NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Dementia;Neurodegenerative;Neurosciences

PHR: Project Narrative: The proposed research is relevant to public health because it provides an innovative approach for linking age-related dysfunction within a specific brain area to cross-regional communication disruptions. By understanding how local impairments alter systems-level network function, it will be possible to promote the development of interventions that broadly improve cognition and meet a mission of the NIA to advance our understanding of age-related cognitive decline.

PI_NAMEs: BURKE, SARA N (contact)

PROJECT_TERMS: Age;age difference;age related;age related changes;Age-associated memory impairment;aged;Aging;aging brain;Alzheimer's Disease;Alzheimer's disease related dementia;American;Anatomy;animal old age;Area;Behavior;behavior measurement;behavioral impairment;behavioral outcome;Brain;Brain region;Cells;Censuses;Cognition;Cognitive;Cognitive aging;cognitive function;cognitive training;Colon;Communication;Compensation;Complex;Data;designer receptors exclusively activated by designer drugs;Development;Direct Costs;Elderly;executive function;experience;experimental study;fluorescence imaging;frontal lobe;functional decline;Functional disorder;Functional Magnetic Resonance Imaging;functional MRI scan;functional restoration;Goals;Hippocampus;human old age (65+);Image;Impaired cognition;Impairment;improved;in vivo;Individual;innovation;Intervention;juvenile animal;Knowledge;late life;Light;Link;medial temporal lobe;Mediating;Memory;Methodology;Mission;Modality;multitask;neglect;Nerve Degeneration;neural network;Neurobiology;Neurons;neurophysiology;older adult;Pathology;Patient Care;Pattern;Performance;Positioning Attribute;Prefrontal Cortex;programs;Property;Psyche structure;Public Health;Quality of life;Rattus;Reporting;Research;Rest;restoration;Risk Factors;sensory input;Series;Structure;support network;System;Task Performances;Techniques;Testing;therapeutic development;therapeutically effective;therapy development;Tissues;Training;United States;United States National Institutes of Health

PROJECT_TITLE: The contribution of declines in functional connectivity to cognitive aging


ADMINISTERING_IC: AG

ARRA_FUNDED: N

ED_INST_TYPE: SCHOOLS OF MEDICINE

FUNDING_MECHANISM: NON-SBIR/STTR RPGS

IC_NAME: NATIONAL INSTITUTE ON AGING

NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Genetics;Human Genome;Neurodegenerative;Neurosciences;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_CITY: MINNEAPOLIS

ORG_COUNTRY: UNITED STATES

ORG_DEPT: NEUROLOGY

ORG_FIPS: US

ORG_NAME: UNIVERSITY OF MINNESOTA

ORG_STATE: MN

PHR: PROJECT NARRATIVE While APOE4 is identified as the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD), the molecular mechanisms underlying the pathogenic nature of APOE4 are not fully elucidated. Motivated by our novel findings, we will characterize in this renewal application, the regulation of microglial function by the APOE-synj1-PIP2 signaling pathway during AD development with in vivo studies of humanized APOE mouse models, ex vivo microglial culture and 3-D co-culture system of human iPSC-derived brain cells, as well as validation studies of human brain samples. The scRNA-seq data from mouse brains and RNA-seq data from human iPSC-derived brain cells will be integrated to perform high resolution multiscale network modeling and to elucidate novel pathways and molecular signatures underlying APOE4-induced neuroinflammation in AD.

PI_NAMEs: CAI, DONGMING  (contact)

PROGRAM_OFFICER_NAME: DIBATTISTA, AMANDA

PROJECT_TERMS: 3-Dimensional;Abeta clearance;Acceleration;Age Months;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease pathology;Amyloid beta-Protein;apolipoprotein E-3;apolipoprotein E-4;Astrocytes;autocrine;Autopsy;Axon;Axotomy;Brain;brain cell;Chronic;Coculture Techniques;Cognitive;cognitive performance;Complex;Cuprizone;cytokine;Data;Data Set;Defect;Degradation Pathway;Demyelinations;Development;Disease;Enzymes;Etiology;Excision;Female;Fluorescence;follow-up;Functional disorder;Funding;genetic risk factor;Goals;Homeostasis;Human;human data;human induced pluripotent stem cells;human RNA sequencing;hyperphosphorylated tau;immune function;Impaired cognition;Impairment;in vivo;induced pluripotent stem cell;Inflammation;Inflammatory;inorganic phosphate;Knock-in;Label;Lipids;Liposomes;Lysosomes;male;Microglia;Molecular;Molecular Profiling;Morphology;motor deficit;mouse model;Mus;Myelin;Nature;network models;Neurites;neuroinflammation;novel;paracrine;Pathogenesis;Pathogenicity;Pathology;Pathway Analysis;Pathway interactions;Phagocytes;Phagocytosis;Phenotype;Phospholipids;Pilot Projects;Play;Process;Regulation;remyelination;Resolution;Role;Sampling;sex;Signal Pathway;Signal Transduction;single-cell RNA sequencing;spatial relationship;Synapses;Synaptosomes;synergism;SYNJ1 gene;System;targeted treatment;Time;transcriptome sequencing;TREM2 gene;validation studies

PROJECT_TITLE: Characterization of ApoE4 Induced Phospholipid Dysregulation in AD Pathogenesis

STUDY_SECTION: CDIN

STUDY_SECTION_NAME: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]


ED_INST_TYPE: SCHOOL OF MEDICINE & DENTISTRY

NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Clinical Research;Coronaviruses;Coronaviruses Disparities and At-Risk Populations;Dementia;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Health Services;Networking and Information Technology R&D (NITRD);Neurodegenerative;Neurosciences;Prevention;Primary Health Care;Racial and Ethnic Minority Health Research;Social Determinants of Health;Telehealth

ORG_CITY: ROCHESTER

ORG_DEPT: PUBLIC HEALTH & PREV MEDICINE

ORG_NAME: UNIVERSITY OF ROCHESTER

ORG_STATE: NY

PHR: Project Narrative: This proposed research aims to examine the effect of CMS' telemedicine policy on health care utilization among community-dwelling older adults with ADRD, and its variations by race/ethnicity. This proposed research is highly relevant to public health because the findings from this study will provide valuable and timely information on how this public policy affects the older population with ADRD, and provide implications on reducing racial disparities in health among this already vulnerable population.

PI_NAMEs: CAI, SHUBING  (contact)

PROGRAM_OFFICER_NAME: NOVAK, PRISCILLA JOY

PROJECT_TERMS: Accounting;Acute;Adopted;Affect;Alzheimer's disease related dementia;Ambulatory Care;Behavioral Symptoms;beneficiary;Black Populations;Black race;burden of illness;Caregivers;Caring;Chronic;Communities;comorbidity;COVID-19;COVID-19 mortality;COVID-19 pandemic;Data;Dementia;Devices;digital;Dimensions;Disparity;Educational Status;Emergency department visit;Equity;ethnic disparity;ethnic health disparity;ethnic minority;Ethnic Origin;Event;experience;Face;Future;Health;health care disparity;health care service utilization;health disparity;Health Services Accessibility;High Prevalence;high risk;hispanic community;Hispanic Populations;Hospitalization;Impaired cognition;improved;Individual;informal caregiver;innovation;Interruption;Interview;Lead;Measures;medical specialties;Medicare;Methods;older adult;Older Population;outpatient programs;Outpatients;pandemic disease;Persons;Policies;Population;post-pandemic;prevent;Primary Care;Psychiatry;psychological symptom;Public Health;Public Policy;Race;racial disparity;racial health disparity;racial minority;Reporting;Research;Risk Reduction;Role;SARS-CoV-2 exposure;SARS-CoV-2 infection;Series;Services;Socioeconomic Status;Statistical Models;Telecommunications;Telemedicine;Telephone;Testing;Time;treatment as usual;United States Centers for Medicare and Medicaid Services;Variant;Visit;Vulnerable Populations

PROJECT_TITLE: Telemedicine and health disparities among community-dwelling older adults with ADRD during COVID-19 pandemic

STUDY_SECTION_NAME: Special Emphasis Panel[ZRG1-PSE-W(56)R]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Dementia;Genetics;Neurodegenerative;Neurosciences

ORG_CITY: NEW YORK

ORG_DEPT: NEUROSCIENCES

ORG_NAME: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI

PHR: Project Narrative: Aging, the strongest risk factor for Alzheimer’s disease, causes detrimental changes in various cell populations in the brain, yet we have little understanding of the mechanisms tying aging to Alzheimer’s-related brain changes. This proposal investigates how exposure to youth-associated blood-borne proteins act through the innate immune cells of the brain to revitalize cognition using several levels of analysis, including gene expression, cellular, and behavioral assessments. Insights gained from pursuing this concept will inform therapies at the intersection between aging and Alzheimer’s disease as well as those directed towards neuroimmune interactions.

PI_NAMEs: CASTELLANO, JOSEPH MICHAEL (contact)

PROJECT_TERMS: Address;adult neurogenesis;Affect;Affinity Chromatography;Age;age related;age-related disease;aged;Aging;aging brain;aging related;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Alzheimer's disease therapy;Amyloid;Amyloid deposition;Amyloidosis;Behavior assessment;Blood;Body System;bone;Brain;brain cell;Brain Diseases;brain dysfunction;CCL11 gene;Cells;cellular targeting;Central Nervous System;Cognition;Cognitive;cognitive change;Cognitive deficits;cognitive function;cognitive performance;Colony-Stimulating Factors;combat;Combined Modality Therapy;Data;Dendritic Spines;Dependence;Deposition;Disease associated microglia;Environment;Exhibits;Exposure to;Functional disorder;Gene Expression;Gene Expression Profile;Genetic study;Genetic Transcription;Gliosis;Goals;Heart;Hippocampus;Human;Immune;Impairment;improved;Injections;innate immune function;insight;Learning;Lesion;Link;Liver;Mediating;Memory;Microglia;Modeling;Molecular;Morphology;mouse model;Mus;Muscle;Myelogenous;neurogenesis;Neuroimmune;Neuronal Plasticity;normal aging;novel;novel strategies;novel therapeutics;old mice;Organism;Pancreas;Parabiosis;Pathologic;Pathology;Pathway interactions;Phenotype;Plasma;Population;Proteins;Regulation;Rejuvenation;Reporting;response;Ribosomes;risk variant;Role;therapy development;Tissue Inhibitor of Metalloproteinases;Tissues;transcriptome sequencing;Transgenic Model;Translating;treatment strategy;Wild Type Mouse;Work;Youth

PROJECT_TITLE: Mechanisms of youth-associated blood-borne factors regulating CNS rejuvenation


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease Related Dementias (ADRD);Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Lewy Body Dementia;Neurodegenerative;Neurosciences;Parkinson's Disease

ORG_CITY: ATLANTA

ORG_DEPT: PHARMACOLOGY

ORG_NAME: EMORY UNIVERSITY

ORG_STATE: GA

PHR: Project Narrative Lewy body dementia is the second most common form of dementia in the elderly, with no effective means of diagnosis, prevention, or disease-modifying therapy. The proposed research will use an innovative approach and cutting-edge technologies to discover and study disease mechanisms and molecular targets for development of biomarkers and therapeutics to treat this debilitating dementia.

