For years, doctors have noticed that many women weakened by osteoporosis end up, a few years later, being diagnosed with Alzheimer’s disease. The coincidence is intriguing, especially since these two pathologies mainly affect women after menopause. A new American study provides the beginnings of a biological answer to this confusing link.
Their results suggest that, in females, this gene weakens bone quality well before cognitive symptoms, which could concern some women already diagnosed with osteoporosis.
Female osteoporosis and the APOE4 gene: what the study shows
Doctors have long observed that people suffering from Alzheimer’s disease have a greater propensity for bone fractures, and that osteoporosis in women is actually the earliest predictive sign of this disease. However, the link between brain and bone health remains a mystery. Researchers from the Buck Institute for Research on Aging and UC San Francisco explored the impact of the APOE4 gene, the leading genetic risk factor for Alzheimer’s, on bones and brains in mice.
In humans, the APOE ε4 allele increases the risk of developing late-onset Alzheimer’s disease from approximately 10 to 20% for a non-carrier to 30 to 50% in heterozygotes, and up to 50 to 70% in homozygotes.
After an exhaustive study of all the proteins present in the bone tissue of aged mice, scientists discovered that this tissue, and in particular the osteocytes (the long-lived cells that make it up), was surprisingly rich in molecules associated with neurological diseases, such as apolipoprotein E (APOE) and amyloid precursor protein. APOE expression in these cells was approximately twice as high in aged female mice as in male or young mice.
To understand its role outside the brain, the team used “humanized” mice carrying APOE2 (reduced risk of Alzheimer’s), APOE3 (neutral risk) or APOE4 (the variant most at risk) and analyzed bone and hippocampal tissues from the same animals. The results showed that APOE4 had significant and sex-specific impacts on bone tissue. The researchers observed that the protein alterations in the bones were actually more pronounced than the equivalent changes in the hippocampus.
Fragile but “normal” bones on imaging: quality rather than quantity
On bone mineral density scans, the bones of APOE4 mice appeared identical to those of APOE3 controls: same shape, same cortical thickness. But in mechanical testing, the bones of APOE4 females were found to be almost twice as fragile, less rigid and less able to absorb shock. The researchers showed that the problem came from perilacunar remodeling, this “maintenance service” provided by osteocytes in a network of tiny canals.
“What makes this finding so striking is that bone quality is altered at a molecular level that a standard bone scan simply cannot detect.”explains Professor Birgit Schilling of Buck University and lead author of the study. “APOE4 insidiously disrupts the cells responsible for bone strength, specifically in women, which corresponds to what we observe for the risk of Alzheimer’s disease..
In other words, the intimate architecture of the bone deteriorated while the images remained reassuring. “These results suggest that osteocytes may serve as early biological sentinels of age-related cognitive decline in women carrying APOE4“, said Professor Lisa Ellerby, also co-lead author of the article.
What does this discovery mean for women who already have osteoporosis?
The authors point out that, in women, a diagnosis of osteoporosis precedes that of Alzheimer’s by an average of seven years and that patients already suffering from dementia suffer 2 to 2.5 times more fractures. Their work suggests that part of this vulnerability is due to the gene APOE4without all osteoporotic women being carriers.
Experts say these findings highlight the importance of seeing the human body as an interconnected whole, rather than approaching diseases in isolation.