Document text
Principal Investigator: Manolis Kellis
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $1,135,203
Funding agency: National Institute on Aging
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to dramatic effects on the
affected individuals and their families. While the characterization of the genetic contribution to AD and
underlying molecular mechanisms have advanced the understanding of the disease in recent years, studies
show that sex differences account for much of the observed differences in risk, progression, and severity
across individuals. Here, we directly dissect the contribution of sex-specific variation down to the region-
specific and cell-type-specific molecular basis by systematic profiling, computational integration, and
experimental validation of the transcriptional, epigenomic, and genetic signatures across individuals, brain
regions, and cell types. In Aim 1, we use genetic, epigenomic, and transcriptional profiles, generating millions
of single-cell (sc) level maps using scRNA-seq and scATAC-seq across human and mouse samples of varying
ages and genetic risk status. In Aim 2, we analyze the resulting datasets in the context of known AD genetic
risk variation and underlying molecular mechanisms, enabling us to discover and converge variants, regulatory
regions, genes, pathways, cell types, and brain regions to functional, causal mechanisms that drive sex-related
differences. In Aim 3, we use our well-established mouse and iPSC models to test our predicted mechanisms
with both high-throughput and cell-type specific assays. The resulting datasets, computational predictions, and
experimentally-supported mechanisms will shed light on the sex-related differences of AD and will help deepen
our understanding the disease in general as we develop more personalized therapeutic approaches in treating
AD.
Terms: <AD dementia><ATAC><Address><Affect><Age><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's patient><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid><Amyloid Substance><Assay><Autopsy><Autoregulation><Bioassay><Biological Assay><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Nervous System><Brain region><Categories><Cell Body><Cells><Cerebrovascular system><Chromosome Mapping><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Computing Methodologies><Cornu Ammonis><DNA><Data><Data Set><Degenerative Neurologic Disorders><Dementia><Deoxyribonucleic Acid><Development><Differences between sexes><Differs between sexes><Disease><Disorder><Dissection><Disturbance in cognition><Dysfunction><Electronic Health Record><Encephalon><Enhancers><Expression Signature><Family><Female><Foundations><Functional RNA><Functional disorder><Gene Expression Profile><Gene Localization><Gene Mapping><Gene Mapping Genetics><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Risk><Genetic Transcription><Genetic defect><Genetic study><Genomics><Genotype><Hemato-Encephalic Barrier><Heterogeneity><Hi-C><Hippocampus><Homeostasis><Hormonal><Human><Image><Impaired cognition><Individual><Intervention><Intervention Strategies><LPTN><Life><Link><Linkage Mapping><Lipids><Maps><Memory Loss><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Mechanisms of Action><Murine><Mus><Mutation><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Pathway interactions><Patients><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Primary Senile Degenerative Dementia><RNA Expression><Regulatory Element><Regulatory Regions><Research Resources><Resolution><Resources><Risk><Risk-associated variant><SCM-1><SCM-1a><SCM1><SCYC1><Sampling><Severities><Severity of illness><Sex Differences><Sexual differences><Synaptic plasticity><System><Testing><Total Human and Non-Human Gene Mapping><Transcription><Transcription Alteration><Untranslated RNA><Validation><Variant><Variation><XCL1><XCL1 gene><age associated alterations><age associated changes><age correlated alterations><age correlated changes><age dependent alterations><age dependent changes><age related alterations><age related changes><age specific alterations><age specific changes><ages><alterations with age><alzheimer risk><blood vessels in the brain><bloodbrain barrier><brain blood vessels><brain cell><brain control><brain vasculature><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cell type><cerebral blood vessel><cerebral vasculature><cerebrovascular vessels><cerebrovasculature><changes with age><cognitive dysfunction><cognitive loss><cohort><computational methodology><computational methods><computer based method><computer methods><computing method><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><disease severity><electronic health care record><electronic health medical record><electronic health plan record><electronic health registry><electronic medical health record><epigenome profiling><epigenomic profiling><epigenomics><frontal cortex><frontal lobe><gene expression pattern><gene expression signature><gene signatures><genetic mapping><genetic regulatory element><genetic signature><genome mutation><healthcare burden><hiPSC><hippocampal><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><imaging><in vitro Model><individualized therapeutic><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><interventional strategy><male><memory decline><mouse model><murine model><necropsy><neurodegenerative illness><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><noncoding><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><personalization of treatment><personalized medicine><personalized therapeutic><personalized therapy><personalized treatment><postmortem><primary degenerative dementia><promoter><promotor><resolutions><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scATAC sequencing><scATAC-seq><scRNA-seq><senile dementia of the Alzheimer type><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><therapeutic agent development><therapeutic development><transcriptional profile><transcriptional signature><validations>