Our ultimate goal is to probe the genes we identify as molecular substrates for therapeutic intervention against neurodegenerative diseases such as Alzheimer's and frontotemporal dementia.
To learn about our past work, see our Publications
Our Projects
Here is an overview of some of the projects happening here at Team NINGIA (New Innovations: Neurogenetics in Aging)!
FTD Center Without Walls (CWOW)
CWOW seeks to improve our understanding of the pathobiological mechanisms underlying FTLD-tau by engaging a diverse transdisciplinary team of scientists. CWOW is structured to enable researchers to systematically identify, test, and share novel insights across multiple institutions. By synergizing our research efforts and creating opportunities for substantive scientific interactions, CWOW creates an efficient pipeline for assessing the functional impact of variation in tau metabolism genes that may promote risk for tauopathy. Our unique team of experts in distinct, complementary disciplines will allow for highly synergistic interactions, where the whole will be much greater than the sum of the parts.
Our Goals
- To understand the normal process of tau metabolism as a series of decisions made at regulatory nodes
- To identify and test the functional relevance of genetic variants in MAPT and other tau-metabolism genes
- To create a Tau Metabolism and Variant Database (TMVdb) providing functional annotation to MAPTand other tau-metabolism genes
- To create a Tau Polygenic Risk Score (TPRS) to stratify genetic risk for tauopathy
We envision that our work to understand the fundamental biology of tau metabolism will impact the broader field of neurodegeneration research and launch subsequent investigations into tau toxicity and pathobiology. Ultimately, we hope that our findings will translate into uplifting the lives of our patients. Please visit the FTD CWOW website to learn more!
Collaborators
Gene Discovery in Early-Onset AD and FTD
Using statistical genetics methodologies, we probe the genome to identify genetic variation associated with risk for (or resilience against) neurodegeneration in diverse populations. This includes analysis of deep resequencing and genotypic data to identify genetic contributions to neurodegeneration and its related phenotypes including brain structure, clinical syndrome, and cognitive function. In addition to common and rare coding and noncoding variants, we also study the effects of immune and mitochondrial gene diversity on cognitive health and neurodegeneration.
Our goals are two-fold: to identify new genetic predictors of disease risk and to elucidate underlying disease mechanisms that may be amenable to therapeutic intervention.
Collaborators
ReDLat (So Amer project)
The Multi-Partner Consortium To Expand Dementia Research In Latin America (ReDLat) combines technological advancements in genomics and neuroscience with the unique genomic diversity of Latin America to uncover novel disease biology in understudied populations. ReDLat provides a platform for the coordinated investigation of neurodegenerative diseases in Latin America, using harmonized clinical and genetic characterization, neuroimaging, banked biospecimens, and the study of social determinants of health.
The long-term goal is to identify the unique genetic markers and socioeconomic variables (SEV) that drive Alzheimer's disease (AD) and Frontotemporal dementia (FTD) presentation in Latin American countries relative to the US. To this end, we will establish a cohort totaling 4,000 participants, including 2,000 controls, 1,000 AD patients, and 1,000 FTD patients. Our main goals are:
- To establish the genetic contributions to AD and FTD in diverse Latin American cohorts;
- To determine whether genetic risk and SEV yield better discrimination between Latin American and US patients as compared with other cognitive, neuroimaging, and clinical variables;
- To elucidate the impact of SEV on clinical, cognitive, and brain imaging signatures in Latin America and the US.
ReDLat brings together institutions in Colombia, Brazil, Argentina, Peru, Chile, Mexico, and the USA. The site PIs represent world experts in the diagnosis, clinical care, and biomedical research. The consortium is currently funded by the National Institutes of Health (NIH/NIA R01 AG057234MPIs: Ibanez/Miller/Yokoyama/Possin), the Alzheimer's Association (PIs: Valcour and Yokoyama), the Tau Consortium (PIs: Possin and Ibanez), and the Global Brain Health Institute (GBHI).
Collaborators
Bruce Miller and Agustin Ibanez
ReDLat and NIH-CARD
The ReDLat consortium is delighted to be collaborating with the NIH Center for Alzheimer’s and Related Dementias (CARD). Through this partnership CARD provides scientific, computational, and training support for ReDLat to facilitate the project’s goals to expand dementia characterization in diverse and underrepresented populations. Members of the Yokoyama lab are currently working with collaborators at CARD to develop novel tools for data analytics relevant to ReDLat objectives.
