal of the FTD center without walls (CWOW), which is composed of two highly synergistic projects (P1, P2) and 4 cores (Proteomics, Human Tissue Validation, Data, Admin) is to understand the mechanisms of risk/protection for neurodegenerative disease conferred by the H1/H2 haplotypes around the MAPT locus. To do this we are combining multi-OMICs in human brain tissue samples and induced pluripotent stem cell models and validating pathways and genetic risk markers using crispr functional genomic screens.

Collaborators: Dan Geschwind & Tim Chang (UCLA), Martin Kampmann & Danielle Swaney (UCSF) and Lea Grinberg (Mayo Clinic)

http://geschwindlab.org/cwow/

NIH award: U54NS123746

Dominantly Inherited Alzheimer Network (DIAN): Genetics Core

Goals: DIAN is an observational study of individuals carrying mutations in APP or PSEN1/PSEN2 and their siblings. The Genetics Core receives participant blood samples from Clinical Core coordinators at all sites and banks DNA/RNA samples for OMICs studies.

Collaborators: Alan Renton, Carlos Cruchaga

NIH award: GR0029587

Defining Causal Transcription Factor Networks that Drive Protective or Pathogenic Microglia Phenotypes in Alzheimer's Disease

Goals: The Major Goals of this project are 1)identification of transcriptional, epigenetic and functional profile of iPSC-derived microglia lacking transcription factors, nominated through our prior bioinformatic analysis as a key drivers of disease-associated microglial network, in 2D and 3D in vitro models, and 2)integration of AD GWAS data with epigenomic and transcriptomic data to identify novel AD risk variants, GREs, and genes in microglia. We hypothesized that characterization of transcription factors functions and epigenetic landscape that they control may inform about therapeutic strategies to reprogram pathological states of microglia in Alzheimer’s disease.

Collaborators: Edoardo Marcora, Chris Glass and Matt Blurton-Jones

Supported by ADSF

Understanding the mechanism of MS4A-dependent AD risk

Goals: The goal of this research is to identify the causal gene(s) in the MS4A cluster (an AD-associated locus) and to use induced pluripotent stem cells and mouse models to investigate their role in AD pathogenesis. We will use this information to develop therapeutic agents targeting the causal mechanism.

Supported by Belfer Neurodegeneration Consortium

Neuroprotective Signaling and Transcriptional Pathways in Microglia Associated with Alzheimer’s Disease

Goals: Alzheimer’s disease (AD) remains a major public health problem with no disease modifying therapies. Converging evidence from human and mouse genetics implicates the gene encoding embryonic ectoderm development (Eed), an essential component of the epigenetic polycomb repressive complex 2 (PRC2), as a regulator of Trem2 signaling in microglia and AD risk. Our goal is to understand the mechanistic link between Eed and Trem2 and in the long term to target these pathways for therapeutics for AD.

Collaborators: Edoardo Marcora, Anne Schaefer, Alexander Tarakhovsky

NIH award: R01AG072489

Collaborative Study on the Genetics of Alcoholism (COGA)

Goal: COGA is an interdisciplinary project that integrates genetic, phenotypic and multi-omic data to better predict risk for alcohol dependence and related traits and to determine the mechanistic underpinnings of this disorder. We are using induced pluripotent stem cells from COGA participants to model genetic risk and determine the molecular and cellular mechanisms underlying risk.

Collaborators: Paul Slesinger and Gita Pathak at ISMMS, Bernice Porjesz, Jacqueline Meyers and Zoe Neale at SUNY Downstate

https://cogastudy.org/

NIH Award: U10AA008401

National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS)

Goals: The central goal of the NIA-AD FBS is to support research by making clinical data, samples and data generated from the samples broadly available to the AD research community. We continue to expand resources to support functional genomics by increasing biospecimen collections including additional DNA, plasma, PBMCs and postmortem brain tissue stored at the National Centralized Repository for Alzheimer’s Disease and Related Disorders for distribution to AD researchers, facilitating molecular profiling instrumental to prediction models that identify drug targets.

Collaborators: Richard Mayeux, Gary Beecham, Christiane Reitz and Tatiana Foroud

NIH award: U24AG056270

Integrative approaches to the identification of AD risk genes and novel therapeutics

Goals: The goal of this project is to explore the functional mechanisms underlying AD disease risk loci by performing in vitro studies using human iPSC-derived microglia and in vivo studies using xenotransplantation of human iPSC-derived hematopoietic progenitor cells into a mouse disease model and using an in silico approach to identify candidate drugs that can be repurposed to modulate myeloid AD risk gene networks or their master regulators.

Collaborators: Edoardo Marcora, Alan Renton

Supported by Freedom Together Foundation

Investigating MEF2C transcription factor as therapeutic targets to reprogram pathological microglial states in Alzheimer's disease

Goals: Our main goal is to understand how the AD-associated gene, MEF2C (myocyte enhancer factor 2C), affects brain debris clearance by human microglia to inform the development of novel therapeutic strategies.

