Spatial transcriptomic patterns underlying amyloid-β and tau pathology are associated with cognitive dysfunction in Alzheimer’s disease
Meichen Yu,
Shannon L. Risacher,
Kwangsik T. Nho,
Qiuting Wen,
Adrian L. Oblak,
Frederick W. Unverzagt,
Liana G. Apostolova,
Martin R. Farlow,
Jared R. Brosch,
David G. Clark,
Sophia Wang,
Rachael Deardorff,
Yu-Chien Wu,
Sujuan Gao,
Olaf Sporns,
Andrew J. Saykin
Affiliations
Meichen Yu
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana University Network Science Institute, Bloomington, IN, USA; Corresponding author
Shannon L. Risacher
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
Kwangsik T. Nho
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana University Network Science Institute, Bloomington, IN, USA
Qiuting Wen
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
Adrian L. Oblak
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
Frederick W. Unverzagt
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
Liana G. Apostolova
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
Martin R. Farlow
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
Jared R. Brosch
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
David G. Clark
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
Sophia Wang
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
Rachael Deardorff
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
Yu-Chien Wu
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
Sujuan Gao
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA
Olaf Sporns
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana University Network Science Institute, Bloomington, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
Andrew J. Saykin
Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Indiana University Network Science Institute, Bloomington, IN, USA; Corresponding author
Summary: Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer’s disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aβ and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. These findings may explain the discordance between regional Aβ and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.
