Identifying the earliest molecular changes in the brain that precede cognitive decline is essential for preventing age-related dementias like Alzheimer’s disease (AD). The Holstege team has access to a unique collection of brain samples from people who lived past 100 (centenarians) through the 100-plus Study cohort. This cohort includes detailed records of how these centenarians’ cognition changed over time, their genetic information, brain tissue samples from different brain regions, and blood samples collected over the years. Using these materials, the team will apply multi-omics profiling—encompassing proteomics, phospho-proteomics, lipidomics, and metabolomics—in two key brain areas (entorhinal cortex and grey temporal matter) from 125 centenarian brains.
Dr. Holstege hypothesizes that initial molecular alterations in these brain regions represent early precursors to late-onset cognitive decline. In Aim 1, the team will characterize these molecular changes by applying multi-omics profiling across the centenarian cohort. In Aim 2, they will define single-cell states associated with cognitive resilience or resistance to amyloid beta accumulation, tau pathology, and APOE4 genotype, using long-read transcriptomics and spatial proteomics in a subset of 30 brains. Aim 3 will test whether the molecular signatures they find in the brain are also reflected in blood samples collected over time, potentially identifying early blood-based biomarkers of cognitive decline.
By integrating these multi-omic data with clinical and genetic information, the team aims to construct a detailed picture of the earliest neurodegenerative events underlying cognitive decline. Validated protein signatures will be shared with the Brain Aging Consortium for independent validation. Collaborations within the consortium will enable cross-platform integration, mechanistic follow-up, and functional studies, advancing understanding of biological resilience and vulnerability in aging and AD.
