Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease

Area of Science:

• Neurogenetics
• Genomics
• Alzheimer's Disease Research

Background:

• The apolipoprotein E (APOE) gene is the primary genetic risk factor for late-onset Alzheimer's Disease (LOAD).
• Gene regulatory mechanisms at the APOE locus are not fully understood, hindering therapeutic development.

Purpose of the Study:

• To identify novel functional elements within the APOE locus associated with Alzheimer's Disease (AD).
• To elucidate the regulatory mechanisms underlying APOE gene expression in the human brain.

Main Methods:

• Integrated single nucleotide polymorphism (SNP) data with multi-omics datasets (RNA-seq, DNA methylation, ChIP-seq) from human postmortem brains across diverse ancestries.
• Analyzed APOE transcript expression trajectories during human brain development.

Main Results:

• Identified a novel AD-linked APOE transcript (jxn1.2.2) predominantly in the dorsolateral prefrontal cortex (DLPFC).
• Associated APOE jxn1.2.2 with neuropathological features, cognitive decline, and the APOE4 allele.
• Prioritized two functional SNPs (rs157580, rs439401) influencing jxn1.2.2 abundance and DNA methylation, located in active chromatin regions affecting transcription factor binding.

Conclusions:

• Discovered novel APOE functional elements offering potential therapeutic targets for Alzheimer's Disease.
• Provided mechanistic insights into AD etiology through the characterization of APOE gene regulation.