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Study of Alzheimer's disease and other dementias (e.g. frontotemporal dementia) and related phenotypes

PI
Goate, Alison
DAR ID
10008
Initial Approval Date
September 17, 2018
Current DAR Status
Active
PI Institution
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
PI Institution Country
United States
PI Institution Type
Non-Profit

Requested Datasets (39)

NG00067Alzheimer's Disease Sequencing Project Umbrella StudyNG00108Profiling microglia expression profiles in AD using single-nuclei RNA-seqNG00105MiGA – Microglia Genomic AtlasNG00106LASI-DAD Genotyping Chip Data (Illumina Infinium GSA-24 v2.0), Imputed Data (1000 Genomes Phase 3 v5 and TOPMed r2)NG00104Dataset from Clinical and Pathological Studies in the Oldest Old (90+ Study)NG00117NCRAD Families GWASNG00129NCRAD Families Whole Exome SequencingNG00134National Health and Aging Trends Study (NHATS) GWASNG00130Large scale CSF proteogenomic atlasNG00131Large scale genetics study on CSF and brain metabolite levelsNG00102Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disordersNG00153Health and Retirement Study (HRS) DNA Methylation
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NG00022ADC1 - Alzheimer's Disease Center Dataset 1NG00023ADC2 - Alzheimer's Disease Center Dataset 2NG00024ADC3 - Alzheimer's Disease Center Dataset 3NG00068ADC4 - Alzheimer's Disease Center Dataset 4NG00069ADC5 - Alzheimer's Disease Center Dataset 5NG00070ADC6 - Alzheimer's Disease Center Dataset 6NG00071ADC7 - Alzheimer's Disease Center Dataset 7NG00136ADC8 - Alzheimer's Disease Center Dataset 8NG00137ADC9 - Alzheimer's Disease Center Dataset 9NG00138ADC10 - Alzheimer's Disease Center Dataset 10NG00139ADC11 - Alzheimer's Disease Center Dataset 11NG00140ADC12 - Alzheimer's Disease Center Dataset 12NG00149ADC13 - Alzheimer's Disease Center Dataset 13NG00150ADC14 - Alzheimer's Disease Center Dataset 14NG00151ADC15 - Alzheimer's Disease Center Dataset 15NG00156Genetic variants and functional pathways associated with resilience to Alzheimer's diseaseNG00147Amyloid Neuroimaging and Genetics Initiative (ANGI) GWASNG00169Progressive Supranuclear Palsy (PSP) Summary Statistics- Farrell et al., 2024NG00172GWAS Summary Statistics of SNVs/INDELs/SVs for Progressive Supranuclear Palsy (PSP) – Wang et al., 2024NG00174Whole Genome Sequencing (WGS) and SNP Array data for the SEA-AD Consortium CohortNG00100Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis. Kunkle et al. (2021)NG00035GWAS of CSF tau levels identifies risk variants for Alzheimer’s DiseaseNG00082UAB/HudsonAlpha Families with Neurodegenerative DiseasesNG00075IGAP Rare Variant Summary Statistics- Kunkle et al. (2019)NG00177ADGC Multi-Ancestry GWAS Meta-Analysis – Rajabli et al., 2025NG00179AD GWAS in participants of African ancestry – Ray et al., 2024NG00175Genome-wide association study of neuropathology endophenotypes

Research Use Statement
Alzheimer's disease (AD) is the most common form of dementia but has no effective prevention or treatment. Developing a comprehensive picture of the genetic architecture of AD including a network level functional assessment of risk/resilience genes is essential to develop novel therapeutic targets. The overarching goals of this study are to use genetic and genomic approaches to: 1) identify genes and variants that are involved in the development of AD and related disorders; 2) identify functional networks enriched for AD or related disorder risk and protective loci; 3) determine how cellular function and physiology is impacted by these genetic factors in disease-relevant cell types and animal models. This study will use publicly available whole genome/exome sequence data generated by the Alzheimer’s Disease Sequencing Project (ADSP) and genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) and others. We will apply a suite of case-control and family approaches to investigate genetic association with dichotomous and continuous disease traits. This study will not only further our understanding of the genetic architecture of AD but also provide key information regarding the molecular mechanisms, setting the stage for novel therapeutic development.

