Neuroproteomics of cognitively healthy centenarians in the context of aging and Alzheimer's disease.

Abstract

Aging is often accompanied by neurodegenerative diseases such as Alzheimer's disease (AD), and their associated neuropathological hallmarks. Few individuals are able to maintain cognitive health until extreme ages, such as cognitively healthy centenarians, despite displaying substantial pathology in their brains. Here we report on a unique and large single-center proteomics study providing insight into proteome changes occurring with AD and aging. We investigate which mechanisms could be involved in maintaining cognitive health at extreme ages in the presence of pathology. We performed quantitative proteomics on middle temporal lobe tissue for a cohort of 61 non-demented and 91 AD individuals across the age-continuum, and 58 centenarians from the 100-plus Study. We performed enrichment analyses for cell-types and GO-terms using multiple approaches (Figure 1). We identified 3,448 proteins, among which proteins associated with AD Braak stage or age. 472 proteins were associated with Braak stages, independent of age. Cell-type enrichment revealed that with increasing Braak stages, the abundance of astrocytic proteins increased while the abundance of neuronal proteins decreased. Among centenarians we identified 13 proteins that that differ in abundance from AD cases with the same Braak stage (IV). These included ubiquitin, cytoskeletal and synaptic proteins. Additionally, we identified 174 age-related proteins in non-demented controls. Of these, 97 were expressed in centenarians at levels different from those predicted for their age. Cell-type enrichment revealed that the abundance of oligodendrocytic proteins decreased with age, whereas the abundance of astrocytic proteins was increased with age and Braak stage. Progressive AD stages are associated with increased abundance of astrocytic- and lower abundance of neuronal proteins, while healthy aging is associated with a lower abundance of oligodendrocytic proteins and higher abundance of astrocytic proteins. In this study we identified proteins in the centenarians that deviate in level from prediction based on age. How these proteins act on cognition needs to be investigated further. Centenarian-specific proteins at Braak stage IV may indicate mechanisms protecting against cognitive decline, whereas the centenarian-specific age-related proteins might indicate processes that prevent adverse brain aging.