Plaque-associated oligodendrocyte proteostatic failure underlies myelin loss in Alzheimer’s disease

Alzheimer’s disease (AD) features amyloid-β plaques and tau pathology, yet the mechanism underlying early and clinically significant myelin loss remains unresolved. Here, we report human iPSC-derived forebrain organoids with doxycycline-inducible expression of SOX10, OLIG2, and NKX6-2 (SON), which generate robust, mature oligodendrocytes and compact myelin in vitro and in vivo. Introducing amyloid precursor protein (APP) pathogenic mutations produces extracellular amyloid-β plaques and phosphorylated tau, accompanied by reduced myelin basic protein (MBP) expression and disrupted myelin ultrastructure. Single-cell and spatial transcriptomics combined with amyloid plaque imaging reveal a plaque density-dependent oligodendrocyte transcriptional reprogramming that coordinately induces immune activation, calcium signaling, lipid remodeling, and proteasomal subunit remodeling, a program incompatible with MBP protein accumulation. This program is conserved in human AD postmortem tissues, implicating proteostatic disruption as a mechanism underlying the transcript–protein disconnect and myelin loss in AD.