Single-Nuclei Transcriptomic Characterization of APOE4 -Associated Alzheimer's Disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Apolipoprotein E (APOE) genotype is a major genetic risk factor for Alzheimer's disease (AD).
• Understanding cell-type specific effects of APOE alleles is crucial for elucidating AD pathogenesis.
• Previous studies faced challenges in characterizing cell-type specific transcriptomes across diverse APOE genotypes.

Purpose of the Study:

• To investigate the impact of APOE genotypes on cell-type specific transcriptomes in the human prefrontal cortex (PFC).
• To identify cellular subpopulations uniquely affected by the APOE4/4 genotype in Alzheimer's disease.
• To explore the relationship between APOE genotype, disease status, and gene expression in specific brain cells.

Main Methods:

• Integration of single-nuclei sequencing (snRNA-seq) data from individuals with various APOE genotypes (2/2, 2/3, 3/3, 3/4, 4/4).
• Clustering analysis to identify distinct neuronal and microglial subpopulations.
• RNAscope validation in an extended cohort to confirm key findings.

Main Results:

• Distinct excitatory neuronal and microglial subpopulations were identified, with some uniquely enriched or depleted in APOE4/4 AD cases.
• An excitatory neuronal cluster showing neurofibrillary tangle (NFT) signatures was selectively depleted in APOE4/4 AD.
• Microglial subpopulations were influenced by APOE4 dosage and AD status, with the AD risk gene FRMD4A showing APOE4 dose and AD-dependent expression.

Conclusions:

• APOE4 significantly reshapes cellular states in the brain, contributing to cell-type specific vulnerability in Alzheimer's disease.
• Specific neuronal and microglial subpopulations exhibit differential responses to APOE genotypes and disease.
• Findings highlight FRMD4A as a potential APOE4-dependent AD risk gene, warranting further investigation.