Epigenomics and Lipidomics Integration in Alzheimer Disease: Pathways Involved in Early Stages

Abstract

Background: Alzheimer Disease (AD) is the most prevalent dementia. However, the physiopathological mechanisms involved in its development are unclear. In this sense, a multi-omics approach could provide some progress. Methods: Epigenomic and lipidomic analysis were carried out in plasma samples from patients with mild cognitive impairment (MCI) due to AD (n = 22), and healthy controls (n = 5). Then, omics integration between microRNAs (miRNAs) and lipids was performed by Sparse Partial Least Squares (s-PLS) regression and target genes for the selected miRNAs were identified. Results: 25 miRNAs and 25 lipids with higher loadings in the sPLS regression were selected. Lipids from phosphatidylethanolamines (PE), lysophosphatidylcholines (LPC), ceramides, phosphatidylcholines (PC), triglycerides (TG) and several long chain fatty acids families were identified as differentially expressed in AD. Among them, several fatty acids showed strong positive correlations with miRNAs studied. In fact, these miRNAs regulated genes implied in fatty acids metabolism, as elongation of very long-chain fatty acids (ELOVL), and fatty acid desaturases (FADs). Conclusions: The lipidomic–epigenomic integration showed that several lipids and miRNAs were differentially expressed in AD, being the fatty acids mechanisms potentially involved in the disease development. However, further work about targeted analysis should be carried out in a larger cohort, in order to validate these preliminary results and study the proposed pathways in detail.

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

“…Lipid peroxidation, caused by oxidative stress, is one of the most-studied markers of disease, and various molecules have been proposed as potential circulating biomarkers (See Section 3.5 Oxidative Stress ) [ 166 , 167 , 182 , 305 , 306 , 307 ]. Concerning fatty acids, dysregulation in their profile is linked to increased risk of dementia, with hexacosanoid acid (C26:0) being the most upregulated both in plasma and red blood cells of AD patients [ 303 , 308 , 309 ]. A correlation between the primary fatty acid amide level in plasma and Aβ pathology, hippocampal volume, and cognitive score was also reported [ 310 ].…”

RNA N6-Methyladenosine Modifications and Its Roles in Alzheimer’s Disease

“… Jaouen and Gascon (2016) described miR-33 function modulating ATP-binding cassette transporter A1 (ABCA1) and interfering with Aβ plaque formation through cholesterol metabolism regulation. Peña-Bautista et al (2021) found hsa-miR-421 showed a positive correlation with some detected lipids (FA (16:0), FA (20:2), FA (18:2), FA (20:4), FA (20:3), FA (18:0), FA (14:0)) in AD plasma samples. Docosahexaenoic acids (DHA) are known to be beneficial in AD.…”

Metabolic Overlap between Alzheimer’s Disease and Metabolic Syndrome Identifies the PVRL2 Gene as a New Modulator of Diabetic Dyslipidemia

“…Several genetic strategies have been carried out in recent years to facilitate the identification of molecular players in AD. GWASs [ 17 , 46 ], targeted polygenic studies [ 47 , 48 ], multiomic strategies [ 49 ], and even genetic pleiotropy approaches have been performed [ 16 ], and a strong relationship between circulating lipids and genetic factors related to AD has been described [ 47 ]. However, other studies have found no conclusive relationship between lipids and AD using Mendelian randomization [ 50 ]; therefore, this is a topic that still requires attention.…”