PI_NAMEs: CHIN, LIH-SHEN  (contact)

PROGRAM_OFFICER_NAME: PETANCESKA, SUZANA

PROJECT_TERMS: Acceleration;Accounting;Address;Affect;Age;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease patient;Alzheimer's disease related dementia;Animal Model;Antipsychotic Agents;Asparagine;Autopsy;Biochemical;Biological;Biological Markers;Biological Process;biomarker development;Brain;brain tissue;case control;Cell Physiology;Cell surface;Cells;Cellular Structures;Clinical;clinical diagnosis;Coupled;curative treatments;Cytoplasm;Dementia;Dementia with Lewy Bodies;Diagnosis;Disease;disease mechanisms study;Drug Targeting;Elderly;experimental study;extracellular;follow-up;Functional disorder;Genomics;Glycoproteins;glycoproteomics;glycosylation;Golgi Apparatus;Human;human disease;Impaired cognition;innovation;insight;Knowledge;Lewy Body Dementia;Lysosomes;Membrane Proteins;Molecular;Molecular Abnormality;Molecular Analysis;Molecular Target;motor symptom;multiple omics;Neurobehavioral Manifestations;Neurodegenerative Disorders;neuropathology;neuropsychiatric symptom;novel;Organelles;Paper;Parkinson's Dementia;Parkinsonian Disorders;Pathogenesis;Pathogenicity;Pathway Analysis;Pathway interactions;Patients;Pharmacotherapy;Phenotype;Polysaccharides;Post-Translational Protein Processing;prevent;Prevention;Protein Conformation;Protein Secretion;Proteins;Proteome;Proteomics;Research;response;Role;Science;Source;Study models;Symptoms;Syndrome;targeted biomarker;Technology;Therapeutic;therapeutic development;trafficking;transcriptomics;Validation

PROJECT_TITLE: Molecular and Network Analyses of Lewy Body Dementia Pathogenesis

STUDY_SECTION: CNN

STUDY_SECTION_NAME: Clinical Neuroscience and Neurodegeneration Study Section[CNN]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Behavioral and Social Science;Brain Disorders;Clinical Research;Dementia;Genetics;Mental Health;Neurodegenerative;Neurosciences

ORG_DEPT: PSYCHIATRY

ORG_NAME: COLUMBIA UNIVERSITY HEALTH SCIENCES

PHR: PROJECT NARRATIVE Alzheimer’s disease (AD) is one of the most persistent and devastating dementias because it eventually leads to a complete loss of memory and the ability to function independently. Patients with AD have abnormal levels of an important neurotransmitter regulatory molecule called BH4, and our previous studies have shown that giving BH4 to psychiatric patients with abnormal BH4 levels helps restore their memory deficits. In this study, we will test if 1) AD patients also have memory deficits due to abnormal levels of BH4 produced by a BH4 gene, and 2) if we can restore this gene pathway and treat cognitive impairment in mouse models of BH4 loss and AD, which may lead to new treatment of memory loss in AD, targeted to patients with BH4 abnormalities.

PI_NAMEs: CLELLAND, CATHERINE L (contact)

PROGRAM_OFFICER_NAME: GROTHAUS, PAUL G

PROJECT_TERMS: 3xTg-AD mouse;Alleles;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;American;Amines;Anabolism;Animal Disease Models;Behavioral;Biochemical;Biological Assay;Central Nervous System;Clinical;clinical efficacy;clinically relevant;cofactor;Cognition;Cognitive;cognitive ability;Cognitive deficits;cognitive function;Consensus;Control Groups;cost estimate;Coupled;Data;Data Set;Dementia;differential expression;Disease;disease phenotype;Dopamine;Down-Regulation;drug development;drug repurposing;efficacy testing;Enzymes;Exhibits;Functional impairment;Future;Genes;Genetic Polymorphism;Genotype;Glutamates;Impaired cognition;improved;in vivo;Individual;interest;Investments;Learning;Lovastatin;Measures;Memory;Memory impairment;Memory Loss;Mental disorders;Messenger RNA;Methods;mild cognitive impairment;Modeling;Molecular;mouse model;Neuropsychological Tests;Neurotransmitters;Nitric Oxide;Norepinephrine;NR4A2 gene;Outcome;Pathway interactions;patient population;Patients;Peripheral;Pharmaceutical Preparations;Phenotype;Physiological;Plasma;preclinical study;promoter;Psychiatric therapeutic procedure;Randomized, Controlled Trials;Regulation;Reporting;Research;restoration;Sampling;Schizophrenia;secondary outcome;sepiapterin;Serotonin;Societies;success;System;targeted agent;Testing;tetrahydrobiopterin;Tetrahydrobiopterin deficiency;Therapeutic;treatment effect;Treatment Failure;Valproic Acid;Variant

PROJECT_TITLE: Tetrahydrobiopterin Effects on Cognitive Function in Alzheimer's Disease: Biochemical, Molecular and Cognitive Analysis


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Genetics;Neurodegenerative;Neurosciences;Prevention

ORG_CITY: SAINT LOUIS

ORG_DEPT: PATHOLOGY

ORG_NAME: WASHINGTON UNIVERSITY

ORG_STATE: MO

PHR: PROJECT NARRATIVE Alzheimer's disease (AD) is the most common form of dementia. Genetic and pathology studies have suggested that certain brain cells, known as microglia, slow down disease progression, but to do so they need a molecule called TREM2. We propose experiments to understand how TREM2 activates microglia, why TREM2 is not functional in AD, and whether an antibody that actvates TREM2 can be used in the therapy of AD in a mouse model.

PI_NAMEs: COLONNA, MARCO  (contact)

PROGRAM_OFFICER_NAME: OPANASHUK, LISA A

PROJECT_TERMS: abeta accumulation;Affect;Age Years;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Alzheimer's disease therapy;American;Amyloid beta-Protein;Antibodies;Anxiety;Automobile Driving;Behavior;Biology;Brain;brain cell;Cognitive;Complement;Complex;Data;Dementia;Disease;Disease associated microglia;Disease Progression;Dose;Environment;Epigenetic Process;experimental study;extracellular;Frequencies;Functional disorder;gain of function;Gene Dosage;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic study;Genetic Transcription;Grant;Heterozygote;Human;hyperphosphorylated tau;Immunofluorescence Immunologic;improved;Injections;insight;Lead;Learning;Lesion;loss of function;Memory;Metabolic;Microglia;Monoclonal Antibodies;mouse model;Mus;Neuroglia;neuron loss;neurotoxicity;Outcome;overexpression;Pathogenesis;Pathology;Pathway interactions;Patients;Peptides;Peripheral nerve injury;Phenotype;Play;preventive intervention;Preventive treatment;Productivity;Proliferating;Publishing;receptor;Regimen;Reporting;response;risk variant;Role;Senile Plaques;Signal Pathway;Signal Transduction;single nucleus RNA-sequencing;single-cell RNA sequencing;Specimen;Synapses;tau aggregation;tau Proteins;Testing;Therapeutic;Therapeutic Intervention;Thinness;trait;transcription factor;Transcriptional Activation;TREM2 gene;Variant

PROJECT_TITLE: TREM2 IN MICROGLIA BIOLOGY AND ALZHEIMER'S DISEASE

STUDY_SECTION: CMBG

STUDY_SECTION_NAME: Cellular and Molecular Biology of Glia Study Section[CMBG]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Dental, Oral, and Craniofacial Disease;Digestive Diseases;Infectious Diseases;Microbiome;Neurodegenerative;Neurosciences;Prevention

ORG_CITY: GRAND FORKS

ORG_DEPT: OTHER BASIC SCIENCES

ORG_NAME: UNIVERSITY OF NORTH DAKOTA

ORG_STATE: ND

PHR: Narrative Periodontal disease has been associated with increased risk of dementia and Alzheimer’s disease although no causitive relationship has been established. Our preliminary data demonstrated the presence of Aβ peptide in saliva in an Alzheimer’s disease transgenic mouse model. This correlated with a unique profile of oral bacteria in diseased mice as well as increased numbers of cavities and enamel thinning in males. Based upon our rodent findings, it appears that Alzheimer’s disease changes are present in the oral cavity. Monitoring these changes may be useful correlates of disease progression. Alternatively, a novel mouth-brain interaction may be involved in disease progression.

PI_NAMEs: COMBS, COLIN K (contact)

PROGRAM_OFFICER_NAME: MARIC, MAJA

PROJECT_TERMS: AD transgenic mice;Affect;Age;Age Months;age related neurodegeneration;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Amyloid beta-Protein Precursor;amyloid precursor protein processing;Amyloidosis;Bacteria;Behavior;beta secretase;Blood;Brain;Characteristics;Colon;Communication;Complex;cytokine;Data;demented;dementia risk;Dental Enamel;Dependence;Diffuse;Disease;Disease Progression;dysbiosis;Exhibits;fecal microbiome;Feces;Female;Fluorides;Functional disorder;gastrointestinal;Gastrointestinal tract structure;Gliosis;gut-brain axis;Health;Human;human disease;immunoreactivity;inhibitor;innovation;Intestinal Mucosa;male;Mediating;Memory;microbial;microbiome;Monitor;mouse model;Mus;Nature;novel;Oral;oral bacteria;Oral cavity;Oral health;oral microbiome;Patients;Peptides;Performance;Periodontal Diseases;Peripheral;Persons;Population;prevent;Process;Property;Reporting;Risk;Rodent;Role;Saliva;saliva secretion;Salivary;Salivary Glands;Sampling;Severities;stool sample;Swab;tau-1;Testing;Thick;Thinness;Tooth Loss;transcriptome sequencing;Transgenic Mice;Weaning;Wild Type Mouse;Work

PROJECT_TITLE: Oral Cavity and Brain Cross-talk in Alzheimer's Disease


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease Related Dementias (ADRD);Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Amyotrophic Lateral Sclerosis (ALS);Biotechnology;Brain Disorders;Clinical Research;Dementia;Frontotemporal Dementia (FTD);Gene Therapy;Genetics;Neurodegenerative;Neurosciences;Orphan Drug;Rare Diseases;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_CITY: SAN FRANCISCO

ORG_NAME: J. DAVID GLADSTONE INSTITUTES

ORG_STATE: CA

PHR: PROJECT NARRATIVE The Alzheimer’s-related disease frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two fatal and incurable neurodegenerative diseases linked by a shared genetic cause – a heterozygous hexanucleotide (GGGGCC) repeat expansion in a single allele of the C9orf72 gene. The goal of this work is to use patient induced pluripotent stem cells (iPSCs) and CRISPR gene editing to reveal novel therapeutic gene editing approaches. The gene editing strategies we are developing are applicable to other repeat expansion and single gene disorders, potentially including genetic cases of Alzheimer’s disease and other dementias.

PI_NAMEs: CONKLIN, BRUCE R (contact)

PROGRAM_OFFICER_NAME: LI, TONG

PROJECT_TERMS: Address;Alleles;ALS patients;Alzheimer's Disease;Alzheimer's disease related dementia;Amyotrophic Lateral Sclerosis;Biological Assay;Biology;c9FTD/ALS;C9ORF72;Cell Line;Cell Physiology;cell type;Cells;cellular pathology;Chromosome 13;Clustered Regularly Interspaced Short Palindromic Repeats;Code;CRISPR/Cas technology;curative treatments;Dementia;Disease;disease phenotype;DNA;effective therapy;Engineering;Enhancers;Excision;Exons;experimental study;fitness;Frontotemporal Dementia;frontotemporal lobar dementia amyotrophic lateral sclerosis;Functional disorder;Future;gain of function;gene editing technology;Gene Expression Regulation;Gene Silencing;gene-editing approach;Genes;Genetic;Genetic Enhancer Element;Genetic Polymorphism;Genome;Genomic Segment;Goals;Heterozygote;Human;human disease;human induced pluripotent stem cells;in vivo;induced pluripotent stem cell;Induced pluripotent stem cell derived human neuron;Induced pluripotent stem cell derived neurons;Knock-out;Learning;Link;loss of function;Mendelian disorder;Methods;Motor Neurons;Mus;Mutagenesis;mutant;Mutation;Neurodegenerative Disorders;Neuronal Dysfunction;Neurons;novel;novel therapeutic intervention;novel therapeutics;Nucleic Acid Regulatory Sequences;Nucleotides;Pathogenicity;Pathology;patient derived induced pluripotent stem cells;Patients;Phenotype;postmitotic;preservation;promoter;Regulation;Regulatory Element;repaired;risk variant;Safety;Series;Site;stem cell model;System;Technology;Testing;Therapeutic;therapeutic genome editing;Therapeutic Uses;therapy design;Time;Untranslated RNA;Work

PROJECT_TITLE: C9orf72 frontotemporal dementia (FTD) and amyotrophic lateral sclerosis(ALS): using patient cells and CRISPR to reveal therapeutic approaches

STUDY_SECTION: MNG

STUDY_SECTION_NAME: Molecular Neurogenetics Study Section[MNG]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Bioengineering;Biomedical Imaging;Brain Disorders;Clinical Research;Data Science;Dementia;Machine Learning and Artificial Intelligence;Networking and Information Technology R&D (NITRD);Neurodegenerative;Neurosciences;Prevention

ORG_CITY: CLEVELAND

ORG_DEPT: INTERNAL MEDICINE/MEDICINE

ORG_NAME: CLEVELAND CLINIC LERNER COM-CWRU

ORG_STATE: OH

PHR: Project narrative The proposed study is highly relevant to public health because advanced mathematical and statistical methods will allow for more in-depth analysis of high-resolution fMRI data, in particular, data used in the characterization of brain function, which offers significant potential for more effective diagnosis and treatment of Alzheimer’s disease (AD). This study will investigate memory activation in the medial temporal lobes with high-resolution imaging at 7 Tesla with multivariate analysis to identify brain dysfunction in prodromal AD. The methods developed from the findings acquired in this study will have a far-reaching influence on MRI/fMRI research in neurodegenerative diseases by improving fMRI data quality, facilitating automated and instantaneous brain segmentation, and more accurately identifying individuals at risk for AD.

