title: Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive.
  
  
  
  To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits.
  
  
  
  The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities.
  
  
  
  This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Minghui
authors: M
authors: Wang
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.
authors: Panos
authors: P
authors: Roussos
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Andrew
authors: A
authors: McKenzie
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Xianxiao
authors: X
authors: Zhou
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Yuji
authors: Y
authors: Kajiwara
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Kristen J
authors: KJ
authors: Brennand
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
authors: Gabriele C
authors: GC
authors: De Luca
authors: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: John F
authors: JF
authors: Crary
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Patrizia
authors: P
authors: Casaccia
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Joseph D
authors: JD
authors: Buxbaum
authors: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.|Departments of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.
authors: Michelle
authors: M
authors: Ehrlich
authors: Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.|Departments of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.|The Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.
authors: Sam
authors: S
authors: Gandy
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Departments of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.|The Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA.
authors: Alison
authors: A
authors: Goate
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.
authors: Pavel
authors: P
authors: Katsel
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors: Eric
authors: E
authors: Schadt
authors: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. vahram.haroutunian@mssm.edu.|Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. vahram.haroutunian@mssm.edu.|Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. vahram.haroutunian@mssm.edu.|The Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA. vahram.haroutunian@mssm.edu.
authors: Vahram
authors: V
authors: Haroutunian
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, 1470 Madison Avenue, New York, NY, 10029, USA. bin.zhang@mssm.edu.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. bin.zhang@mssm.edu.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, 10029, USA. bin.zhang@mssm.edu.
authors: Bin
authors: B
authors: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D012720:Severity of Illness Index; D014158:Transcription, Genetic
chemical_list: D005819:Genetic Markers
keywords: Alzheimer’s disease; Brain cell types; Dementia; Demyelination; Differential expression; Gene co-expression network; Gene module; Selective vulnerability; Systems biology