Collaborators
Mike Nalls, Caroline Pantazis, Andrew Singleton
Asian American AD Genetics
The Asian Cohort for Alzheimer’s Disease (ACAD), is the first large Alzheimer’s Disease (AD) genetics cohort for Asians in United States (US) and Canada. To optimize ACAD’s success, our team is comprised of scientists, clinicians, and community partners with collaborative history and expertise in AD research, human genetics, and Asian community outreach.
We propose to recruit 5,970 participants aged 60 years or older and of Chinese, Korean, and Vietnamese ancestry from metropolitan areas across the US and Canada in collaboration with community partners, clinics, or nursing homes that serve Asian communities. We will collect saliva for DNA and use validated, localized instruments, data forms, and clinical/diagnostic protocols. To support these recruitment and data collection activities, we will set up a coordinating center and develop governance, community outreach and training programs to support recruitment and analysis activities, and conduct a process evaluation of the recruitment and outreach efforts. All samples will be genotyped using SNP arrays and imputed using a large Asian-specific reference panel of whole genome sequencing data from international Asian cohorts. We will analyze genetic and clinical data to investigate impact of lifestyle risk factors, genetic variants for AD risk, evaluate differential effects of sex and APOE genotypes on AD risk, and predict clinical diagnosis of AD using genetic and lifestyle risk scores. We will replicate these findings through meta-analysis collaborations with international Asian cohorts and AD studies from other populations.
Comprising 6% of the US populace, Asian Americans are under-sampled and deserve more scientific investment in Alzheimer’s disease research. The ACAD project will build the first major AD genetics study for Asians in the US and Canada. Successful completion will lead to new genetic and lifestyle screening markers for Asian Americans and insights about novel therapeutic targets for AD. ACAD will be a first network for recruiting and studying AD in Asian Americans that will extend to Asian Indians, Filipino and other Asian American populations in the future, serving the unmet needs of Alzheimer’s disease research for Asian Americans.
Collaborator(s)
Li-San Wang, PhD
Peripheral Gene Expression as a Biomarker in FTD
In order to effectively treat neurodegenerative disease prior to symptom onset, we need robust biomarkers to identify those at highest risk of developing disease and to identify the most likely underlying neuropathology. The overarching goal of this project is to use multi-‘omics information to identify individuals at risk for neurodegenerative disease due to tau vs. TDP-43 pathology. In doing so, we also hope to identify new targets for treating these disorders.
To achieve these goals, we are using whole-genome sequencing data coupled with gene expression data from blood and postmortem brain tissue to identify genetic “signatures” of neuropathology. Our goal is to establish these signatures in both familial and non-genetic forms of disease so that they may be used widely in all patient populations for drug treatment trials and, ultimately, for monitoring disease progression in the clinic. Identifying groups of genes that are expressed differently in patients with known tau pathology versus those with TDP-43 pathology will also provide a means of finding genetic variation that contributes to risk of each neuropathology.
Our study has the potential to provide a non-invasive method of tracking progression of neurodegenerative disease, enable monitoring of therapeutic efficacy for future treatments, and facilitate better predictions of disease risk in individuals prior to symptom onset.
Collaborators
John Ravits (UCSD) and William Seeley (UCSF)
Genetic Resilience to Neurodegenerative Disease
The variation in each of our unique genetic codes globally impacts our individual process of aging. Our research in resilience factors focuses on identifying genetic contributions to healthy brain aging and protection against neurodegenerative disease (either directly through disease resistance or indirectly through functional resilience in the presence of disease neuropathology). We do this by studying how this genetic variation is related to the brain’s structure and cognitive function.
By learning more about what healthy brain aging “looks like”, we can begin to understand and identify new targets for promoting cognitive resilience in aging and disease in all individuals.
