Mapping Brain Resilience in the Oldest-Old: A Multi-Omic Atlas of Cognitive Protection

This project will create the first spatially resolved, single-cell multi-omics atlas of the oldest-old brain to uncover the molecular, epigenomic, and genetic programs that protect some individuals from cognitive decline despite Alzheimer’s disease pathology.

Alzheimer’s disease is the leading cause of dementia, yet people aged 90 and older show striking differences in how their brains are affected. Some remain sharp despite heavy Alzheimer’s changes, while others develop memory loss with little evidence of the disease. This project will use advanced state-of-the art genomics tools to uncover why some of the oldest-old stay resilient, with the goal of identifying new ways to protect brain health as we age and also in disease.

This is the first project to implement a unified single-cell spatial multi-omics framework integrating spatially encoded transcriptomics, epigenomics, and whole-genome sequencing in the oldest-old brain. Unlike prior studies examining individual molecular layers in isolation, our approach preserves native tissue context and bridges transcriptional, regulatory, and genetic layers within the same tissue sections. We will also generate the first spatial eQTL and caQTL maps of the oldest-old brain, enabling genotype-phenotype correlations at single-cell resolution.

This research will identify protective molecular programs and genetic factors that enable some individuals to maintain cognition despite Alzheimer’s disease pathology, shifting the field toward resilience-based therapeutic strategies. The resulting multi-omic atlas will serve as a foundational public resource for the research community, accelerating discovery of new drug targets. For the general public, findings could lead to novel approaches for promoting brain health in late life and precision medicine strategies to prevent or delay cognitive decline.