Basic Science and Pathogenesis

Cerebrospinal fluid (CSF) biomarkers, including amyloid-β 42 (Aβ42), have emerged as essential endophenotypes in genome-wide association studies (GWAS) of Alzheimer's disease (AD), advancing our understanding of AD biological processes beyond traditional case-control studies. Using the largest sample size to date (N = 18,491), we aim to elucidate sex-specific associations with AD pathology by performing sex-stratified GWAS of three well-established CSF endophenotypes, Aβ42, Tau, and phosphorylated tau (pTau181).

We conducted meta-analyses of sex-stratified GWAS for each CSF biomarker, leveraging 22 US and European cohorts with available raw CSF and genotype data (N = 6,785; 51.84% male; age=68), along with summary statistics from six external cohorts (N = 11,706; 45.27% male; age=69). Consistent quality control was applied prior to genetic analyses, including z-score standardization on raw CSF biomarker values in internal cohorts. The GWAS adjusted for age, ten principal components of genetic ancestry, and cohort-array combination as applicable. We defined a sex-specific effect as a variant association that reached genome-wide significance in one sex and had non-overlapping 95% confidence intervals of the effect estimates between sexes.

We identified seven genome-wide significant loci, including four previously reported loci and three novel female-specific associations, including one for Aβ42 (rs372578, p(Females)=1.86E-08, b(F)=-0.09, p(Males)=0.78), Figure 1), one for Tau (rs1582763, p(F)=5.56E-09, b(F)=-0.09, p(M)=0.05, Figure 2), and one for pTau181 (rs6434518, p(F)=2.95E-08, b(F)= 0.17, p(M)=0.80, Figure 3). The lead Aβ42 variant, rs372578, is an eQTL for BMP6 (p = 8.00E-04, http://www.braineac.org), which encodes a TGF-beta ligand involved in iron homeostasis and bone/fat development. Increased expression of BMP6 is linked to hippocampal neurogenesis defects in AD patients and APP-transgenic mice. The lead Tau variant, rs1582763, is in the MS4 locus, an established genetic risk factor for AD with some evidence of female-specificity, and has been linked to soluble TREM2 level regulation in CSF. Finally, the top pTau181 variant, rs6434518, is an eQTL for immune response genes STAT4, STAT1 (p = 2.40E-02), and MYO1B (p = 2.60E-02) involved in lipid metabolism and proteostasis.

Our results highlight significant female-specific genetic associations across CSF biomarkers, underscoring the importance of sex-specific genetic analyses in deepening understanding of AD genetic architecture.