TY - JOUR
T1 - Sex Differences in Alzheimer's Disease
T2 - Insights From the Multiomics Landscape
AU - Guo, Lei
AU - Zhong, Margaret B.
AU - Zhang, Larry
AU - Zhang, Bin
AU - Cai, Dongming
N1 - Funding Information:
This work was supported in part by funding from the National Institutes of Health (Grant Nos. 1R01AG048923 [to DC], RF1AG054014 [to DC and BZ], RO1AG068030 [to DC and BZ], R56AG058655 [to DC and BZ], UO1AG046170 [to BZ], RF1AG057440 [to BZ], RO1AG057907 [to BZ], and UO1AG052411 [to BZ]); and the Department of Veteran Affairs Biomedical Laboratory Research and Development (Grant No. I01BX003380 ) [to DC], and Rehabilitation Research and Development (Grant No. I01RX002290 [to DC]).
Publisher Copyright:
© 2021
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type–specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.
AB - Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type–specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.
KW - Alzheimer's disease, Multiomics analyses, Pathogenesis, Sex differences, Sex-biased molecular mechanisms, Systems biology
UR - http://www.scopus.com/inward/record.url?scp=85106306763&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2021.02.968
DO - 10.1016/j.biopsych.2021.02.968
M3 - Review article
C2 - 33896621
AN - SCOPUS:85106306763
SN - 0006-3223
VL - 91
SP - 61
EP - 71
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 1
ER -