PI_NAMEs: CORDES, DIETMAR  (contact);LOWE, MARK J

PROGRAM_OFFICER_NAME: HSIAO, JOHN

PROJECT_TERMS: 3-Dimensional;Acceleration;Affect;Age;Algorithmic Software;Algorithms;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease pathology;Alzheimer's disease risk;Alzheimer’s disease biomarker;amnestic mild cognitive impairment;Amyloid;Amyloid Proteins;automated segmentation;Automobile Driving;Brain;Brain Diseases;brain dysfunction;cerebral atrophy;cognitive function;Consumption;Data;Data Analyses;data fusion;data quality;Data Set;deep learning;deep neural network;denoising;dentate gyrus;Deposition;design;Detection;Development;Diagnosis;Diagnostic Imaging;Diagnostic tests;diagnostic tool;Elderly;Encephalitis;Episodic memory;Functional disorder;Functional Imaging;Functional Magnetic Resonance Imaging;Head;high resolution imaging;Hippocampus;Image;imaging biomarker;improved;Individual;interest;Lead;Machine Learning;Magnetic Resonance Imaging;Manuals;Maps;mathematical methods;medial temporal lobe;Memory;Memory impairment;memory process;Methodology;Methods;Modality;Modeling;Motion;Multimodal Imaging;Multivariate Analysis;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurosciences;Noise;novel;Pattern;Performance;Physiological;Physiological Processes;Populations at Risk;Positron-Emission Tomography;prevent;prodromal Alzheimer's disease;Property;Protocols documentation;Public Health;Reproducibility;Research;Research Personnel;Resolution;Rest;Signal Transduction;Software Tools;Specific qualifier value;Statistical Methods;structural imaging;System;Techniques;Technology;Testing;Time;user friendly software;Weight;Work

PROJECT_TITLE: Machine and deep learning for finding multimodal imaging biomarkers in prodromal AD


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Genetics;Neurodegenerative;Neurosciences;Prevention

ORG_CITY: HOUSTON

ORG_DEPT: GENETICS

ORG_NAME: BAYLOR COLLEGE OF MEDICINE

ORG_STATE: TX

PHR: Project Narrative: Results from this study are important for public health. Improvement of healthy aging and prevention of Alzheimer’s disease (AD) in the elderly represents a big challenge for pubic health. This study will provide new insight into the signaling role of lysosomal NADPH metabolism in proteostasis, aging and AD as well as address many fundamental issues in organelle homeostasis, cellular signaling, and aging biology.

PI_NAMEs: DANG, WEIWEI  (contact)

PROGRAM_OFFICER_NAME: OROSZ, ANDRAS

PROJECT_TERMS: abeta accumulation;Active Sites;AD transgenic mice;Address;Age;age related;age related neurodegeneration;Aging;aging process;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid beta-Protein;Animal Model;Attenuated;Binding;Biochemical;Bioinformatics;biological adaptation to stress;Biology of Aging;Brain;Caenorhabditis elegans;Cell Nucleus;Cells;ChIP-seq;Dedications;design;detection of nutrient;Development;Disease;Disease Progression;effective therapy;Elderly;Endoplasmic Reticulum;endoplasmic reticulum stress;Enzymes;Epigenetic Process;extracellular;fitness;fluorescence lifetime imaging;FRAP1 gene;Future Generations;Gene Expression;Genes;Genetic Transcription;hallmarks of aging;Health;healthspan;healthy aging;Histones;Homeostasis;Homologous Gene;Human;Hydrolysis;hyperphosphorylated tau;improved;innovation;insight;Knockout Mice;Knowledge;Link;Longevity;loss of function mutation;Lysosomes;Mediating;Metabolic;Metabolism;metabolomics;Methods;microscopic imaging;Molecular;mouse model;Mus;Mutation;NADP;Nervous System;Neurodegenerative Disorders;Neurons;novel;Nuclear;Nuclear Hormone Receptors;nucleotide metabolism;Organelles;Organism;Pathogenesis;Pathologic;Pathway interactions;Phosphoric Monoester Hydrolases;Physiological;Play;Post-Translational Protein Processing;prevent;Prevention;Promoter Regions;protective effect;protein aggregation;Protein Biosynthesis;Proteins;Proteome;Proteomics;proteostasis;proteostasis loss;Public Health;Quality Control;Regulation;Resolution;response;RNA interference screen;Role;Signal Pathway;Signal Transduction;Societies;Tauopathies;Time;Transcriptional Regulation;transcriptome sequencing;transcriptomic profiling;vacuolar H+-ATPase

PROJECT_TITLE: Lysosomal NADPH metabolism regulates proteostasis, aging and tauopathy

STUDY_SECTION_NAME: Special Emphasis Panel[ZRG1-CB-L(02)M]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Dementia;Genetics;Machine Learning and Artificial Intelligence;Mental Health;Neurodegenerative;Neurosciences

ORG_CITY: BOSTON

ORG_DEPT: BIOLOGY

ORG_NAME: HARVARD MEDICAL SCHOOL

ORG_STATE: MA

PHR: Narrative In Alzheimer's disease (AD), changes in movement often presage cognitive decline; in these proposed experiments, we will characterize behavioral changes in mouse models of AD using advanced machine learning techniques, and ask how AD-related pathophysiological lesions might lead to altered neural codes and therefore changes in movement.

PI_NAMEs: DATTA, SANDEEP R (contact)

PROGRAM_OFFICER_NAME: ST  HILLAIRE-CLARKE, CORYSE

PROJECT_TERMS: 3-Dimensional;Address;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Behavior;behavior influence;Behavioral;behavioral phenotyping;behavioral study;Biological Assay;Biological Markers;Cessation of life;Characteristics;Code;Cognition;Cognitive;cognitive change;cognitive performance;Confusion;Corpus striatum structure;Data;Disease;disease phenotype;Disease Progression;Emotional;Evolution;Exhibits;experimental study;Failure;Financial cost;Functional disorder;Gait;Genes;Genetic;Histopathology;Human;Impaired cognition;Intervention;Joints;Laboratories;Left;Lesion;life span;loss of function;Machine Learning;machine vision;Memory Loss;Methods;Moods;Motion;Motor;mouse model;Mouse Strains;Movement;movement analysis;Mus;Mutate;Mutation;neural;neural circuit;neural correlate;neurobehavioral;Neurofibrillary Tangles;normal aging;novel;object recognition;Pathology;Pattern;Phenotype;Population;pre-clinical;Pre-Clinical Model;Predictive Value;Prevalence;Risk;Sampling;Self Direction;Sensory;Societies;Supervision;Support System;Techniques;Testing;Time;unsupervised learning;Withdrawal

PROJECT_TITLE: Neurobehavioral phenotyping of AD model mice using Motion Sequencing


ADMINISTERING_IC: NS

ED_INST_TYPE: SCHOOLS OF ARTS AND SCIENCES

IC_NAME: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

NIH_SPENDING_CATS: Genetics;Neurosciences;Rare Diseases

ORG_CITY: CHAMPAIGN

ORG_DEPT: PHYSIOLOGY

ORG_NAME: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN

ORG_STATE: IL

PHR: PROJECT NARRATIVE  Missense mutations in neural precursor cell expressed developmentally down-regulated gene 4-like (Nedd4L) are associated with periventricular nodular heterotopia (PNH), a rare neurological disorder caused by impaired cortical neuron migration. Our recent work suggests that Nedd4L functions to promote cofilin phosphorylation and subsequent actin polymerization, both of which are critical to neuronal migration. We will test the hypothesis that Nedd4L, which is an E3 ubiquitin ligase, ubiquitinates certain phosphatases to promote cofilin phosphorylation, and PNH-associated missense mutations on Nedd4L impair this process and neuronal migration.

PI_NAMEs: LEE, KWAN YOUNG ;TSAI, NIEN-PEI  (contact)

PROGRAM_OFFICER_NAME: LEENDERS, MIRIAM

PROJECT_TERMS: actin depolymerizing proteins;Actins;Adolescence;Affect;Affinity;Binding;brain malformation;C-terminal;Catalytic Domain;Cells;Clinical;cofilin;conditional knockout;Cytoskeletal Proteins;Data;Defect;design;Development;excitatory neuron;Exhibits;experience;Funding;Genes;Homeostasis;Impairment;improved;Individual;insight;Intelligence;Knock-out;Knockout Mice;Lead;learned behavior;Learning Disorders;Link;loss of function;Mediating;Microfilaments;migration;Missense Mutation;Molecular;mouse model;mutant;Mutation;nerve stem cell;Nervous System Disorder;Neuronal Dysfunction;Neurons;Neurophysiology - biologic function;Peptides;periventricular heterotopia;Permeability;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Point Mutation;polymerization;Polymers;Predisposition;prevent;Process;Prosencephalon;Protein Dephosphorylation;Protein Isoforms;Proteins;Rare Diseases;Reporting;Research;response;Risk Factors;Role;Seizures;Testing;therapeutic target;tool;ubiquitin-protein ligase;Ubiquitination;Work

PROJECT_TITLE: Study of Nedd4L in Periventricular Nodular Heterotopia

STUDY_SECTION_NAME: Special Emphasis Panel[ZTR1 RD-1 (01)]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease Related Dementias (ADRD);Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Atherosclerosis;Biomedical Imaging;Brain Disorders;Cerebrovascular;Dementia;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Neurodegenerative;Neurosciences;Racial and Ethnic Minority Health Research;Vascular Contributions to Cognitive Impairment and Dementia (VCID)

ORG_CITY: WINSTON-SALEM

ORG_NAME: WAKE FOREST UNIVERSITY HEALTH SCIENCES

ORG_STATE: NC

PHR: Project Narrative The specific molecular mechanism(s) linking vascular factors to AD remains unclear. Here we propose that molecular characterization of neurovascular cells-derived exosomes could serve as a reliable biomarker for AD and help us to understand better the cause-effect relationship between vascular risk factors and AD pathogenesis across multi-races/ethnic groups

PI_NAMEs: DEEP, GAGAN  (contact);HUGHES, TIMOTHY M.

