Kyle Severson: 

Leyla Akay: Vulnerability and Resilience in Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, but the cellular pathways underlying its progression across brain regions remain poorly understood. Here, we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without AD. We identify vulnerable populations of excitatory and inhibitory neurons depleted in specific brain regions in AD, and provide evidence for the involvement of the Reelin signaling pathway in modulating these neurons’ vulnerability. We uncover an astrocyte program associated with cognitive resilience to AD pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our work develops a regional atlas of the aging human brain and provides insights into cellular vulnerability, response, and resilience to Alzheimer’s disease pathology.