Alzheimer's Disease: Causal Effect between Obesity and APOE Gene Polymorphisms

Area of Science:

• Neuroscience
• Genetics
• Metabolic Disorders

Background:

• The relationship between obesity and Alzheimer's disease (AD) remains unclear.
• Existing research often uses limited obesity indicators, hindering comprehensive analysis of body fat's impact on AD.
• A need exists to identify key molecular targets and causal links between obesity metrics and AD pathogenesis.

Purpose of the Study:

• To identify key molecular targets linking obesity and Alzheimer's disease (AD) using bioinformatics.
• To investigate the causal associations between various obesity indicators and these targets via Mendelian randomization (MR).
• To clarify the role of body fat mass and distribution in obesity-related AD.

Main Methods:

• Screened common targets of obesity and AD using the GeneCards database.
• Performed functional and pathway annotations to identify key targets.
• Conducted Mendelian randomization (MR) analysis using an IVW model with body anthropometric indexes and the identified target.

Main Results:

• Apolipoprotein E (APOE) was identified as the key target connecting obesity and AD.
• Body mass index (BMI), body fat percentage (BFP), and trunk fat percentage (TFP) showed a negative causal association with APOE3.
• No significant causal associations were found between BMI, BFP, TFP, and APOE2 or APOE4.

Conclusions:

• Obesity's correlation with AD is primarily mediated by APOE gene polymorphism, not adipose tissue distribution.
• APOE3 carriers may have increased susceptibility to obesity, potentially increasing AD risk.
• Obesity may not be a direct causal factor for AD in APOE2 and APOE4 carriers; early body fat regulation in APOE3 carriers is suggested to mitigate AD risk.