PROGRAM_OFFICER_NAME: LUO, YUAN

PROJECT_TERMS: abeta deposition;adjudication;African American;African American population;Age;age difference;Alzheimer disease prevention;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer's disease risk;Alzheimer’s disease biomarker;Amyloid beta-Protein;apolipoprotein E-4;Astrocytes;Biological Markers;biomarker development;Blood;Blood specimen;Blood Vessels;Brain;cell type;Cells;cerebrovascular;Cerebrovascular Disorders;Circulation;Cognition;Cognitive;cognitive testing;cohort;Collection;Constitution;Data;Dementia;density;Development;Disparity;Endothelial Cells;Endothelium;ethnic disparity;Ethnic Origin;Ethnic Population;Exclusion;exosome;Gender;Genetic;Heterogeneity;Hippocampus;Hispanic Populations;Hypoxia;imaging biomarker;Immune;Impaired cognition;Injury;insight;Light;Link;Lipid Binding;liquid biopsy;magnetic beads;Magnetic Resonance Imaging;Mediator;Methods;Microglia;MicroRNAs;Mind;Molecular;Multi-Ethnic Study of Atherosclerosis;multi-racial;multimodal neuroimaging;nanovesicle;Nerve Degeneration;Neurites;neurofilament;neuroimaging;neuroimaging marker;Neurons;neurovascular;neurovascular unit;novel;older adult;Oligodendroglia;Participant;Pathogenesis;Pathology;Pathway interactions;Pericytes;Plasma;Positron-Emission Tomography;Proteins;Race;racial disparity;racial population;recruit;Research;Resources;Role;sample archive;Site;Subgroup;Supporting Cell;tau-1;Thick;Time;tool;vascular contributions;Vascular Dementia;Vascular Diseases;vascular factor;vascular risk factor;Visit;White Matter Hyperintensity

PROJECT_TITLE: Multi-Ethnic Study of Atherosclerosis- Cellular Exosomes in Neurodegeneration and Dementia (MESA-CEND)


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Machine Learning and Artificial Intelligence;Neurodegenerative;Neurosciences;Racial and Ethnic Minority Health Research;Social Determinants of Health

ORG_CITY: LAWRENCE

ORG_DEPT: CHEMISTRY

ORG_NAME: UNIVERSITY OF KANSAS LAWRENCE

ORG_STATE: KS

PHR: Project Narrative: The overarching goal of this application is to develop a better understanding of race-associated differences in Alzheimer's disease so that plasma-based biomarker panels can be developed for a diverse group of Americans.

PI_NAMEs: DESAIRE, HEATHER R (contact)

PROGRAM_OFFICER_NAME: ELLIOTT, CERISE

PROJECT_TERMS: Address;Adult;African American;African American population;Age;Aging;Alzheimer's Disease;Alzheimer's disease patient;Alzheimer’s disease biomarker;American;apolipoprotein E-4;Basic Science;Biological;biomarker discovery;biomarker panel;Biomedical Research;Black race;cancer biomarkers;Clinical;Clinical Sciences;Collaborations;Data;Data Set;design;Diagnosis;Diagnostic;Disadvantaged;Disease;disease diagnostic;Disease Progression;Disparity;Education;ethnic disparity;Ethnic Origin;Ethnic Population;European ancestry;feature selection;field study;Goals;health disparity;Hispanic;Incidence;innovation;Institutional Racism;Investigation;Knowledge;lipidomics;Lipids;Literature;Machine Learning;machine learning algorithm;Mass Spectrum Analysis;Methods;Minority Groups;Modeling;novel;Outcome Study;Participant;Patients;Persons;Plasma;Population;Proteins;Proteomics;Public Health;Race;racial bias;racial difference;racial disparity;racial population;Research;Research Personnel;research study;Sampling;Serum;sex;spheroids;Testing;Training;Work

PROJECT_TITLE: A Study of Race Differences in Alzheimer's Disease Biomarkers


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Neurodegenerative;Neurosciences

ORG_CITY: LA JOLLA

ORG_NAME: UNIVERSITY OF CALIFORNIA, SAN DIEGO

PHR: Project Narrative This project will characterize key cellular and molecular events that participate in the development of Alzheimer’s disease and identify therapeutic pathways to reverse these pathological events. We discovered that synapses containing elevated amounts of PSD-95 are protected against the detrimental effects of amyloid- beta, a peptide thought to cause Alzheimer’s disease. We will study PSD-95 in several brain regions as it might explain cell vulnerability and develop a pharmacological approach to increase synaptic PSD-95, which has the potential to open a new therapeutic avenue against Alzheimer’s.

PI_NAMEs: DORE, KIM BOHEMIE (contact)

PROJECT_TERMS: Acute;Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease therapeutic;Amyloid beta-Protein;APP-PS1;Autopsy;behavior test;Behavioral Assay;Biochemical;Biological Assay;Biological Markers;Brain;Brain region;brain tissue;Cells;Characteristics;Chemicals;Chemosensitization;Chiroptera;Data;Dendritic Spines;density;Development;Disease;Disease Progression;DLG4 gene;Dose;efficacy testing;Electrophysiology (science);Enzyme Inhibitor Drugs;Enzymes;Event;experimental study;Exposure to;fluorescence imaging;Genetic;Glutamate Receptor;Grant;Hippocampus;Human;Immunohistochemistry;Impairment;improved;In Vitro;in vivo;Individual;inhibitor;Injections;innovation;Intervention;intraperitoneal;Intraperitoneal Injections;Knockout Mice;Long-Term Potentiation;Measures;Mediating;Memory;Memory impairment;Molecular;mouse model;Mus;N-Methyl-D-Aspartate Receptors;Neurons;neuroprotection;new therapeutic target;normal aging;novel;novel therapeutics;palmitoylation;Pathologic;Pathway interactions;Peptides;Performance;Pharmaceutical Preparations;pharmacologic;Physiological;Physiology;Postsynaptic Membrane;prevent;Process;Proteins;Proteome;Receptor Signaling;Sampling;Scaffolding Protein;Slice;Specificity;Synapses;synaptic depression;Testing;Therapeutic;trafficking;translational approach;Translational Research;Vertebral column

PROJECT_TITLE: Increasing synaptic PSD-95, a neuroprotection approach against Alzheimer's disease

STUDY_SECTION: SYN

STUDY_SECTION_NAME: Synapses, Cytoskeleton and Trafficking Study Section[SYN]


ED_INST_TYPE: SCH ALLIED HEALTH PROFESSIONS

NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Burden of Illness;Caregiving Research;Clinical Research;Dementia;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Health Services;Neurodegenerative;Neurosciences;Prevention;Racial and Ethnic Minority Health Research;Social Determinants of Health

ORG_CITY: GALVESTON

ORG_DEPT: PHYSICAL MEDICINE & REHAB

ORG_NAME: UNIVERSITY OF TEXAS MED BR GALVESTON

PHR: RELEVANCE TO PUBLIC HEALTH Knowledge of the contextual and individual factors in countries like Mexico that influence older adults' risk for dementia as well as their access and use of care resources are established gaps in population aging research. This project will investigate the life course pathways that influence dementia risk, the availability of care resources, and how care resources are used by older adults in a country with the likely care burden of dementia for families and institutions. Our findings will help determine the resource needs in countries like Mexico.

PI_NAMEs: DOWNER, BRIAN GREGORY (contact)

PROGRAM_OFFICER_NAME: NGUYEN, EMERALD THAI HAN

PROJECT_TERMS: Adult;Adult Children;Age;aged;Aging;aging population;Alzheimer's Disease Pathway;Alzheimer's disease related dementia;Alzheimer's disease risk;care burden;care systems;caregiving;Caring;Child;Childhood;Cognitive;contextual factors;Country;cultural values;Data;Data Files;dementia burden;dementia risk;Disadvantaged;Economic Conditions;Economics;Education;Event;expectation;Exposure to;Extended Family;Family;Family Planning Policy;Family Sizes;family support;Friends;Generations;Health;Health behavior;Health care facility;health care service;Health Insurance;health knowledge;Health Services Accessibility;Health Status;Healthcare;Housing;human old age (65+);Incidence;Individual;Inequality;informal care;Infrastructure;Institution;Insurance Coverage;Knowledge;Latin America;Life;Life Cycle Stages;Life Expectancy;Link;Long-Term Care;Medicine;Mexican;Mexican Americans;Mexico;middle age;migration;Migration Policy;older adult;Participant;Pathway interactions;Pensions;Persons;Policies;Population;protective factors;Public Health;Research;Resources;Risk;Risk Factors;Series;Shapes;Shock;social;Social Change;social influence;Testing;Time;Work

PROJECT_TITLE: The influence of social and cultural context on life course pathways for Alzheimer's disease, related dementias, and care resources for older Mexican adults

STUDY_SECTION: SSPA

STUDY_SECTION_NAME: Social Sciences and Population Studies A Study Section[SSPA]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Genetics;Neurodegenerative;Neurosciences;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_CITY: La Jolla

ORG_NAME: SALK INSTITUTE FOR BIOLOGICAL STUDIES

PHR: Project Narrative Cellular senescence is a hallmark of age-related tissue dysfunction and is enhanced in the brain during Alzheimer's disease (AD), but very little is known about the causes or consequences of senescent-like states in post-mitotic cells, especially neurons. This project seeks to understand neuronal senescence during aging and AD using a neuronal culture system that preserves age-related cellular features lacking in other in vitro models. By comparing gene expression, metabolism, and senescence-associated secreted factors in neurons and fibroblasts from the same individuals, this work will reveal cellular processes that differentiate healthy aging from AD and those that specifically impact neurons.

PI_NAMEs: GAGE, FRED H (contact)

PROJECT_TERMS: Age;age related;Age-associated memory impairment;aged;Aging;aging brain;aging population;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Astrocytes;ATAC-seq;Biology;Brain;CDKN2A gene;Cell Aging;Cell Physiology;Cell Size;cell type;Cells;Cellular Metabolic Process;Characteristics;Chronic;clinically relevant;Country;CSF1 gene;Data;Disease;effective therapy;Elderly;Environment;Epigenetic Process;Etiology;experimental study;extracellular;Fibroblasts;functional decline;Functional disorder;Gene Expression;Genes;Genetic Transcription;Genomics;healthy aging;Human;IL6 gene;In Vitro;in vitro Model;Individual;Induced Neurons;induced pluripotent stem cell;Induced pluripotent stem cell derived neurons;Inflammation;Inflammatory;inflammatory marker;Inflammatory Response;insight;Lead;Life;life span;Metabolic;Metabolic Pathway;Metabolism;Methods;Microglia;Molecular;Morphology;Neuroglia;neuron component;Neuronal Differentiation;Neurons;neutralizing antibody;novel;nucleotide metabolism;Nucleotides;Organ;pathological aging;Pathway interactions;permissiveness;Phase;Physiological;postmitotic;Predictive Factor;preservation;Process;protein biomarkers;Proteomics;Rejuvenation;response;Sampling;senescence;senescence associated secretory phenotype;senescent cell;Signal Transduction;small molecule;Source;stem cells;System;Technology;Test Result;Testing;Tissues;transcriptome sequencing;transcriptomics;transdifferentiation;Up-Regulation;Work

PROJECT_TITLE: Neuronal senescence and inflammation in Alzheimer's disease


ORG_CITY: LEXINGTON

ORG_NAME: UNIVERSITY OF KENTUCKY

ORG_STATE: KY

PHR: PROJECTIVE NARRATIVE Recent data support that changes in the functional properties of glutamate and GABA neurotransmission in the hippocampus and frontal cortex in the CNS contribute to Alzheimer’s disease (AD) and age-related declines in cognition and memory. A further understanding of the balance between glutamate levels and glutamate and GABA neurotransmission in vivo are needed from the frontal cortex and hippocampus in AD models and in normal aging. These studies will aid in the identification of targets and consistent, comparable non-invasive spectroscopic monitoring techniques for existing FDA approved drugs as well as possibly new targets for drugs to treat AD to address the growing population with dementia.

PI_NAMEs: GERHARDT, GREG A. (contact)

PROJECT_TERMS: Address;Affect;Age;Age Months;age related;age related changes;Age-associated memory impairment;aged;Aging;Alzheimer's Disease;Alzheimer's disease model;Animals;awake;Behavioral;Brain;Cell Death;cognitive function;Complex;Data;Dementia;design;Development;Disease Progression;Elements;Enzymes;Equilibrium;excitotoxicity;familial Alzheimer disease;FDA approved;Female;Fostering;frontal lobe;Future;gamma-Aminobutyric Acid;Glial Fibrillary Acidic Protein;Gliosis;glutamatergic signaling;Glutamates;Goals;Hippocampus;Impaired cognition;Impairment;improved;In Vitro;in vivo;Individual;Knock-in Mouse;Knowledge;male;Measurement;Measures;Memantine;Memory;Metabolic;Methodology;Methods;Microelectrodes;Monitor;morris water maze;mouse model;Mus;Mutation;Nerve Degeneration;neuron loss;neuronal circuitry;Neurons;neuropathology;neurotransmission;neurotransmitter release;new therapeutic target;Noise;normal aging;novel;novel therapeutics;old mice;Pathologic;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Phase;Population;Prefrontal Cortex;Process;promoter;Property;Rattus;Regulation;Rodent;Role;Signal Transduction;spatial memory;Structure;System;Techniques;Technology;Testing;therapeutic development;Time;United States National Institutes of Health;Variant

PROJECT_TITLE: Dynamic GABA and Glutamate Neurotransmission in Alzheimer’s Disease and Aging


ED_INST_TYPE: SCHOOLS OF PUBLIC HEALTH

NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Behavioral and Social Science;Brain Disorders;Clinical Research;Clinical Trials and Supportive Activities;Dementia;Infectious Diseases;Neurodegenerative;Neurosciences;Prevention;Social Determinants of Health

PHR: The primary objectives of this project are to assess the effects of a cash transfer program on the slowing of biological aging and reduction of dementia risk in younger and older individuals. Additionally, we aim to quantify associations between biological aging and cognitive function in this population. Results of this research could have substantial impact for public health by revealing causal, long-term consequences of economic interventions for health and cognitive aging. Moreover, it will generate new knowledge about biological aging and Alzheimer’s Disease risk in low resource settings.

