Shifts in protein aggregate stability define proteostasis decline in the aging human brain

Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Using detergent-fractionation proteomics, we show that human brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife. Maximum-stability aggregates decline sharply in old age whereas intermediate-stability aggregates accumulate gradually before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched with Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone abundance predict individual differences in aggregate burden as strongly as age, offering supportive evidence, in humans, for therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position the accumulation of intermediate-stability aggregates as a molecular event on the path to neurodegenerative disease.