Seeing inside the brain: the in-tissue structure of living and postmortem Alzheimer’s disease human donor brain by high-resolution cryo-electron tomography.

Alzheimer’s disease (AD) is a challenging problem because it spreads insidiously within the brain decades before cognitive decline. Consequently, our understanding of molecular and cellular pathological mechanisms in early- stage AD is incomplete. AD progression is also affected by prevalent genetic APOE variants, and co-pathology associated with related dementias. To address this challenge requires new technology capable of interrogating molecular and cellular mechanism within AD patient brain. We recently used cryo-electron tomography to determine the first in-tissue structure and molecular architecture of AD pathology within post-mortem donor brain. Building on this advance, we will develop an interdisciplinary framework to investigate AD pathology directly in brain tissue—spanning length scales from protein structure to molecular and cellular architecture—using both surgical biopsies from living donors with early-stage AD (pre-symptomatic/prodromal) and fresh late-stage AD brain. We will directly link our in-tissue molecular and cellular resolution maps with clinical profile (genetics, cognitive assessments and neuropathology) and longitudinal profiling of living donor participants. Through this we aim to understand the structural basis of pathological mechanisms in early-stage AD human brain and how this drives conversion to late-stage AD, how APOE haplotype accelerates disease progression, and the structural relationship between AD and co-pathology.