A Dutch woman who died at age 115 without any symptoms of cognitive decline proved that cognitive decline is not inevitable. This leads to the question: how can cognitive health be maintained during human aging? To learn about the molecular mechanisms underlying this extraordinary phenomenon, we set up the 100-plus Study, a longitudinal cohort study of cognitively healthy centenarians with the primary aim to identify protective genetic and biomolecular factors that associate with the escape of cognitive decline.
Currently the cohort includes more than 450 healthy centenarians whom we subject annually to an extensive neuropsychological testing battery. We collect medical, family and life history, and various biomaterials including blood samples, faeces samples, and ~30% of the centenarians agrees to post-mortem brain donation.
Compared to individuals born in the same birth-year, centenarians are mostly from the higher social economic classes, have a relatively high education, and slightly more children, and they are mostly optimistic individuals. After reaching 100 years in cognitive health, many centenarians remain cognitively healthy until death. Centenarians are depleted with genetic elements associated with increased risk of Alzheimer's Disease, while they are enriched with protective genetic elements. This genetic protection is especially focused on maintaining a functional immune- and endolysosomal system. Amyloid-beta is widely spread in centenarian-brains, while loads stay low. Some centenarians are resistant, while others are resilient to tau and/or other neuropathological hallmarks of neurodegenerative disease. Based on specific aspects of their brain proteome, centenarian-brains are up to decades younger than expected according to their age, which pinpoints important proteomic determinants of maintaining brain health.
In my presentation, I will cover the latest results of the 100-plus Study, covering neuropsychological, genetic, neuropathological, brain proteomic, and immunological findings.