Cataloging the role of brain cell types on suppressing the effect of APOE ε4 on Alzheimer’s disease risk
Yiyi Ma, Kevin W Chen, Masashi Fujita, Lei Yu, Vilas Menon, Julie A Schneider, David A. A Bennett, Philip L De Jager- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
We have previously developed a research pipeline to identify potential suppressors of APOE ε4 risk on Alzheimer’s disease (AD), and we have successfully identified an epigenomic factor which may act as ε4 suppressor. However, it is unknown which cell type is more important to contain this ε4 suppressor on the transcriptome level.
Method
We included single‐nucleus RNA sequencing (snRNAseq) data of the postmortem human brains from 424 subjects of the Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). Based on this snRNAseq data, we have derived the estimate of the percentage and transcriptomic profiles of different types of brain cells including excitatory neurons, inhibitory neurons, endothelial cells, pericytes, oligodendrocytes, astrocytes, and microglia. Besides the main cell types, we further derived the estimates on the cell subtype level. With the generalized linear regression model, the final prioritized cell types and genes should fulfill two criteria: (1) be associated with AD pathologies (pTAU and neuritic plaque) in all subjects; and (2) reduce the effect of ε4 on AD susceptibility.
Result
Based on the transcriptome‐wide association study (TWAS) of the main brain cells, almost all the brain cell types contain at least one genome‐wide significant (P≤6.5×10−6) gene which can act as the APOE ε4 suppressor on AD risk. However, the subtype cellular analysis suggested that neuronal subtypes are more important than the other cell types because almost all the subtypes of the excitatory neuronal cells (15 out of 16) contain the genome‐wide significant ε4 suppressor while this percentage for microglia is only 25% (4 out of 16). The pathway analysis suggested that the top 179 genes expressed in the neuronal cells were involved in the trans‐synaptic signaling by trans‐synaptic complex and synapse assembly.
Conclusion
On the transcription level, APOE ε4 suppressor effects are present across a variety of different brain cell types but enriched in neurons where synapse pathways appear to play a predominant role in suppressing the effect of APOE ε4.