Sex differences in the association between plasma and CSF p‐tau

Background Mounting evidence from cerebrospinal fluid (CSF) studies suggests that women on the AD spectrum have higher levels of pathological tau in the CSF than men. Several studies suggest that plasma tau phosphorylated at threonine 181 (p‐tau181) is strongly associated with CSF biomarkers of tau and may constitute an accessible and informative biomarker of AD. However, sex stratified analyses of plasma and CSF tau associations are lacking. Here, we examine the relationship between plasma and CSF p‐tau181 separately in 476 men and 422 women on the AD continuum. Method Our sample included 280 cognitively normal (CN), 453 mild cognitively impaired (MCI) and 165 AD dementia participants from ADNI with concurrent plasma p‐tau181 and CSF p‐tau181 determined by the Roche Elecsys assay. We stratified our sample by sex, to examine plasma p‐tau181 differences between diagnostic groups separately in men and women. Furthermore, we examined the association between plasma and CSF p‐tau181 separately in each sex, within each diagnostic group. Models were first adjusted for APOE ε4 status and age, and then additionally adjusted for amyloid status. Result Participants with AD dementia had higher levels of plasma p‐tau181 than controls in both sexes, while MCIs had higher plasma p‐tau than normal controls only among women. In the CN group, higher plasma p‐tau181 correlated with higher CSF p‐tau181 in women (β=0.18, P=0.025), but not men (β=0.025, P=0.75). In the MCI group, higher plasma p‐tau181 was associated with higher CSF p‐tau181 in both men (β=0.22, P=0.001) and women (β=0.56, P<0.001), but the association was significantly stronger in women ( z =2.47, P=0.007). In the AD dementia group, higher plasma p‐tau181 was associated with higher CSF p‐tau181 in men (β=0.6, P=0.001) but not women (β=0.33, P=0.19). Our result Conclusion These findings suggest that in women, associations between p‐tau181 levels in plasma and CSF are strongest early in the disease and weaker at later stages, while the opposite is true for men. Sex should be taken into account when interpreting plasma tau findings, and further investigation into sex‐specific relationships between plasma tau and CSF tau are warranted.