Collaborators
Radiogenomics in the Developing and Aging Brain
Radiogenomics, defined as the combined use of radiologic imaging and genetic data, is an increasingly common strategy not only to predict clinical diagnosis and prognosis, but also to enhance the field’s understanding of the pathophysiologic processes underlying diverse conditions ranging from cancer and heart disease to dementia. Imaging and genetics are key tools in the clinical evaluation and scientific study of neurodegeneration. Taken together, genetic variation explains propensity to ultimately develop a complex phenotypic trait like neurodegenerative disease while imaging informs an individual’s state or progression toward that underlying phenotype. From a research perspective, imaging can be thought of as a continuous measure — or endophenotype — of disease progression and is thus better powered, relative to more complex symptom-based disease phenotypes, to detect subtle genetic effects.
We utilize radiogenomics methods to enhance our understanding of how genetic variation affects the brain and, conversely, to identify genetic loci associated with endophenotypes of disease. We do so across the lifespan--acknowledging that the variation in our genome is present throughout life and that the way our brain is 'built' in development may affect the way degenerates in aging.
Similarly, we leverage radiogenomics to gain a better understanding of how the same structures or brain circuits can be affected across neurological and neuropsychiatric diseases due to shared — as well as divergent — genetic contributions.
Collaborators
We lost our dear friend and colleague Rahul Desikan to ALS in the summer of 2019. We honor the memory of our dear friend and colleague, Dr. Rahul Desikan, by continuing his research through these projects, originally awarded to Rahul.
Traumatic Brain Injury and Alzheimer's Disease
W81XWH-19-1-0709 (9/20/19 – 9/19/22)
Department of Defense
The goal of this project is to examine whether Alzheimer’s disease (AD) polygenic hazard scores (PHS) and vascular PHS predict cognitive decline, vascular, and AD pathology among non-demented individuals with a history of traumatic brain injury.
Collaborators
PROJECT: Sex in Alzheimer's disease
R03-AG063260 (4/1/19 – 12/31/20)
NIH-NIA
This study will improve our understanding of how sex differences impact AD pathobiology to facilitate identification and recruitment of participants into clinical studies aimed at slowing cognitive decline and development of AD and dementia.
Collaborator
Genetic Data Sharing Guidelines in FTLD Research
This study aims to develop data management, disclosure, and sharing guidelines for researchers conducting studies in FTLD. In addition to filling this critical gap in the field, these guidelines would provide insight for other conditions similarly situated to benefit from robust data sharing guidelines that protect patient privacy. This study leverages unique expertise of its investigators to develop and disseminate genetic data sharing guidelines that aim to advance research while mitigating the ethical, legal, and social ramifications of mishandling sensitive data.
Collaborator
Tau Open Data
Scientific discovery is becoming increasingly transdisciplinary, requiring cutting-edge strategies that leverage big data and powerful analytical platforms while also providing equitable access via open data sharing and collaborative tools. The field of genomics research has been a leader in this arena, with large-scale national and international collaboration to support the advancement of our understanding of human disease, but this approach has thus far been lacking for tauopathy research.
The Tau Consortium is an ideal incubator for this collaborative model, uniting world-class research and innovation with the goal of curing tau-mediated neurodegeneration. Research from the Rainwater Charitable Foundation has spearheaded substantial improvements of our understanding of neurodegeneration due to tau pathology over the past decade. Nevertheless, effective treatments for tauopathy remain elusive; patients and stakeholders are eager to expedite identification of effective interventions for these disorders.
In addition to primary research, secondary data analysis provides the opportunity to make new scientific discoveries by leveraging existing datasets. Beyond their lower cost and faster turnaround times, secondary analyses provide the unique ability to identify intersecting findings across disparate datasets that converge upon new, and often overlooked, disease targets. Secondary analyses of data already generated by Tau Consortium investigators is an untapped and promising resource as the field continues to search for therapeutic targets. To fully capitalize on this available data and facilitate new research, we are developing a cloud-based platform to store and catalog ‘omics data in a configuration that enables rapid, open data sharing and promotes collaboration between investigators. In addition to building capacity to store and link large amounts of complex data across the Consortium, we are developing an embedded and complementary suite of online analysis tools to further expedite new discoveries in tau-related disorders.
Our long-term goal is to accelerate the discovery and development of treatments for tauopathy and related disorders by establishing an active, open research environment available to all researchers.
Collaborator(s)
Translational Research in Novel Genes Underlying ALS
We are excited to be collaborating on several projects with different basic scientists to follow up the clinical ramifications of genes of interest that they have identified—largely through unbiased studies—as potentially functionally relevant contributors to motor neuron diseases, including ALS.