TN2 Symposium: Causality through the lens of ageing

Henne Holstege shares her time as a full professor at the Center for Brain Research (VIB/KU Leuven Belgium), and as an Associate Professor at Amsterdam UMC, (The Netherlands).

How can cognitive health be maintained during human aging? To identify protective genetic and biomolecular factors that associate with the escape of cognitive decline, we set up the 100-plus Study, a longitudinal cohort study of cognitively healthy centenarians. Currently, the cohort includes >500 centenarians. We collect blood and faeces samples, and ~30% of the centenarians agree to postmortem brain donation. This centenarian brain cohort offers a unique window into mechanisms underlying this neuroprotection.
Centenarians with very high levels of cognitive performance mostly maintain this until death. Neuropathological analysis indicates that these high performers resisted critical development of amyloid-β plaques, and tau abundance was low across all centenarians. We estimated that ~60% of the probability of becoming a cognitively healthy centenarian is heritable, suggesting that there is a genetic basis underlying this protection against the accumulation of neuropathology despite reaching extreme ages. Indeed, closer investigations indicate that the genomes of this group are enriched with genetic variants that protect against Alzheimer’s Disease, while they are depleted with risk-increasing genetic variants. Brain protein profiling indicated that centenarians conserved brain health by maintaining proteostasis (low ubiquitin peptides, high proteasome components), high PCSK1 (prohormone maturation), high PFKFB2 (glycolysis regulation), mitochondria-coupled lipid β oxidation and lower APOE levels. Together, our findings suggest that, in a model where Aβ facilitates tau seeding, centenarians maintain brain health by actively buffering against tau accumulation.