From a recent study published in the International Journal of Molecular Sciencesa group of researchers systematically evaluated the genetic overlap between Alzheimer’s disease (AD) (a neurodegenerative disorder that causes memory loss and cognitive decline), lipid profiles, and features of coronary artery disease (CAD) using large-scale genetic data and robust analytical methods.
Study: Investigating genetic overlap between Alzheimer’s disease, lipids and coronary artery disease: a large-scale genome-wide cross-trait analysis. Image credits: angellodeco/Shutterstock.com
Background
AD is a leading neurodegenerative disorder, with more than 139 million cases expected worldwide by 2050. In Australia, it is the leading disease burden among older adults. AD is associated with tau tangles and beta-amyloid (Aβ) plaques in the brain.
Research suggests links between lipid disorders, CAD and AD, with genetic studies pointing to possible overlapping mechanisms.
However, the precise relationships and underlying biology remain unclear, highlighting the need for further research to better understand these complex connections.
About the study
The relationship between AD and various lipid traits, representing eight major lipid classes, was thoroughly investigated.
These lipid classes include fatty acyls, glycerophospholipids, high-density lipoproteins (HDL) and low-density lipoproteins (LDL), neutral lipids (triglycerides), medium-chain fatty acids, steroids (total cholesterol), and sphingolipids.
The study used summary data from the Genome-Wide Association Study (GWAS) from large-scale research consortia including Cooperative Health Research in the Region of Augsburg (KORA), Twins United Kingdom (TwinsUK) and the Global Lipids Genetics Consortium.
The analysis also looked at the relationship between AD and seven CAD traits, using data from the Lee Lab for Statistical Genetics and the CARDIoGRAMplusC4D consortium.
To investigate the genetic relationships, the study used linkage disequilibrium score regression (LDSC) and local analysis of [co]variant association (LAVA) methods at both Single Nucleotide Polymorphism (SNP) and gene levels.
Additionally, the study performed gene-based association analyzes to identify overlapping genes between AD, lipid and CAD traits, using multi-marker analysis of genomic annotation (MAGMA) within the Functional Mapping and Annotation (FUMA) platform .
The study identified significant global genetic correlations between AD and specific lipid traits such as LDL, triglycerides and total cholesterol, and a positive correlation between AD and several CAD traits.
However, Mendelian randomization analyzes did not support a causal relationship, suggesting shared genetic susceptibility as a more plausible explanation. Local genetic correlation analyzes identified specific genomic loci that contributed to these associations, providing further insight into the complex genetic landscape linking AD to cardiovascular health.
Study results
Initially, the researchers used LDSC to assess and quantify the global genetic correlations at the SNP level between 13 lipid traits, seven CAD traits, and AD.
This analysis revealed significant global genetic correlations between AD and specific lipid traits, specifically triglycerides, LDL, and total cholesterol.
Similarly, strong correlations were found between AD and several CAD features, including angina (chest pain due to reduced blood flow to the heart), cardiac arrhythmias (abnormal heart rhythms), and coronary arteriosclerosis (hardening and narrowing of the heart arteries). These results suggested that shared genetic components may predispose individuals to both AD and certain lipid and CAD traits.
The study applied two-sample bidirectional Mendelian randomization analyzes (2SMR) to test for possible causal associations between these traits. However, the 2SMR analyzes provided no evidence for a causal relationship between AD, lipid, and CAD traits, indicating that the observed correlations may be due to shared genetic susceptibility rather than direct causal relationships.
The researchers conducted gene-based analyzes to delve deeper into the genetic overlap, identifying genome-wide significant (GWS) genes shared by AD, lipid, and CAD traits. In particular, genes such as Apolipoprotein E (APOE), APOC1 and Translocase of Outer Mitochondrial Membrane 40 (TOMM40) overlap AD and several CAD traits, strengthening the genetic connection between these conditions.
Furthermore, Fisher’s combined p-value (FCP) method was used to identify shared genes achieving GWS across AD, lipid and CAD traits, highlighting genes that could play a crucial role in the pathogenesis of these conditions.
In addition, local genetic correlation analysis using the LAVA method was performed to identify specific genomic regions that contribute to the genetic correlations observed at the global level. This analysis revealed several loci, especially on chromosomes 6, 8, 17, and 19, that are significantly associated with AD and various lipid and CAD traits.
Of these, the locus on chromosome 19 was notably involved in multiple traits, indicating a hotspot for shared genetic influences.
Finally, the study compared the results of LDSC and LAVA to assess the consistency of the findings. Although both methods identified significant genetic correlations, some discrepancies were observed, especially in the direction of the effects, highlighting the importance of using multiple analytical approaches to fully understand genetic relationships.
Conclusions
This study systematically assessed the genetic correlations between AD, 13 lipid traits, and seven CAD traits using advanced statistical tools. Significant correlations were found between AD and specific lipids (LDL, triglycerides, total cholesterol) and all CAD features, indicating a shared genetic susceptibility.
However, Mendelian randomization analyzes found no causal relationships, suggesting that these associations arise from shared genetics rather than direct causality. Local genetic analysis identified key loci on chromosomes 6, 8, 17 and 19 that contributed to these associations.