PI_NAMEs: AIELLO, ALLISON E (contact);BELSKY, DANIEL WALKER;HANDA, SUDHANSHU

PROGRAM_OFFICER_NAME: BRAUDT, DAVID BRUCE

PROJECT_TERMS: Acceleration;Activities of Daily Living;Address;Adult;Africa;Africa South of the Sahara;Age;age acceleration;Aging;aging population;aging related;aging related disease;Algorithms;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimer's disease risk;Biological;biological age;Biological Aging;Biological Assay;Blood;burden of illness;Cells;Chronic Disease;Cognition;Cognitive aging;cognitive function;cognitive testing;cohort;Communicable Diseases;Consumption;Control Groups;Data;Dementia;dementia risk;Development;Disease;Disease Outcome;disorder risk;DNA Methylation;Dryness;early life adversity;Early Onset Alzheimer Disease;Economics;epigenetic clock;Exhibits;experience;Generations;Government;Health;Health Benefit;healthspan;Household;Hypertension;Immune;Immunity;improved;Individual;Influentials;innovation;insight;International;Intervention;intervention effect;Knowledge;Life;life span;Link;Longitudinal Studies;Longterm Follow-up;Malawi;Measurement;Measures;Methods;mortality;Neurocognitive;neurocognitive test;novel;nutrition;Obesity;older adult;Older Population;Participant;pathogen;Pattern;Phenotype;Population;Prevalence;prevent;programs;Protocols documentation;Public Health;randomized trial;Randomized, Controlled Trials;rate of aging;Research;Resource-limited setting;Risk;Risk Factors;Risk Reduction;Role;Sampling;social;South Africa;Specimen;Spottings;Surveys;Testing;Time;tool;treatment group;Underweight;Waiting Lists;young adult

PROJECT_TITLE: Testing effects of cash transfers on biological aging and risk for Alzheimer's Disease

STUDY_SECTION: AIMR

STUDY_SECTION_NAME:
Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study
Section[AIMR]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Clinical Research;Dementia;Genetics;Neurodegenerative;Neurosciences;Prevention;Women's Health Research

ORG_NAME: MASSACHUSETTS GENERAL HOSPITAL

PHR: Narrative Alzheimer's disease (AD) is one of the most important public health challenges of our time, with women disproportionately impacted. We will uniquely examine whether sex differences in immune pathophysiology, in part, underlies the sex-dependent impact of cardiometabolic dysfunction on AD risk in midlife. Understanding this shared etiology could provide insights into development of sex-dependent early interventions to prevent AD or attenuate disease burden.

PI_NAMEs: GOLDSTEIN, JILL M (contact)

PROGRAM_OFFICER_NAME: CHAKROBORTY, SHREAYA

PROJECT_TERMS: Age;Alzheimer's Disease;Alzheimer's disease risk;Alzheimer’s disease biomarker;Amyloid beta-Protein;amyloid pathology;Attenuated;biobank;Biological Markers;Blood;Blood Vessels;blood-based biomarker;Brain;Brain region;burden of illness;Cardiometabolic Disease;cardiometabolism;Cardiovascular alteration;Cells;Cellular Metabolic Process;Chronic;Circulation;Clinic;Clinical;cognitive function;Data;Development;Diabetes Mellitus;Disease;Disease Progression;disorder risk;Disproportionately impacts women;DNA Library;Early Intervention;Electronic Health Record;entorhinal cortex;Etiology;experience;Fetal Development;Functional disorder;Functional Magnetic Resonance Imaging;Genes;Genetic;Genetic Risk;Genetic Transcription;Genotype;glial activation;High Prevalence;Hormones;Hypertension;Immune;immune function;Immune System Diseases;Individual;Inflammation;Inflammatory;inflammatory marker;insight;locus ceruleus structure;Medial;Mediating;Mediation;Memory;men;Metabolic;Metabolism;Methods;middle age;mild cognitive impairment;Mitochondria;monocyte;Neuroimmune;neuroinflammation;neurovascular;Outcome;paraventricular nucleus;Pathology;Pathway interactions;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Persons;polygenic risk score;Positron-Emission Tomography;Postmenopause;pre-clinical;Prefrontal Cortex;prevent;Prevention;protein biomarkers;Public Health;Recontacts;recruit;regional difference;Reporting;Research;Respiration;response;risk sharing;RNA;Sample Size;Secondary to;sex;Sex Differences;sexual dimorphism;Structure;Testing;Therapeutic;Time;Vascular Diseases;Visit;Woman;women versus men

PROJECT_TITLE: Impact of sex differences in immune function on shared risk for cardiometabolic disorder & Alzheimer's disease


ADMINISTERING_IC: GM

FUNDING_MECHANISM: OTHER RESEARCH-RELATED

IC_NAME: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

ORG_CITY: ANN ARBOR

ORG_DEPT: EMERGENCY MEDICINE

ORG_NAME: UNIVERSITY OF MICHIGAN AT ANN ARBOR

ORG_STATE: MI

PHR: PROJECT NARRATIVE Sepsis, or dysregulated host response to infection, is one of the most common causes of hospitalization in the U.S. with a high mortality rate. DHCR7, an enzyme involved in cholesterol synthesis, was associated with mortality in human sepsis, and fish treated with a DHCR7 inhibitor were protected from toxicity in a zebrafish model that recapitulates features of human sepsis. This proposal will clarify the mechanisms by which inhibition of this enzyme exerts a protective effect, with implications for the development of human sepsis therapeutics.

PI_NAMEs: JACOB, VINITHA  (contact)

PROGRAM_OFFICER_NAME: BLATCH, SYDELLA ANNE

PROJECT_TERMS: 7-dehydrocholesterol;7-dehydrocholesterol reductase;Acute;Acute Disease;aging population;Antibiotic Resistance;Antibiotics;Award;AY9944;Blood Vessels;career;Cell membrane;Cells;Cessation of life;Cholesterol;Cholesterol Homeostasis;Clinical;Collaborations;Complement;Data;Death Rate;Dehydrocholesterols;Development;Disease;Doctor of Philosophy;drug candidate;drug discovery;Drug Utilization;Emergency Medicine;Endotoxemia;Endotoxins;enzyme activity;Enzyme Inhibition;Enzymes;experience;Extravasation;FDA approved;Fishes;Genes;genome editing;Goals;Hospitalization;Human;Immune;immune activation;Immune response;improved;In Vitro;in vivo;Infection;Inflammation;Inflammatory;inflammatory modulation;Inflammatory Response;inhibitor;K-Series Research Career Programs;Knowledge;Leukocytes;Libraries;Lipids;Lipopolysaccharides;Macrophage;Mammals;Mediating;Membrane;Membrane Microdomains;Mentors;Mentorship;Messenger RNA;Michigan;Modeling;mortality;mouse model;Mus;novel;novel therapeutics;Organ;Outcome;Oxidoreductase;Pathogenesis;Pathway interactions;Pharmaceutical Preparations;Physicians;Platelet aggregation;prevent;protective effect;Publishing;Recording of previous events;Role;Sampling;Scientist;Sepsis;septic patients;Supportive care;System;Techniques;Teratogens;Testing;Therapeutic;tool;Toxic effect;Training;transcriptome sequencing;Translating;translational pipeline;Universities;Viral;Work;Zebrafish;zebrafish development

PROJECT_TITLE: The Role of DHCR7 in Endotoxemia

STUDY_SECTION: SAT

STUDY_SECTION_NAME: Surgery, Anesthesiology and Trauma Study Section[SAT]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Genetics;Human Genome;Neurodegenerative;Neurosciences

ORG_CITY: INDIANAPOLIS

ORG_NAME: INDIANA UNIVERSITY INDIANAPOLIS

ORG_STATE: IN

PHR: Project Narrative In a recent large-scale of genome-wide analysis study, a rare coding variant was identified in Abelson interactor family member 3 (ABI3) gene and this variant is associated with an increased risk of late-onset Alzheimer’s disease (AD). The overarching goal of this application is to understand the role of ABI3 in microglia and the mechanisms by which ABI3 affects AD. This may lead to identifying the key regulators of the mechanism and subsequent identification of the new therapeutic targets in AD.

PI_NAMEs: KIM, JUNGSU  (contact)

PROJECT_TERMS: abeta accumulation;Abeta clearance;Actins;Affect;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease risk;Amyloid;Amyloid beta-Protein;Amyloidosis;Automobile Driving;Biochemical;Brain;Brain imaging;Brain region;cancer cell;Cell Culture Techniques;Cell Physiology;Cellular Assay;Coculture Techniques;Code;complement system;Complex;CRISPR/Cas technology;cytokine;Cytokinesis;Cytoskeletal Modeling;Data;Disease;druggable target;effective therapy;Electrophysiology (science);Endocytosis;Etiology;experimental study;Family member;Gene Expression;Genes;genetic risk factor;Genetic study;genome-wide;genome-wide analysis;Gliosis;Goals;Hippocampus;Human;Human Genetics;human induced pluripotent stem cells;Immune response;Immunity;immunoreactivity;Impairment;In Vitro;in vivo;Inflammatory;innovative technologies;insight;interest;knock-down;Knock-in;Knock-in Mouse;Knock-out;Knowledge;Late Onset Alzheimer Disease;Magnetic Resonance Imaging;Mass Spectrum Analysis;Mediating;Microglia;migration;Modeling;mouse model;Mus;Neurons;neuropathology;new therapeutic target;novel;Pathogenesis;Pathologic;Pathology;Pathway interactions;Peer Review;Phagocytosis;Pharmacology;Phenotype;Play;Positron-Emission Tomography;Proteome;Proteomics;Reporting;Risk;risk variant;RNA Interference;Role;Senile Plaques;single-cell RNA sequencing;superresolution microscopy;Synapses;synaptic function;System;Systems Biology;Testing;transcriptome;transcriptomics;uptake;Variant;β-amyloid burden

PROJECT_TITLE: The role of ABI3 in Alzheimers disease


ADMINISTERING_IC: CA

IC_NAME: NATIONAL CANCER INSTITUTE

NIH_SPENDING_CATS: Biotechnology;Cancer;Clinical Research;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_CITY: CHARLOTTESVILLE

ORG_NAME: UNIVERSITY OF VIRGINIA

ORG_STATE: VA

PHR: Most human disease, especially cancer, is based in abnormalities of tissues. The University of Virginia will support the Cooperative Human Tissue Network by recruiting patients to donate samples and then by giving high quality human tissue specimens and biofluids (blood, urine, etc.) to scientists to help them understand the causes of disease, to create new diagnostic tests for disease and to create new therapies for disease, with an emphasis on cancer.

