The relationship between plasma matrix metalloproteinase‐9 and cerebrospinal fluid biomarkers of tau is sex‐dependent

Background Matrix metalloproteinase‐9 (MMP‐9) is a proinflammatory, proteolytic enzyme that is dysregulated in Apolipoprotein ( APOE ) ε4 carriers, patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and has been shown to accelerate tau oligomerization, blood‐brain barrier breakdown and amyloid‐β (Aβ) accumulation. Evidence suggests that MMP‐9 activity may be regulated by sex hormones, yet it is unknown whether the association between plasma MMP‐9 and cerebrospinal fluid (CSF) AD biomarker levels varies by sex. Method In 335 ADNI participants (128 women, mean age 74.8±7.4), including 56 cognitively normal adults, 183 MCI patients and 96 AD dementia patients, we examined whether sex modulates total and free plasma MMP‐9 associations with CSF total tau (t‐tau), tau phosphorylated at threonine 181 (p‐tau181) and Aβ 42 . Result Free and total plasma MMP‐9 levels were not associated with sex, age, APOE ε4 status or cardiovascular disease risk (CVDR). Total plasma MMP‐9 levels were higher in AD dementia patients versus MCI patients but did not differ between normal controls and MCI or AD patients. Free and total MMP‐9 levels were not associated with CSF Aβ 42 regardless of sex. There was a sex × total plasma MMP‐9 interaction on CSF t‐tau (β=24.7; 95% CI, 82.5 to 355.2; P=0.002) and p‐tau181 (β=24.7; 95% CI, 8.9 to 40.4; P=0.002). Higher total MMP‐9 correlated with higher t‐tau and p‐tau181 levels in women, but with lower levels in men. There was a sex × free plasma MMP‐9 interaction on CSF p‐tau181 (β=19.5; 95% CI, 6.0 to 33.1; P=0.005) and t‐tau (β=147.8; 95% CI, 30.2 to 265.3; P=0.01). Higher free plasma MMP‐9 correlated with lower CSF p‐tau181 and t‐tau in men, but not women. These relationships were independent of age, education, diagnosis, CVDR, and CSF Aβ 42 levels, and were likely driven by APOE ε4‐carriers as free or total MMP‐9 levels were not significantly associated with CSF biomarkers among non‐carriers regardless of sex. Conclusion Our findings provide preliminary evidence of sex differences in associations between MMP‐9 and CSF tau biomarkers, particularly among APOE ε4‐carriers. Compared to male ε4‐carriers, female ε4‐carriers might be more vulnerable to MMP‐9 activity, possibly promoting higher levels of AD‐related tau pathology.