Johns Hopkins researchers employing limited proteolysis mass spectrometry (LiP-MS) identified over 200 misfolded proteins associated with cognitive decline in aged rat models, challenging the amyloid-beta and tau-centric paradigm dominating Alzheimer’s disease research. These cognition-associated structural changes (CASCs) suggest broader proteostatic impairments may contribute to dementia. Published in Science Advances, the study supports investigating diverse protein misfolding events as novel therapeutic targets to address major societal burdens posed by age-related cognitive decline.