Alzheimer's age-dependent molecular signatures in individuals with the loss of function CETP I405V variant

Isshori Gurung

Document Type

Article

Publication Date

8-9-2024

Keywords

JMG

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Alzheimer’s disease (AD) risk genes have been associated with lipid biology, including the strongest late-onset AD (LOAD) risk allele, APOE4. Research indicates that other lipid associated genes such as Cholesteryl Ester Transfer Protein (CETP) are also associated with AD risk; the CETP variant I405V (rs5882) is associated with greater longevity and reduced cognitive decline in centenarians. Other studies suggest that CETP*I405V may play pathogenic role in AD, however genetic studies indicate that the protective effect of CETP*I405V is dependent on the presence of APOE4 and has an age-specific effect in female individuals. Our goal was to determine the influence of aging on the transcriptomic signatures of individuals with CETP*I405V to better understand how lipid metabolism contributes to LOAD pathology. We achieved this by using two independent datasets to identify transcriptional signatures altered in CETP*I405V carriers and perform correlation analysis and enrichment analysis to determine enrichment of known AD transcriptomic signatures and gene ontology pathways with CETP*I405V carriers. The results indicate that there are transcriptional signatures that change in CETP*I405V carriers with age and are associated with LOAD pathways. Anti-correlation of CETP*I405V transcriptional signatures with AD transcriptional signatures in immune response and mitochondrial metabolism gene modules in older individuals suggest this variant may provide protection from AD through these pathways, however, correlation with AD transcriptional signatures in neuronal and glial pathways suggests that CETP*I405V may also contribute to AD pathogenic mechanisms through these specific biological processes.

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