Unraveling the impact of blood RANKL and OPG levels on Alzheimer's disease: Independent of bone mineral density and inflammation

Introduction: Observational studies have revealed a close relationship between reduced bone mineral density (BMD) and Alzheimer's disease (AD) risk. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) system, pivotal in regulating bone metabolism, has been implicated in brain function, but the causal impact on AD risk remains unclear.

Methods: We employed bi-directional Mendelian randomization (MR) and multivariable MR (MVMR) approaches to elucidate the effect of blood soluble RANKL (sRANKL) and OPG levels on AD, assessing whether this influence was independent of BMD and inflammation. Three distinct AD genome-wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary-level data on blood sRANKL and OPG were sourced from deCODE Genetics.

Results: Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.72-0.94, p = 0.004; UKB: OR = 0.85, 95% CI = 0.78-0.91, p < 0.001; FinnGen: OR = 0.83, 95% CI = 0.73-0.94, p = 0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin-1α and chemoattractant protein-1.

Discussion: Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. These findings enhance our understanding of the complex interactions between bone metabolism and AD.

Highlights: Blood soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) levels are linked to a reduced risk of Alzheimer's disease (AD).The association between sRANKL levels and AD is independent of bone mineral density (BMD) and inflammation.No causal link exists between blood osteoprotegerin levels and AD.AD does not affect blood levels of sRANKL or osteoprotegerin.