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NOBEL PRIZE 2026

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NIHNATIONAL INSTITUTE ON AGINGR01

Systems Genetics Analysis of Sex Differences in Alzheimer's Disease

Completed
Institution
UNIVERSITY OF MICHIGAN AT ANN ARBOR, MI
Principal investigator
Catherine Cook Kaczorowski
Funding
$1.1M
Duration
2021–2026
Open portfolio

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Still being scored

Abstract

PROJECT SUMMARY Our proposed research aims to identify sex-specific genetic drivers of neuropathologic, cognitive, and metabolic phenotypes of Alzheimer’s disease by integrating longitudinal behavioral and molecular data from AD mice with genetic, genomic and clinical data from human cohorts. We will leverage a newly generated mouse population that incorporates high-risk familial AD (FAD) mutations on a genetically diverse background (BXD panel) to identify modifiers that contribute to AD resilience in this ‘humanized’ mouse population. In parallel, we will incorporate cutting-edge single-cell omic approachs to generate a molecular atlas of human brains from carriers of FAD mutations (in APP, PSEN1 and PSEN2) and non-carriers with sporadic AD. By combining and validating analyses in both mouse and human datasets, we expect to find molecular candidates that robustly contribute to sex-specific variation in symptoms of AD. We will further validate these candidates using unparalleled in vivo mouse technology to not only empircally assess their role in sex-specific mechanisms of disease, but also to evaluate sex X genotype X treatment interactions in a subset of candidates (i.e., Apoe) to inform more personalized therapeutic approaches. The approach we propose benefits from the enhanced discovery power and value of existing human genetics resources and novel, precision AD mouse models across multiple institutions to investigate the mechanisms of sex differences in AD.

Research team

  • Oscar HarariPI
  • Timothy J HohmanPI
  • Catherine Cook KaczorowskiPI

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R01NATIONAL INSTITUTE ON AGINGZAG1-ZIJ-8(M1)mousesex differencessexgenetically diversehuman brainsfadsex-specificcandidates

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