Consideration of Sex Differences in the Measurement and Interpretation of Alzheimer Disease-Related Biofluid-Based Biomarkers

BACKGROUND: The development of cerebrospinal fluid and blood-based biomarkers for Alzheimer disease (AD) and related disorders is rapidly progressing. Such biomarkers may be used clinically to screen the population, to enhance diagnosis, or to help determine prognosis. Although the use of precision medicine methods has contributed to enhanced understanding of the AD pathophysiological changes and development of assays, one aspect not commonly considered is sex differences. CONTENT: There are several ways in which sex can affect the concentration or interpretation of biofluid biomarkers. For some markers, concentrations will vary by sex. For others, the concentrations might not vary by sex, but the impact or interpretation may vary by sex depending on the context of use (e.g., diagnostic vs prognostic). Finally, for others, there will be no sex differences in concentrations or their interpretation. This review will first provide a basis for sex differences, including differences in brain structure and function, and the means by which these differences could contribute to sex differences in biomarker concentrations. Next, the current state of sex differences in AD-related biofluid markers (i.e., amyloid-β, phosphorylated τ, total τ, neurofilament light chain, and neurogranin) will be reviewed. Lastly, factors that can lead to the misinterpretation of observed sex differences in biomarkers (either providing evidence for or against) will be considered. SUMMARY: This review is intended to provide an impetus to consider sex differences in the measurement and interpretation of AD-related biofluid-based biomarkers.