Abstract
Introduction: Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer's disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain;however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer's diseased tissue to highlight the differences between healthy andpathological brain ageing. Results: Our data indicates that compared to an Alzheimer's disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However,morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed. Conclusions: Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change.