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. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.