Scientists at the Buck Institute on Aging, along with collaborators at the University of California, San Francisco, have discovered that APOE4, the most common genetic risk factor for Alzheimer’s disease, causes bone defects specifically in female mice through a mechanism that is invisible to standard imaging and can appear as early as middle age.
The survey results are cutting edge sciencerevealed an unexpected biological link between Alzheimer’s disease risk and skeletal health and identified a new molecular pathway that may one day inform early diagnosis of cognitive decline or guide treatment of bone loss in women who carry the APOE4 gene.
What makes this finding so impressive is that bone quality is compromised at a molecular level that cannot be captured by standard bone scans. APOE4 quietly destroys the very cells responsible for keeping bones strong, especially in women, and this mirrors what we’re seeing with Alzheimer’s disease risk. ”
Dr. Birgit Schilling, Professor Back, lead author of the study
Doctors have long observed that patients with Alzheimer’s disease have higher fracture rates and that a diagnosis of osteoporosis in women is actually the earliest known predictor of Alzheimer’s disease. However, the fundamental mechanism linking brain and bone health remains unclear.
To investigate this link, researchers led by research scientist and co-lead author Charles Schulman, Ph.D., first conducted a proteomic analysis of the bones of aging mice, a comprehensive survey of all the proteins present in the tissue. “The research team discovered that bones, and in particular the long-lived cells embedded within them, osteocytes, are unusually enriched in proteins associated with neurological diseases, such as apolipoprotein E (APOE) and amyloid precursor protein,” says Professor Schulman. “Notably, APOE expression in bone cells was twice as high in old female mice as in young or male mice.”
The team then turned to humanized mouse models carrying either APOE2 (associated with reduced Alzheimer’s disease risk), APOE3 (considered neutral), or APOE4 (a risk variant) and analyzed bone and hippocampal tissue from the same animals. APOE4 had strong sex-specific effects on both the bone transcriptome and proteome. The researchers found that the disruption of protein levels in bone was actually more pronounced than the corresponding changes in the hippocampus.
Despite the disruption of protein levels, the cortical bone structure appeared normal on imaging. The researchers found that defects in bone quality result not from changes in bone shape or density, but from APOE4’s inhibition of periluminal/canalicular remodeling, a process in which osteocytes actively maintain microscopic channels that maintain bone mechanical elasticity. When this maintenance is disrupted, the quality of the bone deteriorates, even if it appears intact.
“These results suggest that bone cells may act as early biological sentinels against age-related cognitive decline in women who carry APOE4,” said Professor Lisa Ellerbee, senior author of the paper. The Ellerbee Lab studies genetic risk factors for Alzheimer’s disease. “We believe that targeting bone cell function may open new avenues in maintaining bone quality in this population.”
Researchers say this study has significant implications for linking brain and bone science. “While we believe this study is relevant to human patients with Alzheimer’s disease and osteoporosis, it also highlights the need for researchers to think of the human body as a whole system, rather than separating organs and diseases from each other,” Ellerbee says.
sauce:
Buck Aging Research Institute
Reference magazines:
Schulman, California Others. (2026). Alzheimer’s disease risk factor APOE4 has dimorphic effects on bones in women. cutting edge science. DOI: 10.1002/advs.202523511. https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202523511