PI_NAMEs: MOSKALUK, CHRISTOPHER A. (contact)

PROGRAM_OFFICER_NAME: CHUAQUI, RODRIGO F

PROJECT_TERMS: Adult;African American;Archives;Area;biobank;Blood;Board Certification;Bone Marrow;Cell Survival;Chemicals;Clinic;Clinical Data;cohort;Collection;Consent;Cooperative Human Tissue Network;Custom;Data;data sharing;Databases;demographics;Diagnostic tests;digital pathology;digital repositories;Disease;Dissociation;DNA;ethnic diversity;Freezing;Funding;Genetic;Genetic Research;Geography;Germ-Line Mutation;Hispanic;Histologic;Histology;Human;human disease;human subject;human tissue;Image;Image Analysis;induced pluripotent stem cell;Informatics;informatics infrastructure;Infrastructure;Institution;Leukocytes;Link;Machine Learning;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant Neoplasms;manufacture;Marketing;Medical;Modeling;NCI-Designated Cancer Center;New Mexico;Normal tissue morphology;novel diagnostics;novel therapeutics;Nucleic Acids;online resource;Paraffin Embedding;Pathologist;Pathology;pathology imaging;patient derived induced pluripotent stem cells;Patient Recruitments;Patients;Population;Predisposition;Preparation;Procedures;Process;prospective;Quality Control;Race;recruit;repository;Research;Research Personnel;Resources;RNA;Sampling;Scanning;Scientist;Services;Site;South Carolina;Specific qualifier value;Specimen;Surveys;Syndrome;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;tumor;tumor registry;Universities;Urine;Virginia

PROJECT_TITLE: Biospecimen procurement and tissue microarray manufacture for the CHTN

STUDY_SECTION_NAME: Special Emphasis Panel[ZCA1 SRB-K (J1)]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Behavioral and Social Science;Biomedical Imaging;Brain Disorders;Cerebrovascular;Clinical Research;Dementia;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Neurodegenerative;Neurosciences

ORG_CITY: ROCHESTER

ORG_NAME: MAYO CLINIC ROCHESTER

PHR: PROJECT NARRATIVE To be able to optimally use neurodegenerative biomarkers in clinical practice and as surrogate endpoints to clinical trials, several unanswered questions in the field must be addressed. We will evaluate different proposed neurodegenerative biomarkers using a population-based community sample of Mayo Clinic Study of Aging, a biracial cohort from Mayo Clinic Jacksonville and ADNI in order to will develop a deeper understanding of how to utilize these neurodegenerative markers for clinical care of Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD).

PI_NAMEs: GRAFF-RADFORD, JONATHAN  (contact);MIELKE, MICHELLE M;VEMURI, PRASHANTHI

PROJECT_TERMS: Address;African American;Age;age effect;age related;Aging;alpha synuclein;Alzheimer's Disease;Alzheimer's disease care;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer’s disease biomarker;Amyloid;Amyloid beta-Protein;apolipoprotein E-4;Autopsy;Axon;Biological Markers;biracial;Blood;Cerebrovascular Disorders;Clinic;Clinical;clinical care;clinical practice;Clinical Trials;Clinical Trials Design;Cognition;Cognitive;cognitive testing;cohort;Communities;Data;Data Set;Dementia;Demographic Factors;demographics;density;Education;Etiology;Exclusion;fluorodeoxyglucose positron emission tomography;Future;General Population;Goals;Grant;hippocampal sclerosis;Hippocampus;Image;Impaired cognition;in vivo;in vivo imaging;Investigation;Knowledge;Light;low socioeconomic status;Magnetic Resonance Imaging;Maps;Measures;Modality;Nerve Degeneration;Neurobehavioral Manifestations;neurofilament;neurogranin;neuroimaging;neuroimaging marker;Neurologic;Neurons;neuropathology;Outcome;Participant;Pathologic;Pathology;Plasma;Population;population based;Population Study;Positron-Emission Tomography;predictive modeling;Prognosis;protein TDP-43;Psychometrics;Race;Risk;Sampling;sex;Socioeconomic Status;Source;specific biomarkers;Surrogate Endpoint;Synapses;Syndrome;synucleinopathy;tau Proteins;Tauopathies;Thick;Uncertainty;Validation;validation studies;white matter;β-amyloid burden

PROJECT_TITLE: "What is N?" Towards operationalizing neurodegeneration in Alzheimer's and related dementias


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Clinical Research;Dementia;Genetics;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Human Genome;Neurodegenerative;Neurosciences;Prevention;Racial and Ethnic Minority Health Research

ORG_CITY: CORAL GABLES

ORG_NAME: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE

ORG_STATE: FL

PHR: PROJECT NARRATIVE This study will complement ongoing large-scale Alzheimer disease (AD) genomic studies in individuals of diverse ancestry including non-Hispanic whites, African Americans, and Hispanics from Puerto Rico and Peru. Since DNA variants identified in these studies may not provide information on the underlying biological mechanisms, we propose to 1) use high throughput RNA sequencing, single cell RNA sequencing, and genome-wide methylation microarrays to define gene expression and DNA methylation differences between AD and control; 2) characterize how DNA variants modulate those expression and methylation changes and 3) use statistical methods to extend these findings into large existing genomic datasets. Performing this study in diverse populations including African American and Hispanic populations will broaden the spectrum of AD genomics to individuals that are underrepresented in most existing research.

PI_NAMEs: BUSH, WILLIAM S;GRISWOLD, ANTHONY JOHN (contact)

PROGRAM_OFFICER_NAME: YAO, ALISON Q

PROJECT_TERMS: Address;African American;African American population;aged;Alleles;Alternative Splicing;Alzheimer's Disease;Alzheimer's disease risk;Architecture;Bioinformatics;Biological;Biology;Caribbean region;caucasian American;cell type;Cognitive;cohort;Collection;Communities;Complement;Complex;Data;data imputation;Data Set;Dementia;Development;Disease;disorder risk;Disparity;DNA;DNA Methylation;Elderly;Epigenetic Process;epigenetic variation;epigenomics;Equilibrium;ethnic diversity;Ethnic Origin;Ethnic Population;Follow-Up Studies;functional genomics;Gene Expression;Genes;Genetic;Genetic Risk;Genetic study;Genetic Transcription;Genetic Variation;genome resource;genome sequencing;genome wide association study;genome wide methylation;genome-wide;Genomic approach;genomic data;genomic locus;Genomics;Genotype;Genotype-Tissue Expression Project;High-Throughput RNA Sequencing;Hispanic Americans;Hispanic Populations;Individual;Methylation;Modeling;Molecular;multi-ethnic;multiple omics;Not Hispanic or Latino;older adult;Pathway interactions;Peripheral Blood Mononuclear Cell;Peru;Peruvian;Population;Population Heterogeneity;Process;Puerto Rico;Quantitative Trait Loci;racial population;Regulation;Research;response;risk variant;RNA;RNA Splicing;Role;Sampling;single-cell RNA sequencing;Site;Statistical Methods;Susceptibility Gene;Tissues;trait;transcriptome;transcriptome sequencing;transcriptomics;United States;Variant;Whole Blood;whole genome

PROJECT_TITLE: Genomic, Epigenomic, and Transcriptomic Mechanisms of Contributing to Alzheimer's Disease Risk in Diverse Ancestral Populations

STUDY_SECTION: NAME

STUDY_SECTION_NAME: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]


ORG_CITY: SOLNA

ORG_COUNTRY: SWEDEN

ORG_FIPS: SW

ORG_NAME: KAROLINSKA INSTITUTE

PHR: PROJECT NARRATIVE Drugs to prevent or treat Alzheimer´s disease (AD) are desperately needed, and this project proposes an innovative reverse translational approach to repurpose drugs for AD, by bringing together researchers from the fields of molecular epidemiology and basic science in a cross-disciplinary effort. We will analyze drugs with indications for other age-related conditions for their preventive effect on AD, using a series of causal inference methods on epidemiological data, followed by drug screening in human cultured cells and C. elegans, as well as validation in mouse models of aging and AD pathology. Our approach is a cost-effective strategy to discover new drugs for AD prevention, and since we are investigating already approved substances, they may arrive at the bedside more quickly, due to a reduced need for clinical testing.

PI_NAMEs: HAGG, SARA  (contact)

PROGRAM_OFFICER_NAME: ARUNKUMAR, NANDINI

PROJECT_TERMS: abeta accumulation;Adoption;Age;age acceleration;age effect;age related;Aging;aging brain;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease risk;Amyloid beta-42;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Animal Model;Animals;anti aging;Astrocytosis;Autophagocytosis;Baltimore;Basic Science;beta amyloid pathology;biological age;Biological Aging;Caenorhabditis elegans;candidate selection;Cell model;Cells;Clinical;cost effective;Cultured Cells;Data;Dementia;Disease;disease phenotype;Disease Progression;drug candidate;drug development;Drug Prescriptions;drug repurposing;Drug Screening;Drug Targeting;drug testing;Drug usage;Economic Burden;epidemiologic data;Epidemiology;Equation;ethnic diversity;Exhibits;follow-up;Genes;Genetic;genome wide association study;Genomics;Genotype;Human;human data;human old age (65+);Impaired cognition;in silico;In Vitro;in vitro Assay;in vivo;Incidence;Individual;innovation;instrument;Knock-in;Knock-in Mouse;Knockout Mice;Lead;life span;Link;Longevity;Longitudinal cohort;Longitudinal Studies;Measurement;Memory Loss;Mendelian randomization;Methods;Microglia;Modeling;Molecular;Molecular Epidemiology;Moods;mouse model;Mus;Nematoda;Nerve Degeneration;neuroinflammation;novel therapeutics;Participant;Pathology;Patients;Personality;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Population;prevent;Preventive;preventive intervention;Primary Prevention;Process;Progeria;promoter;proteostasis;Randomized;reduce symptoms;Registries;research clinical testing;Research Personnel;Risk;safety assessment;Sampling;screening;Series;Societies;socioeconomics;Speed;statistics;Sweden;Symptoms;Synapses;Syndrome;System;targeted therapy trials;tau aggregation;tau Proteins;Testing;Toxic effect;translational approach;Twin Studies;Validation;Work

PROJECT_TITLE: Repurposing drugs for Alzheimer´s disease using a reverse translational approach


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease Related Dementias (ADRD);Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Cerebrovascular;Clinical Research;Dementia;Hematology;Neurodegenerative;Neurosciences;Vascular Contributions to Cognitive Impairment and Dementia (VCID)

ORG_CITY: Nashville

ORG_NAME: VANDERBILT UNIVERSITY

ORG_STATE: TN

PHR: Project Narrative Protease-activated receptor-4 (PAR4) is part of a unique family of GPCRs activated by cleavage of the amino terminus by thrombin and generation of a tethered ligand. PAR4 is thought to play important roles in generation of excess thrombin and thrombosis, but these roles are unconfirmed due to the lack of appropriate tools and bioavailable antagonists. We will optimize SAR around PAR4 to explore the role of PAR4 activation in cerebrovascular damage during Alzheimer’s Disease.

PI_NAMEs: HAMM, HEIDI E (contact);MEILER, JENS

PROGRAM_OFFICER_NAME: GROTHAUS, PAUL G

PROJECT_TERMS: abeta accumulation;Acute;Age;aged;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease risk;Amyloid beta-Protein;Animal Model;antagonist;apolipoprotein E-4;Behavior assessment;Binding;Biological Assay;Biological Availability;Biological Markers;Blood - brain barrier anatomy;Blood coagulation;Blood Platelets;Blood Tests;Cardiovascular Diseases;Cardiovascular Pathology;Cerebral Amyloid Angiopathy;cerebrovascular;Cerebrovascular Disorders;Cerebrovascular system;Characteristics;Chemicals;Chronic;Chronic Disease;Coagulation Process;comparative;Data;Dementia;Deposition;Development;Diabetes Mellitus;Disease;Docking;Drug Kinetics;Elderly;Endothelial Cells;Epigenetic Process;Evaluation;Exposure to;F2R gene;familial Alzheimer disease;Family;Fibrin;Fibrinogen;flexibility;G-Protein-Coupled Receptors;Generations;Genes;Genetic;Genome;glial activation;Hemorrhage;Hippocampus;Histologic;Homing;Human;human old age (65+);Impaired cognition;improved;in vivo;in vivo evaluation;Inflammation;Inflammatory;inflammatory marker;inflammatory milieu;Laboratories;Lead;Learning;Legal patent;Leukocytes;Libraries;Ligand Binding;Ligands;Lymphocyte;Lymphocytic Infiltrate;Mediating;Microglia;Modeling;mortality;mouse model;mouse protease-activated receptor 4;Mus;Mutation;Neurons;neuropathology;non-genetic;overexpression;PAR-1 Receptor;particle;Pathologic;Pathology;Peptides;Pharmaceutical Chemistry;Plasmin;Platelet Activation;Play;Prefrontal Cortex;Procedures;Property;protease-activated receptor 4;Proteinase-Activated Receptors;Proteins;Protocols documentation;Resistance;Role;scaffold;screening;Site;small molecule libraries;Smoker;Structure;success;Symptoms;Testing;Therapeutic;therapeutic target;Thrombin;Thrombosis;Tissues;tool;Traditional Medicine;Traumatic Brain Injury

PROJECT_TITLE: Cerebrovascular involvement in Alzheimer's Disease:  PAR4 Antagonism

STUDY_SECTION: DDNS

STUDY_SECTION_NAME: Drug Discovery for the Nervous System Study Section[DDNS]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Clinical Research;Dementia;Neurodegenerative;Neurosciences;Prevention;Social Determinants of Health;Violence Research

ORG_CITY: Los Angeles

ORG_DEPT: PSYCHOLOGY

ORG_NAME: UNIVERSITY OF SOUTHERN CALIFORNIA

PHR: PROJECT NARRATIVE The overall goal of this study is to examine the association of financial exploitation in old age with markers of Alzheimer’s Disease. We will investigate whether financial exploitation due to poor financial decision making is associated with cognitive decline, change in economic preferences, decline in brain functional connections, and Alzheimer’s Disease genetic risk. Findings will inform early detection and intervention programs focused on cognitive health and wellbeing in old age.