Collaborators: Edoardo Marcora, Anna Podlesny-Drabiniok

Supported by Cure Alzheimer’s Foundation

Understanding the mechanism of LactB-dependent AD risk

Goals: The goal of this research is to use induced pluripotent stem cells and mouse models to investigate the mechanistic role of LactB in AD pathogenesis. We will use this information to develop therapeutic agents targeting the causal mechanism.

Supported by Belfer Neurodegeneration Consortium

Team

Edoardo M Marcora, PhD
Professsor
edoardo.marcora@mssm.edu

Alan E Renton, PhD
Assistant Professor
alan.renton@mssm.edu

Bartek Jablonski
Associate Director
bartek.jablonski@mssm.edu

Ellie Zhang
Executive Assistant
ellie.zhang@mssm.edu

Charlotte Labrie-Cleary
Lab Manager
charlotte.labrie-cleary@mssm.edu

Brian Fulton-Howard, Ph.D
Senior Scientist
brian.fulton-howard@icahn.mssm.edu

Ania Podlesny-Drabiniok, PhD
Instructor
anna.podlesny-drabiniok@mssm.edu

Tulsi Patel, PhD
Instructor
tulsi.patel2@mssm.edu

Carmen Romero-Molina, PhD
Instructor
carmen.romeromolina@mssm.edu

Francesca Garretti, PhD
Postdoctoral Fellow
francesca.garretti@mssm.edu

Chiara Pedicone, PhD
Postdoctoral Fellow
chiara.pedicone@mssm.edu

Hyo Lee, PhD
Postdoctoral Fellow
hyo.lee@mssm.edu

Michael Sewell, PhD
Postdoctoral Fellow
michael.sewell@mssm.edu

Hamilton Oh, PhD
Postdoctoral Fellow
hamilton.oh@mssm.edu

Alexandra E. Münch
Graduate Student
alexandra.munch@icahn.mssm.edu

Grace Peppler
Graduate Student
grace.peppler@icahn.mssm.edu

Nicholas Church
Graduate Student
nicholas.church@icahn.mssm.edu

Jeanne Kim
Graduate Student
jeanne.kim@icahn.mssm.edu

Alexander Frank
Graduate Student
alexander.frank@icahn.mssm.edu

Sun Hao
Graduate Student
hao.sun@icahn.mssm.edu

Danielle Picarello
Associate Computational Scientist
danielle.picarello@mssm.edu

Marcelina Ryszawiec
Associate Researcher
marcelina.ryszawiec@mssm.edu

Anthony Walley
Associate Researcher
anthony.walley@mssm.edu

Joshua Orrick
Associate Researcher
joshua.orrick@mssm.edu

Jae-Won Jang MD, PhD
Visiting Scholar
jaewon.jang@mssm.edu

Sarah Weitzman
Graduate Student
sarah.weitzman@icahn.mssm.edu

Wen Yi See
Associate Researcher
wenyi.see@mssm.edu

Publications

Goate Lab Gatherings

An Important Test for the Amyloid Hypothesis — November 4, 2016

Merck’s Director of Neuroscience Matthew Kennedy shares why these early results have him feeling hopeful. He is joined by Alison Goate, the director of the Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai. Read More

Daily Checkup: Alzheimer's disease expert identifies risk factors — November 29, 2015

As the director of the Ronald M. Loeb Center on Alzheimer’s Disease at Mount Sinai, Dr. Alison Goate specializes in researching the disease’s basic mechanisms to improve our treatment options. November is National Alzheimer’s Disease Awareness Month. Read More

Alzheimer's Association recognizes four scientists with Lifetime Achievement Awards at AAIC 2015 — July 21, 2015

The Alzheimer’s Association recognizes four leading scientists for their contributions to advancing Alzheimer’s disease and dementia research. The awards were presented during the opening session at the Alzheimer’s Association International Conference® 2015 (AAIC® 2015) in Washington, D.C. Read More

Genetic markers found to predict Alzheimer's — April 5, 2013

Scientists have identified early genetic markers that can potentially predict who is at an increased risk for developing Alzheimer’s, Medical Daily reported.Currently, in order to determine if someone will develop Alzheimer’s disease, doctors use tests that analyze the amount of Tau protein buildup in the central nervous system. The more Tau in an individual’s system, the more likely he or she will progress towards dementia. Read More

Dr. Goate elected into the National Academy of Medicine

“Election to the National Academy of Medicine is considered one of the highest honors in medicine,” says Dennis S. Charney, MD, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai. “The election of Drs. Goate and Richardson is a notable achievement and well-deserved recognition of each of their leadership efforts and important contributions to their particular fields of study.” Read More.

Machlovi et al., 2022 APOE4 confers transcriptomic and functional alterations to primary mouse microglia

Click Here

Huang et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

A genome-wide survival analysis of 14,406 Alzheimer’s disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. Read More.

TCW et al. An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells.

Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. Read More.

Pimenova et al. A Tale of Two Genes: Microglial Apoe and Trem2.

Microglial cell function is implicated in the etiology of Alzheimer’s disease by human genetics. In this issue of Immunity, Krasemann et al. (2017) describe a gene expression signature associated with an APOE- and TREM2-dependent response of microglia to brain tissue damage that accumulates in aging and disease, defining an axis that might be amenable to therapeutic targeting. Read More.