Non-Technical Summary
Alzheimer’s disease (AD) is the only disease among the top ten killers in the U.S. without a disease modifying therapy. Genetic studies provide a powerful means to identify genes and pathways that are causally linked to disease etiology. We propose to use genomic and functional approaches to identify genes that alter the risk of AD and investigate how these genes disrupt cellular pathways leading to disease.

Reported Publications (26)

Publications shown are those reported by investigators through NIAGADS DAR reporting and renewal processes and may not represent a complete list of publications associated with the project.

  1. CASP8 intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer's disease risk. Nguyen L, et al. Proceedings of the National Academy of Sciences of the United States of America. 2025. PMID: 39937857
  2. Evaluating the causal effect of mitochondrial dysfunction on Alzheimer's and Parkinson's disease using Polygenic Risk Scores and Mendelian Randomization. Chatterjee A, et al. medRxiv : the preprint server for health sciences. 2025. PMID: 41040731
  3. Frequency of variants in Mendelian Alzheimer's disease genes within the Alzheimer's Disease Sequencing Project. Wang D, et al. Journal of Alzheimer's disease : JAD. 2025. PMID: 40084664
  4. GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy. Cruchaga C, et al. Research square. 2025. PMID: 40470240
  5. Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing. Humphrey J, et al. Nature genetics. 2025. PMID: 40033057
  6. Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease. Rajabli F, et al. Genome biology. 2025. PMID: 40676597
  7. Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease. Phillips JM, et al. Brain : a journal of neurology. 2025. PMID: 40111762
  8. Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations. Nicolas A, et al. Nature genetics. 2025. PMID: 40533518
  9. BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues. Podleśny-Drabiniok A, et al. Nature communications. 2024. PMID: 38448474
  10. Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes. Farrell K, et al. Nature communications. 2024. PMID: 39251599
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  1. BHLHE40/41 regulate macrophage/microglia responses associated with Alzheimer's disease and other disorders of lipid-rich tissues. Podlesny-Drabiniok A, et al. bioRxiv : the preprint server for biology. 2023. PMID: 36824752
  2. The complex genetic architecture of Alzheimer's disease: novel insights and future directions. Andrews SJ, et al. EBioMedicine. 2023. PMID: 36907103
  3. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Tcw J, et al. Cell. 2022. PMID: 35750033
  4. Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD. Bowles KR, et al. Acta neuropathologica. 2022. PMID: 34874463
  5. Genome-wide association study and functional validation implicates JADE1 in tauopathy. Farrell K, et al. Acta neuropathologica. 2022. PMID: 34719765
  6. Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease. Horgusluoglu E, et al. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2022. PMID: 34757660
  7. New insights into the genetic etiology of Alzheimer's disease and related dementias. Bellenguez C, et al. Nature genetics. 2022. PMID: 35379992
  8. The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery. Reyes-Dumeyer D, et al. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2022. PMID: 34978149
  9. A globally diverse reference alignment and panel for imputation of mitochondrial DNA variants. McInerney TW, et al. BMC bioinformatics. 2021. PMID: 34470617
  10. Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population. Riaz M, et al. Aging cell. 2021. PMID: 34041846
  11. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Chia R, et al. Nature genetics. 2021. PMID: 33589841
  12. Heterogeneous effects of genetic risk for Alzheimer's disease on the phenome. Wu HM, et al. Translational psychiatry. 2021. PMID: 34301914
  13. Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes. Novikova G, et al. Nature communications. 2021. PMID: 33712570
  14. Large-scale sequencing studies expand the known genetic architecture of Alzheimer's disease. Xue D, et al. Alzheimer's & dementia (Amsterdam, Netherlands). 2021. PMID: 35005195
  15. Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases. Kapoor M, et al. Nature communications. 2021. PMID: 34417470
  16. Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes. Huq AJ, et al. Alzheimer's & dementia (Amsterdam, Netherlands). 2021. PMID: 34386572