Response to the letter titled “Expanding the Horizon of Sex-Specific Proteomic Insights in Alzheimer's Disease”

Dear Editor,

We thank Zhou et al. for their interest in our recent work and for providing additional context around our findings. As they suggested, we examined the intersectional effect of apolipoprotein E (APOE) ε4 status by adding a three-way interaction term (sex × trait × APOE ε4) into our models. This allowed us to test whether the sex × trait interactions differed by APOE ε4 status. As shown in Table 1, we continue to see significant sex × trait interactions without significant three-way interactions. These results suggest that the sex-biased disease associations are independent of APOE ε4 dosage, but we acknowledge that at our current sample size is likely underpowered to detect higher ordered interactions.

We agree with Zhou et al. that integrating our findings with single cell transcriptomics datasets is an important next step, given the evidence of sex-biased gene expression in specific cell types such as microglia.¹ Future studies could also investigate whether genetic or epigenic mechanisms may contribute to the observed sex-biased disease associations. This hypothesis is supported by our prior work which has identified 150 proteins with sex-biased protein quantitative trait loci (pQTLs) in human brain proteomes.² Moreover, sex hormones have been shown to regulate chromatin states in males and female neurons,³ and microRNAs were also identified as sex-specific regulators in the microglial transcriptome and tau pathology.⁴ Studying the potential genetic and epigenetic regulation of these sex-biased proteins and their interactions with sex hormones will advance our understanding of sex difference in Alzheimer's disease (AD).

We agree that it is also important to examine other brain regions that might be affected in the early stages of AD and to expand omics analysis across diverse populations. The limited availability of post mortem brain tissue presents significant challenges for conducting large-scale studies and examining sex-based or other higher-ordered interactions. Using less invasive biospecimens, such as plasma and cerebrospinal fluid (CSF), to test these sex-specific brain proteins as fluid biomarkers in AD will be an important direction for future research.

Sincerely,

Zhen Mei, Aliza P. Wingo, Thomas S. Wingo

The authors declare no competing interests. Author disclosures are available in the supporting information

This work was supported by I01 BX003853 (A.P.W.); IK4 BX005219 (A.P.W.); I01 BX005686 (A.P.W.); R01 AG075827 (A.P.W., T.S.W.); R01 AG072120 (A.P.W., T.S.W.); R01 AG079170 (T.S.W.); U01 AG088425 (T.S.W.). ROS/MAP is supported by P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, and U01AG61356.