Sex Differences in the Metabolome of Alzheimer's Disease Progression.

Tomás González Zarzar,Dokyoon Kim,Brian Lee,Rory Coughlin,Molly A Hall,Li Shen

doi:10.3389/fradi.2022.782864

Tomás González Zarzar, Dokyoon Kim + Show 4 more

Open Access

https://doi.org/10.3389/fradi.2022.782864

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Abstract

Alzheimer's disease (AD) is the leading cause of dementia; however, men and women face differential AD prevalence, presentation, and progression risks. Characterizing metabolomic profiles during AD progression is fundamental to understand the metabolic disruptions and the biological pathways involved. However, outstanding questions remain of whether peripheral metabolic changes occur equally in men and women with AD. Here, we evaluated differential effects of metabolomic and brain volume associations between sexes. We used three cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI), evaluated 1,368 participants, two metabolomic platforms with 380 metabolites in total, and six brain segment volumes. Using dimension reduction techniques, we took advantage of the correlation structure of the brain volume phenotypes and the metabolite concentration values to reduce the number of tests while aggregating relevant biological structures. Using WGCNA, we aggregated modules of highly co-expressed metabolites. On the other hand, we used partial least squares regression-discriminant analysis (PLS-DA) to extract components of brain volumes that maximally co-vary with AD diagnosis as phenotypes. We tested for differences in effect sizes between sexes in the association between single metabolite and metabolite modules with the brain volume components. We found five metabolite modules and 125 single metabolites with significant differences between sexes. These results highlight a differential lipid disruption in AD progression between sexes. Men showed a greater negative association of phosphatidylcholines and sphingomyelins and a positive association of VLDL and large LDL with AD progression. In contrast, women showed a positive association of triglycerides in VLDL and small and medium LDL with AD progression. Explicitly identifying sex differences in metabolomics during AD progression can highlight particular metabolic disruptions in each sex. Our research study and strategy can lead to better-tailored studies and better-suited treatments that take sex differences into account.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia
We have shown that diverse phosphatidylcholines (PC), sphingomyelins (SM), acylcarnitines, amino acids, and different lipids in very low-density lipoproteins (VLDL) and lowdensity lipoproteins (LDL) have different associations between men and women with AD progression
Because the brain segments are corrected by intracranial volume (ICV), caution needs to be taken when interpreting the contribution of the different segments

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia. In the U.S, 5.7 million people lived with AD in 2018, and it is projected that by 2025, 7.1 million people in the U.S will have developed AD [1]. Most cases of AD and dementia occur in women, in the most elderly [2]. In the U.S, out of the 5.5 million people age 65 or older with AD, 3.4 million are women, and only 2 million are men [1]. The principal genetic risk factor of AD, the presence of the ǫ4 allele in the apolipoprotein E gene (APOEǫ4), confers a greater risk of developing AD in women compared to men [3]. Hippocampus atrophy rates occur faster in women than men [4]

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