PI_NAMEs: HAN, DUKE  (contact)

PROGRAM_OFFICER_NAME: STOECKEL, LUKE

PROJECT_TERMS: abeta accumulation;Address;Adult;age related;age related changes;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Anterior;apolipoprotein E-4;Attention;behavioral economics;Brain;Brain imaging;Brain region;Characteristics;Clinical;Coercion;Cognition;Cognitive;cohort;contextual factors;Decision Making;Deterioration;discounting;Disease;Early Diagnosis;Early Intervention;Economics;Elder Abuse;Episodic memory;experience;financial decision making;financial exploitation;Genetic Risk;Goals;Health;Heterogeneity;human old age (65+);imaging facilities;Impaired cognition;intervention program;Measurement;Measures;Medial;Methods;mild cognitive impairment;neglect;Neurocognitive;Neurofibrillary Tangles;neuropathology;Neuropsychology;older adult;Older Population;Parietal;Parietal Lobe;Participant;Personal Satisfaction;Persons;Phenotype;pre-clinical;Predisposition;preference;Qualitative Research;recruit;Research;Resources;Risk;Risk Factors;Senile Plaques;Sensory impairment;social;Structure;Temporal Lobe;Time;tool;Trust

PROJECT_TITLE: Finance, Cognition, and Default Network in Aging (FCDNA)


ED_INST_TYPE: BIOMED ENGR/COL ENGR/ENGR STA

NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Clinical Research;Dementia;Neurodegenerative;Neurosciences

ORG_CITY: RIVERSIDE

ORG_DEPT: ENGINEERING (ALL TYPES)

ORG_NAME: UNIVERSITY OF CALIFORNIA RIVERSIDE

PHR: Narrative The proposed research is relevant to public health because a greater understanding of mechanisms related to the Locus Coeruleus (LC) circuit can inform new therapies for diseases including Alzheimer's and Parkinson's. This focus to create a more detailed understanding of LC circuit and function is of particular interest to the NIA as well as the missions of NIMH, NINDS, NIHCD and other NIH agencies.

PI_NAMEs: HU, XIAOPING P (contact);SEITZ, AARON R

PROGRAM_OFFICER_NAME: WAGSTER, MOLLY V

PROJECT_TERMS: Address;Adult;age-related disease;aging related;Alzheimer's Disease;Alzheimer's disease related dementia;Amygdaloid structure;Arousal;Attention;Auditory;Auditory area;Behavior;Behavior assessment;Behavioral;Biological Markers;Brain region;candidate identification;candidate marker;Cerebellum;Cognition;cognitive ability;cognitive function;cognitive performance;cognitive process;Computer Analysis;Data Set;design;Detection;Diagnosis;Disease;Evaluation;Exertion;Goals;grasp;Hand;Hippocampus;Human;Image;Impaired cognition;Impairment;in vivo;Individual Differences;interest;Intervention;Learning;Link;locus ceruleus structure;Magnetic Resonance Imaging;Measures;Mediating;Memory;memory process;Methods;Mission;Modality;Mydriasis;National Institute of Mental Health;National Institute of Neurological Disorders and Stroke;Neocortex;Neurodegenerative Disorders;neuroimaging;neuromelanin;neuron loss;Neurons;Norepinephrine;normal aging;novel therapeutics;older adult;Parkinson Disease;Pathology;Pattern;Perception;Performance;Play;Pontine structure;Population;preservation;Psychophysics;Public Health;Research;Resolution;Role;Series;Source;stem;Stimulus;Stress;stressor;structural imaging;Structure;Task Performances;Tegmentum Mesencephali;Testing;Thalamic structure;tractography;United States National Institutes of Health;Vision;Visual;Visual Cortex;visual memory;Visual Perception

PROJECT_TITLE: How LC Integrity in Older Adults Mediates Perceptual and Memory Processes


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Dementia;Neurodegenerative;Neurosciences;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_CITY: JACKSONVILLE

ORG_NAME: MAYO CLINIC  JACKSONVILLE

PHR: The renewal application will test our hypothesis that amyloid-β deposition in human Alzheimer's disease (AD) brain, which activates brain macrophage “microglia,” and enhances seeding of tau aggregates via phagocytosis of tau-containing neuronal processes and secretion of extracellular vesicles. This will be conducted by 1) characterization of the tau seeding activity of extracellular vesicles isolated from AD brains, 2) microglia-specific deletion of microglia activator or glia specific deletion of extracellular vesicle producing enzyme in animal models and 3) characterization of extracellular vesicles isolated from activated pluripotent stem cell-derived microglia-like cells. This study is critically relevant to understand the progression of neurodegenerative diseases and will elucidate potential therapeutic targets.

PI_NAMEs: IKEZU, TSUNEYA  (contact)

PROGRAM_OFFICER_NAME: YANG, AUSTIN JYAN-YU

PROJECT_TERMS: abeta deposition;Acceleration;aged;Alzheimer's Disease;Alzheimer's disease brain;Animal Model;Apolipoprotein E;apolipoprotein E-3;apolipoprotein E-4;APP-PS1;Astrocytes;base;Biochemical;Biology;Biophysics;Brain;C57BL/6 Mouse;Cell Adhesion Molecules;Cells;Chemical Structure;Clinical;cohort;comparison control;Data;Deposition;Development;Disease;Disease Progression;entorhinal cortex;Enzymes;extracellular vesicles;Functional disorder;Funding;glial activation;Goals;Hippocampus;Human;human induced pluripotent stem cells;In Vitro;in vitro activity;in vivo;induced pluripotent stem cell;Inflammatory;knock-down;Knock-in;Knock-in Mouse;Lentivirus;Link;lipid metabolism;lipidomics;Lipids;Macrophage;Mediating;Microglia;Molecular;Molecular Profiling;Molecular Structure;Mus;Mutation;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;neuroinflammation;Neurons;non-demented;novel;Oligodendroglia;Pathogenicity;Pathologic;Pathology;Phagocytosis;Phosphorylation;Play;Pluripotent Stem Cells;Post-Translational Protein Processing;preventive intervention;Process;Production;Proteins;Proteomics;Reporter;Reporting;Research;Role;Sampling;Symptoms;tau aggregation;tau interaction;tau Proteins;Tauopathies;Testing;Therapeutic Intervention;therapeutic target;transmission process;uptake;Vesicle;Work

PROJECT_TITLE: APOE and microglia-mediated progression in tau pathology in AD

STUDY_SECTION_NAME: Synapses, Cytoskeleton and Trafficking Study Section[SYN-M]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Bioengineering;Biotechnology;Brain Disorders;Data Science;Dementia;Genetics;Human Genome;Networking and Information Technology R&D (NITRD);Neurodegenerative;Neurosciences

ORG_CITY: NEW YORK

ORG_DEPT: BIOSTATISTICS & OTHER MATH SCI

ORG_NAME: COLUMBIA UNIVERSITY HEALTH SCIENCES

ORG_STATE: NY

PHR: Alzheimer’s Disease (AD) is a complex, heterogeneous disorder, partly influenced by genetics. Identifying new genes for AD is very important as it can lead to a better understanding of the molecular mechanisms underlying AD and can identify novel therapeutic targets. We propose here analytical tools that leverage diverse omics datasets including genomics, transcriptomics and epigenomics in order to improve gene discovery. We will apply these methods to some of the largest genetic datasets in AD to identify new risk genes for AD.

PI_NAMEs: IONITA, IULIANA  (contact);WEI, YING

PROJECT_TERMS: Affect;Alzheimer's Disease;Amyloid;analytical tool;Base Sequence;causal variant;Chromosomes;Clinical;Code;cognitive function;Collection;Communities;Complex;Computer software;Computing Methodologies;cost of dementia;Data;Data Set;Dementia;dementia care;design;Deterioration;Disease;epigenomics;extracellular;gene discovery;Gene Expression;Gene Targeting;Genes;Genetic;genetic testing;genome sequencing;genome wide association study;Genomics;Genotype-Tissue Expression Project;Goals;heterogenous data;high dimensionality;hyperphosphorylated tau;improved;Individual;large scale data;Memory;metabolomics;Methods;Molecular;Molecular Conformation;Multiomic Data;multiple omics;Nature;Neurofibrillary Tangles;neuron loss;new therapeutic target;novel;Pathologic;Proteins;Regulatory Element;repository;Resources;Risk;risk variant;Senile Plaques;Societies;Software Tools;Statistical Methods;statistics;targeted treatment;tau Proteins;Testing;therapeutic development;Tissues;tool;trait;transcriptome;transcriptomics;Variant;web based software;web portal;whole genome

PROJECT_TITLE: Multi-omics approaches for gene discovery in Alzheimer's Disease.

STUDY_SECTION: BMRD

STUDY_SECTION_NAME: Biostatistical Methods and Research Design Study Section[BMRD]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Gene Therapy;Genetics;Neurodegenerative;Neurosciences;Prevention

ORG_CITY: HOUSTON

ORG_NAME: BAYLOR COLLEGE OF MEDICINE

PHR: NARRATIVE This proposal will explore the idea that a modified version of the Ab peptide might be used therapeutically to block aggregation of the wild-type peptide. Our study endeavors to identify the biophysical mechanism of inhibition and to test a gene therapy vector for delivery of variant Ab in mouse models. We intend this work to serve as a framework for exploring peptide self-inhibition in Alzheimer's disease and other disease-associated aggregation disorders.

