Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

27Citations
Citations of this article
78Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Background: Alzheimer's disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored. Methods: We developed and optimized a cell-type-specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. Results: We found that neuronal and astrocyte relative proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1, or PSEN2 presented lower neuron and higher astrocyte relative proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neuronal and increased astrocyte relative proportions compared to AD non-carriers. In contrast, carriers of variants in TREM2 risk showed a lower degree of neuronal loss compared to matched AD cases in multiple independent studies. Conclusions: These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-sequencing studies for cell composition and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.

Cite

CITATION STYLE

APA

Li, Z., Del-Aguila, J. L., Dube, U., Budde, J., Martinez, R., Black, K., … Harari, O. (2018). Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure. Genome Medicine, 10(1). https://doi.org/10.1186/s13073-018-0551-4

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free