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. 2023 Aug;19(8):3496-3505.
doi: 10.1002/alz.12954. Epub 2023 Feb 22.

Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study

Sokratis Charisis  1 , Honghuang Lin  2   3   4 , Roshni Ray  5 , Roby Joehanes  3   6 , Alexa S Beiser  2   3   7 , Daniel Levy  3   6 , Sudha Seshadri  1   2   3 , Muralidharan Sargurupremraj  1 , Claudia L Satizabal  1   2   3
Affiliations

Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study

Sokratis Charisis et al. Alzheimers Dement. 2023 Aug.

Abstract

Introduction: We investigated associations of obesity with the expression of Alzheimer's disease (AD)-related genes in a large community-based cohort.

Methods: The sample consisted of 5619 participants from the Framingham Heart Study. Obesity metrics included body mass index (BMI) and waist-to-hip ratio (WHR). Gene expression was measured for a set of 74 AD-related genes, derived by integrating genome-wide association study results with functional genomics data.

Results: Obesity metrics were associated with the expression of 21 AD-related genes. The strongest associations were observed with CLU, CD2AP, KLC3, and FCER1G. Unique associations were noted with TSPAN14, SLC24A4 for BMI, and ZSCAN21, BCKDK for WHR. After adjustment for cardiovascular risk factors, 13 associations remained significant for BMI and 8 for WHR. Dichotomous obesity metrics exhibited unique associations with EPHX2 for BMI, and with TSPAN14 for WHR.

Discussion: Obesity was associated with AD-related gene expression; these findings shed light on the molecular pathways linking obesity to AD.

Keywords: Alzheimer's disease; dementia; functional genomics; gene expression; genome-wide association study; obesity.

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Conflict of interest statement

Conflicts of Interest

The authors report no disclosures relevant to the manuscript. Author disclosures are available in the supporting information.

Figures

Figure 1:
Figure 1:
Summary of TWAS results. Each data point represents a gene grouped by chromosome (x-axis) and its respective z-score (y-axis), illustrating the direction of effect for expression of transcripts encoding AD-related genes. Only significant transcriptome-wide associations are presented.
Figure 2:
Figure 2:
Associations of different obesity metrics (x-axis) with Alzheimer’s disease-related gene expression (y-axis). Results from linear mixed models with gene expression as the outcome and the different obesity metrics as the main predictors. Models are adjusted for age, sex, and differential cell counts. BMI, body mass index; WHR, waist-to-hip ratio.
Figure 3:
Figure 3:
Associations of different obesity metrics (x-axis) with Alzheimer’s disease-related gene expression (y-axis). Results from linear mixed models with gene expression as the outcome and the different obesity metrics as the main predictors. Models are adjusted for age, sex, differential cell counts, and cardiovascular risk factors. BMI, body mass index; WHR, waist-to-hip ratio.
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