Sex Differences in Neurodegeneration: The Role of the Immune System in Humans

Biol Psychiatry. 2022 Jan 1;91(1):72-80. doi: 10.1016/j.biopsych.2021.01.002. Epub 2021 Jan 8.


Growing evidence supports significant involvement of immune dysfunction in the etiology of neurodegenerative diseases, several of which also display prominent sex differences across prevalence, pathology, and symptomology. In this review, we summarize evidence from human studies of established and recent findings of sex differences in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discuss how sex-specific central nervous system innate immune activity could contribute to downstream sex differences in these diseases. We examine human genomic and transcriptomics studies in each neurodegenerative disease through the lens of sex differences in the neuroimmune system and highlight the importance of stratifying sex in clinical and translational research studies. Finally, we discuss the limitations of the existing studies and outline recommendations for further advancing sex-based analyses to uncover novel disease mechanisms that could ultimately help treat both sexes.

Keywords: GWAS; Immune responses; Inflammation; Neurodegeneration; Sex difference; Transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease* / genetics
  • Female
  • Humans
  • Immune System
  • Male
  • Neurodegenerative Diseases* / genetics
  • Parkinson Disease*
  • Sex Characteristics