Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. We find 579 proteins associated with cognitive trajectory after meta-analysis. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery ( nā=ā104) and replication cohort ( nā=ā39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline.
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