@article{c7ac9db0fb854d979f96d5a0a3ccc0e3,
title = "Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure",
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.",
keywords = "Alzheimer's disease, Autosomal dominant AD, Brain cellular composition, Bulk RNA-sequencing, Digital deconvolution, TREM2",
author = "{the Dominantly Inherited Alzheimer Network (DIAN)} and Zeran Li and Del-Aguila, {Jorge L.} and Umber Dube and John Budde and Rita Martinez and Kathleen Black and Qingli Xiao and Cairns, {Nigel J.} and Dougherty, {Joseph D.} and Lee, {Jin Moo} and Morris, {John C.} and Bateman, {Randall J.} and Karch, {Celeste M.} and Carlos Cruchaga and Oscar Harari",
note = "Funding Information: This work was supported by grants from the National Institutes of Health (R01-AG044546, P01-AG003991, RF1AG053303, R01-AG035083, and R01-NS085419) and the Alzheimer{\textquoteright}s Association (NIRG-11-200110). This research was conducted while CC was a recipient of a New Investigator Award in Alzheimer{\textquoteright}s disease from the American Federation for Aging Research. CC and CMK are recipient of a BrightFocus Foundation Alzheimer{\textquoteright}s Disease Research Grant (A2013359S). This work was supported in part by NIH K01AG046374 awarded to CMK, and also the Tau Consortium (CMK). JDD is supported by the Brain and Behavior Research Foundation and the NIH (R01NS102272). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG005681, P01 AG003991, and P01 AG026276. DIAN data collection and sharing for this project were supported by The Dominantly Inherited Alzheimer{\textquoteright}s Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). Mayo Clinic RNA-seq data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson{\textquoteright}s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer{\textquoteright}s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05–901, and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium), and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research. MSSMiPSC data collection was supported by the Brain and Behavior Research Foundation, NIH grant R01 MH101454, and the New York Stem Cell Foundation. We analyzed iPSC-derived microglia RNA-seq data funded by NIH U01AG046170. Funding Information: We thank all participants and their families for their commitment and dedication to helping advance research into the early detection and causation of AD; and the Knight-ADRC research and support staff at each of the participating sites for their contributions to this study. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. We would like to thank the operations staff at the Elizabeth H. and James S. McDonnell III Genome Institute at Washington University with their assistance in constructing the RNA-seq libraries and generating sequence data for our project. This work was also supported by accessing to equipment made possible by the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine. We also thank Allison M. Lake for her comments and suggestions. The results published here are in whole or in part based on data obtained from the AMP-AD Knowledge Portal accessed at doi:https:// doi.org/10.7303/syn2580853. Mayo Clinic RNA-seq data were provided by the following sources: The Mayo Clinic Alzheimer{\textquoteright}s Disease Genetic Studies, led by Dr. Nilufer Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer{\textquoteright}s Disease Research Center, and the Mayo Clinic Brain Bank. MSBB RNA-seq data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. MSSMiPSC data were generated by Kristen Brennand, a New York Stem Cell Foundation - Robertson Investigator. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = jun,
day = "8",
doi = "10.1186/s13073-018-0551-4",
language = "English",
volume = "10",
journal = "Genome medicine",
issn = "1756-994X",
number = "1",
}