Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone

ABSTRACT Individuals with Alzheimer's disease (AD) are at an increased risk of bone fracture, while osteoporosis in women is one of the earliest predictors of AD. Yet the mechanisms linking cognitive decline and skeletal deterioration remain poorly defined. Proteomic analysis of cortical bone from aged 21‐month‐old mice revealed strong enrichment of neurodegeneration‐associated proteins, including apolipoprotein E (Apoe) and amyloid precursor protein. Apoe localized specifically to osteocytes, with expression in aged female bone nearly twice that of young 4‐month‐old male bone. Because human APOE alleles confer different age‐related AD risks, we examined their roles in bone using humanized APOE2, APOE3, and APOE4 knock‐in mice and analyzed bone and hippocampus from the same animals. APOE4 produced marked sex‐specific effects on the bone transcriptome and proteome compared with APOE2 or APOE3. Strikingly, APOE4‐associated proteomic disruptions were stronger in female bone than in the hippocampus. Functionally, APOE4 caused bone fragility in females without altering cortical structure. These deficits stemmed from impaired osteocyte perilacunocanalicular remodeling. Our findings identify APOE4 as a molecular driver of early osteocyte dysfunction and reduced bone quality, disproportionately affecting females. These findings highlight osteocytes as potential targets for early diagnosis of age‐related cognitive impairment and treatment for bone fragility, in females.