PI_NAMEs: JANKOWSKY, JOANNA L (contact)

PROGRAM_OFFICER_NAME: LI, TONG

PROJECT_TERMS: abeta accumulation;abeta toxicity;adeno-associated viral vector;Aducanumab;Adult;age related changes;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease therapy;Amyloid;Amyloid beta-Protein;amyloid pathology;analytical method;Antibodies;antibody engineering;APP-PS1;Base Sequence;Biophysical Process;Birth;blood-brain barrier penetration;Brain;Cell Line;Cell membrane;Chromatography;Chronic;Circular Dichroism Spectroscopy;cognitive function;comparison intervention;cost;Data;delivery vehicle;Dependovirus;Disease;Disease Marker;Disease Progression;dosage;Electron Microscopy;Engineering;expression vector;Extracellular Space;Gene Expression Profiling;gene therapy;Gene Transduction Agent;Genes;Gliosis;Growth;Half-Life;Histologic;Human;Immune;Immune response;Impaired cognition;In Vitro;in vivo;Inflammation;inflammatory marker;inhibitor;Injections;Knock-in Mouse;Life;Measures;Memantine;Molecular Sieve Chromatography;Morphology;mouse model;Mus;neonatal brain;Nervous System Disorder;Neuroimmune;Neurons;novel;Outcome;Penetration;peptide drug;Peptide Hydrolases;Peptides;Phase;phase III trial;pre-clinical;prevent;Prevention;Preventive treatment;protein misfolding;Reaction;Recommendation;Research;response;Route;Safety;secretase;Severities;Spectrum Analysis;Surveys;tau Proteins;Technology;Testing;Therapeutic;therapeutic candidate;therapeutic evaluation;Therapeutic Uses;tool;Toxic effect;transduction efficiency;Transgenic Mice;Tube;Variant;Viral;Work

PROJECT_TITLE: Gene therapy for Alzheimer's disease using virally delivered Aβ variants


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Neurodegenerative;Neurosciences

ORG_CITY: LOS ANGELES

ORG_NAME: UNIVERSITY OF CALIFORNIA LOS ANGELES

PHR: PROJECT NARRATIVE This proposal evaluates a new approach for AD therapeutics; we would screen small molecules and peptidomimetics for their ability to mimic Humanin (HN) activity for normalizing brain phospho-Akt (p-Akt) levels, with the goal of identifying potential candidates for preclinical development with enhanced potency, drug-like properties, oral brain permeability and efficacy in an Alzheimer's disease (AD) model. Such a new therapeutic class for AD could be used alone or in combination with currently approved drugs to protect neurons from NMDA- and Aβ-related toxicity. An efficacious candidate may have broader therapeutic applications in traumatic brain injury (TBI), stroke, Aβ-induced cerebrovascular dementia, amyotrophic lateral sclerosis (ALS), but specifically could provide a new therapeutic approach for AD.

PI_NAMEs: JOHN, VARGHESE  (contact)

PROJECT_TERMS: acetylcholine transporter;Affect;Age;age related;aged;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease therapeutic;Amino Acids;Amyloid beta-Protein;Amyotrophic Lateral Sclerosis;analog;antagonist;apolipoprotein E-3;apolipoprotein E-4;Artificial Membranes;Atherosclerosis;Binding;Binding Proteins;Biological;Biological Assay;Biological Availability;Brain;brain tissue;Cause of Death;Cell Membrane Permeability;Cell surface;Cells;cerebrovascular;Chemistry;Choline O-Acetyltransferase;Chondrocytes;Ciliary Neurotrophic Factor Receptor;Cognition;Complex;Critical Pathways;Data;data modeling;Dementia;design;Development;Diabetes Mellitus;Disease;Docking;Dose;Drug Kinetics;efficacy evaluation;efficacy testing;Evaluation;Exposure to;Extracellular Domain;Genes;Genetic Transcription;Goals;high throughput screening;Hippocampus;Human;humanin;IL6ST gene;Impaired cognition;improved;in silico;In Vitro;in vivo;Lead;lead candidate;lead optimization;Learning;Libraries;Membrane;Memory;meter;Microsomes;mimetics;Mitochondria;MK801;Modeling;mouse model;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Nerve Degeneration;neuron loss;Neuronal Plasticity;neuronal survival;Neurons;neuroprotection;neurotoxicity;novel strategies;novel therapeutic intervention;novel therapeutics;Oral;Pathway interactions;Patients;Penetrance;Peptides;peptidomimetics;Permeability;Persons;Pharmaceutical Chemistry;Pharmaceutical Preparations;phosphoproteomics;PI3 gene;Population;postsynaptic;pre-clinical;preclinical development;prevent;Property;Protein Isoforms;Proteins;Proteomics;receptor;Reporting;response;Risk Factors;Safety;screening;Series;Signal Transduction;simulation;Site;small molecule;Solubility;Stroke;Study models;Testing;Therapeutic;therapeutic candidate;therapeutic development;Tissues;Toxic effect;Traumatic Brain Injury

PROJECT_TITLE: Small molecule mimetics of Humanin that normalize neuronal p-Akt as novel therapeutics for AD


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease Related Dementias (ADRD);Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Brain Disorders;Cerebrovascular;Dementia;Genetics;Neurodegenerative;Neurosciences;Vascular Contributions to Cognitive Impairment and Dementia (VCID)

PHR: PROJECT NARRATIVE MAYO CLINIC JACKSONVILLE Aging-related disturbances in cerebral blood supply and blood-brain barrier (BBB) integrity leads to neuronal damage and white matter lesions, which often results in cognitive decline known as vascular cognitive impairment and dementia (VCID). APOE4 significantly exacerbates cerebrovascular pathology and the cognitive performance of the elderly. Since p16INK4a triggers cellular senescence during aging, we will comprehensively examine how endothelial cell senescence induced by p16INK4a contributes to the pathogenesis of VCID and how APOE4 modulates the mechanisms using mouse models.

PI_NAMEs: KANEKIYO, TAKAHISA  (contact)

PROGRAM_OFFICER_NAME: DIBATTISTA, AMANDA

PROJECT_TERMS: Affect;Age;Age Months;age related;Aging;aging population;aging related;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Apolipoprotein E;apolipoprotein E-3;apolipoprotein E-4;Astrocytes;Biological Aging;Blood - brain barrier anatomy;Blood Vessels;Brain;Breeding;Carbon Dioxide;CDKN2A gene;Cell Aging;Cell Physiology;Cell Senescence Induction;cell type;Cells;cerebrovascular;Cerebrovascular Circulation;Cerebrovascular Disorders;cerebrovascular pathology;Cerebrovascular system;Cerebrum;Cholesterol;Clinic;Cognition;cognitive function;cognitive performance;Complex;Critical Pathways;Cyclin-Dependent Kinase Inhibitor 2A;Dasatinib;Dementia;Dependovirus;Diffuse;Disease;Elderly;Endothelial Cells;Endothelium;epidemiology study;Excision;Functional disorder;Gene Delivery;gene delivery system;Genes;genetic risk factor;Goals;Homeostasis;Human;Impaired cognition;Impairment;Incidence;Individual;Induction of Apoptosis;Injections;insight;Intraperitoneal Injections;Late Onset Alzheimer Disease;Lead;Lesion;Mediating;mild cognitive impairment;Modeling;Molecular;mouse model;Mus;Nerve Degeneration;neuroinflammation;Neurons;neurovascular;neurovascular unit;novel;Nutrient;Oligodendroglia;Oxygen;Pathogenesis;Pathogenicity;Pathway interactions;Pericytes;Pharmaceutical Preparations;Phenotype;Play;population based;precursor cell;Prevalence;prevent;Protein Isoforms;Quercetin;Risk;Risk Factors;Role;senescence;senescent cell;senolytics;single-cell RNA sequencing;Smooth Muscle Myocytes;Symptoms;Synapses;synaptic function;Tamoxifen;Testing;Tetanus Helper Peptide;Therapeutic Intervention;transcriptome;transcriptome sequencing;Vascular blood supply;vascular cognitive impairment and dementia;vascular contributions;Vascular Smooth Muscle;white matter;white matter injury;Wild Type Mouse

PROJECT_TITLE: Endothelial cell senescence and APOE4 in vascular cognitive impairment and dementia


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Genetics;Neurodegenerative;Neurosciences;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_CITY: LA JOLLA

ORG_NAME: SCRIPPS RESEARCH INSTITUTE, THE

PHR: Six million Americans live with Alzheimer’s disease or related dementias and there are no disease modifying drugs. The proposed research will potentially lead to new treatment options based on lysosomal degradation activators, which would address this significant public health need. Defining the mechanism by which our lysosomal degradation activators function to normalize familial Alzheimer’s disease phenotypes in cellular and organoid models is aligned with NIH’s mission to develop fundamental knowledge of human disease that can be translated into benefits for patients.

PI_NAMEs: KELLY, JEFFERY W (contact)

PROJECT_TERMS: Activator Appliances;Address;Affinity Chromatography;Aftercare;Alkynes;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Alzheimer's disease related dementia;American;analog;Astrocytes;Autophagocytosis;Biological;Biological Assay;Biology;Biotin;Brain;brain cell;Cell Line;Cell model;Cells;Cellular Assay;Cellular Stress;Cellular Structures;Central Nervous System Degenerative Diseases;Cerebral cortex;Chronic;Communicable Diseases;Complex;CRISPR/Cas technology;cytotoxicity;Data;Diazomethane;Disease;disease phenotype;Dose;efficacy evaluation;Elderly;Ensure;Enzymes;Exhibits;experimental study;familial Alzheimer disease;FRAP1 gene;Functional disorder;Generations;Genetic;Genetic Transcription;Heterozygote;high risk;human disease;Hydrolase;Image;Immune system;improved;induced pluripotent stem cell;Induced pluripotent stem cell derived neurons;Inherited;Knowledge;Lead;Learning;lipidomics;Lipids;Literature;Lysosomes;Mass Spectrum Analysis;Mediating;metabolomics;Microglia;Mission;mitochondrial dysfunction;Modeling;Molecular Chaperones;molecular phenotype;Molecular Profiling;mTOR inhibition;mutant;Mutation;Neurodegenerative Disorders;Neuroglia;neuroinflammation;novel;Nucleic Acids;Oligosaccharides;Organoids;Oxidative Stress;Pathogenicity;Pathway interactions;Patients;Peptide Hydrolases;Pharmaceutical Preparations;pharmacologic;Pharmacologic Substance;Phenotype;Physiology;Population;programs;Proteins;Proteomics;Protocols documentation;Public Health;Reaction;Recycling;Regimen;Reproducibility;Research;Risk;RNA;screening;Signal Pathway;small molecule;Statistical Data Interpretation;Streptavidin;Stress;Testing;Toxic effect;transcription activator-like effector nucleases;transcriptional reprogramming;Translating;United States National Institutes of Health

PROJECT_TITLE: Pharmacologic Lysosomal Flux Activators to Ameliorate Alzheimer's Disease and Related Dementias

STUDY_SECTION: CMND

STUDY_SECTION_NAME: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]


NIH_SPENDING_CATS: Acquired Cognitive Impairment;Aging;Alzheimer's Disease;Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD);Biotechnology;Brain Disorders;Dementia;Genetics;Human Genome;Neurodegenerative;Neurosciences;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human

ORG_NAME: UNIVERSITY OF CALIFORNIA, SAN DIEGO

PHR: Microglia play both protective and pathogenic roles in neurodegenerative disease but mechanisms that specify or restrict these opposing activities remain poorly understood. In this proposal, we will test the hypothesis that defects in homeostatic functions of LXRs and SREBPs are broadly linked to pathological microglia phenotypes and investigate the potential of synthetic mimetics of endogenous LXR ligands to exert protective effects without causing side effects associated with conventional LXR agonists.

PI_NAMEs: COUFAL, NICOLE GABRIELE;GLASS, CHRISTOPHER K (contact);HOLTZMAN, DAVID M.

PROJECT_TERMS: Address;Age;Aging;Agonist;Alzheimer's disease related dementia;Animals;apolipoprotein E-3;apolipoprotein E-4;Binding;Brain;cell growth regulation;Cell Nucleus;Cholesterol;Clinical;clinical development;Defect;Desmosterol;Development;Engraftment;Epigenetic Process;experimental study;fatty acid metabolism;Gene Deletion;Genetic study;genome-wide;Goals;Haplotypes;Homeostasis;Human;human induced pluripotent stem cells;humanized mouse;Hypertriglyceridemia;immunodeficiency;In Vitro;in vivo;induced pluripotent stem cell;Inflammation;insight;Knock-out;Ligands;Link;lipid metabolism;lipidomics;Lipids;Macrophage;Microglia;mimetics;Modeling;Molecular;mouse model;Mus;Nerve Degeneration;Neurodegenerative Disorders;neuron loss;new technology;Pathogenicity;Pathologic;Pathway interactions;Pattern;Peripheral;Phagocytosis;Pharmaceutical Preparations;pharmacologic;Phenotype;Physiology;Play;Prevention;protective effect;Regulation;response;risk variant;Role;side effect;single-cell RNA sequencing;Sorting;Specific qualifier value;tau function;tau Proteins;technology development;Testing;Therapeutic;transcriptome;transcriptome sequencing;transcriptomics;translational potential;Work;Xenograft Model

PROJECT_TITLE: Perturbing the LXR/SREBP axis to decipher protective and pathogenic AD/ADRD microglial phenotypes