Alzheimer Disease

Alzheimer disease is the primary focus of the research done within the NGI. We have several ongoing, funded projects dedicated to understanding more about what causes Alzheimer disease and what we can do to detect it earlier and potentially treat it.

Alzheimer Disease Endophenotypes GeneticsThe Familial Alzheimer Sequencing (FASe) project
Recent genetic studies of complex traits and diseases have focused on the identification of common variants associated with risk through genome-wide association studies (GWAS).
In this study, we will use GWAS and sequence data data to identify variants, genes and pathways associated with cerebrospinal fluid levels of known AD biomarkers (tau, ptau, Aβ, YKL40, VILIP1) and other AD-related proteins (CLU, APOE, TREM2), and other AD-related endophenotypes
Funded by the NIA

The aim of this research is to identify rare functional variants with large effect size on risk for Alzheimer’s disease (AD).
We hypothesize that families with extensive history of dementia are enriched for genetic risk factors and that by sequencing those families, we will identify rare variants with large effect size. In this project, we will combine sequencing data in families with late-onset AD and genotyping data in large case-control series. FASe
Funded by the NIA
Early Onset Alzheimer Disease (EOAD)Amyloid PET Neuroimaging

Mutations in the APP, PSEN1, and PSEN2 genes, which follow Mendelian inheritance patterns explain only 10% of EOAD cases. Large-scale, whole-genome sequencing is needed to identify additional EOAD-associated variants that explain the remaining 90% of cases.
We are collaborating with investigators at Columbia University and University of Miami to perform a large, whole-genome sequencing study including thousands of EOAD cases and controls.
We expect to identify novel genetic contributors to EOAD, uncover mechanisms of AD, and provide a basis for the development of novel therapeutics.
Funded by the NIA
This image has an empty alt attribute; its file name is Imaging-1024x692.jpgNeuroimaging, using positron emission tomography (PET), has emerged as a non-invasive way to measure the accumulation of amyloid and hyperphosphorylated tau in the brain at early stages of the Alzheimer disease process.
We work with other researchers at WashU to use amyloid imaging data from multiple, multiethnic cohorts to identify genes and variants associated with amyloidosis. With biomarkers, detectible from early disease stages, we can identify the genetic variations that contribute to these early warning signs, form prediction models based on these variants, and possibly identify drug targets to slow or reverse these early changes.
TREM2 variantsMulti-tissue Multi-omics

While 1-2% of AD cases are inherited dominantly with mutations in APP, PSEN1, and PSEN2, most cases occur sporadically.
One goal of our research has been to identify genetic changes that explain some of the heterogeneous nature of sporadic AD cases. To this end, we have identified variants in TREM2 that are associated with increased risk of AD. The effect of these variants impacts the interaction between TREM2 and MS4A4A proteins.
Using this knowledge, we are able to add another level of stratification in our other studies based on TREM2 status. This enables us to identify other differences between seemingly similar AD cases based on a patient’s genetic background.
Funded by the NIA
Experimental process of Multi-Omic and Functional Genomics analysisTo completely understand a disease, such as Alzheimer disease, it is not enough to study it from a single angle. only the relationship between gene variants and disease status in a single tissue, even if it clinically relevant (e.g. brain for AD). For this reason, we have committed to the study of multiple “omic” layers, including transcriptomics, proteomics, lipidomics, and metabolomics in multiple tissue that are clinically relevant to AD diagnosis and treatment.
We are leveraging our access to large, well-characterized AD and control cohorts with brain, CSF, and plasma tissue samples. We plan to use high-throughput, multi-comic methods and advanced computational approaches, such as machine learning, to identify genes, pathways, molecular signatures, and potential biomarkers and drug targets for AD. This knowledge will lead to better informed risk prediction, diagnostics, and treatment of AD. Multi-tissue Multi-omics
Circular RNAsTransposable Elements
Alzheimer’s disease (AD) results from complex interactions of risk factors that cause pleiotropic changes in molecular networks linking a host of biological processes. A variety of genetic factors contribute to risk with varying degrees of penetrance. It is not understood how the transcriptomic and molecular changes are organized into networks and how the implicated pathways are modulated in AD. Brain transcriptomic studies have helped identify novel genes and networks involved in AD, but most of them focus on linear transcripts. Dr. Cruchaga recently developed the first human brain atlas of circRNAs. This proposal will systematically identify additional circRNAs implicated in AD and functionally characterize circHOMER1, which has consistently been associated with AD risk. CircRNA
Funded by the National Institute on Aging.
Transposable elements, small segments of foreign DNA able to move and inset in various sites in the genome, have been implicated in neurodegeration, including Alzheimer disease. Recent genetic studies have highlighted the role of not only neurons but also microglia in the pathogenesis of AD. Therefore, to fully understand the biology of the disease there is a need to perform depth molecular characterization in a cell-specific manner. The overall goal of this proposal is to identify and characterize neuronal and microglia-specific TE and downstream (chromatin accessibility, transcript levels and new transcript) changes implicated on disease. Functional characterization of TE implicated in disease will also be instrumental to identify potential therapeutical targets. Transposable elements
Funded by the National Institute on Aging.
Press release
Comprehensive identification of molecular changes during AD time course
Dr. Carlos Cruchaga Zenith Fellowship Award will provide critical support to perform extensive testing on brain cells, cerebrospinal fluid and plasma collected at the Knight Alzheimer Disease Research Center. The final goal is to characterize, in high detail, molecular changes in gene expression, proteins, lipids and metabolites during Alzheimer’s disease progression.
Funded by The Zenith Fellows Award Program.
Press release.

Rare Diseases
Alzheimer’s Biomarker Consortium – Down SyndromeDystonia Coalition
We are contributing to a project led by the University of Pittsburgh that focuses on the connection between Alzheimer disease and Down syndrome (DS).
Trisomy 21, the cause of DS, results in an extra copy of the APP gene and overproduction of Aβ. This, coupled with increasing lifespans of those with DS is leading to a rise in the prevalence of AD in this community. The underlying biology of DS provides an unparalleled opportunity to identify biomarkers of preclinical AD.
The Cruchaga Lab is focused on the task of identifying other genes on chromosome 21 that may contribute to the development of AD in those with Down syndrome.
Funded by the NIA
We are part of a multi-institution study of movement disorders called isolated dystonias.
The overall project seeks to establish a fundamental understanding of these diseases that will be necessary for the development of future treatments.
The Cruchaga Lab is focused on the investigation of bio samples to identify potential biomarkers, with the hope of providing improved diagnostic and severity markers for different types of dystonia.
Funded by the NINDS
COVID-19 and Dementia
COVID-19 has recently been linked to persistent cognitive deficits, and faster progression of Alzheimer disease symptoms and pathology.
We have begun to investigate the impact of COVID-19 infections within our current AD cohorts.
In collaboration with other institutions, we will investigate whether there are underlying genetic factors associated with infection by the SARS-CoV-2 virus, and acute outcomes and post-acute sequelae.
We will also explore the bidirectional interaction between SARS-CoV-2 infection and memory decline and dementia.
Funded by the NIA

Stroke Genetics
Illustration of stroke bioprocesses
Stroke is the second leading cause of death throughout the world, and the leading cause of long-term disability.
In the first hours after stroke onset, neurological deficits can be highly unstable, with many patients improving while others deteriorate. These early changes have a major impact on long-term outcome. The goal of this research is to identify genetic variants associated with early neurological outcome after ischemic stroke …