Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism

Area of Science:

• Neuroscience
• Metabolic Health
• Genetics

Background:

• Osteocalcin (OCN) is a bone-derived peptide influencing glucose and lipid metabolism.
• An association between OCN and Alzheimer's disease (AD) risk is suggested, but causality and mechanisms are unclear.

Purpose of the Study:

• To investigate the causal effect of blood OCN levels on AD risk using Mendelian randomization (MR).
• To assess the potential role of glucose and lipid metabolism in mediating the OCN-AD relationship.

Main Methods:

• Utilized MR with genetic instrumental variables for blood OCN levels from proteome-wide association studies.
• Analyzed AD summary statistics from IGAP and FPAD datasets.
• Incorporated data on glucose and lipid metabolites (fasting glucose, total cholesterol) for multivariable MR analysis.

Main Results:

• Genetically determined higher blood OCN levels showed a significant protective effect against AD risk (IGAP & FPAD).
• Multivariable MR indicated that the OCN-AD causal link was abolished after adjusting for fasting glucose and total cholesterol.
• Analyses confirmed no significant horizontal pleiotropy and stable estimates.

Conclusions:

• Blood OCN levels exert a protective effect on AD risk.
• This protective effect is primarily mediated by the regulation of fasting glucose and total cholesterol levels.
• Further research is needed to elucidate the specific physio-pathological mechanisms involved.