Department of Neurosciences, School of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA.
Alzheimers Res Ther. 2022 Nov 2;14(1):160. doi: 10.1186/s13195-022-01106-4.
Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.
Our sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.
Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = -2.10 [-3.97 to -0.27], p = 0.027 and β = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).
MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.
研究报告称，轻度认知障碍（MCI）和阿尔茨海默病（AD）患者的血浆基质金属蛋白酶-9（MMP-9）水平较高。尽管有证据表明 MMP-9 活性及其对 AD 病理生理学的影响可能受到性激素的调节，但 MMP-9 与 AD 生物标志物和认知之间的关联在性别上的差异尚未得到探索。
我们的样本包括来自阿尔茨海默病神经影像学倡议（Alzheimer's Disease Neuroimaging Initiative，ADNI）的 238 名 Aβ阳性的 MCI 或 AD 痴呆患者（37.4%为女性，74.6±7.3 岁）。我们使用线性回归模型来检验性别是否改变了游离和总血浆 MMP-9 与 CSF t-tau、p-tau181 和 Aβ的相关性。我们使用线性混合效应模型来检验性别是否改变了总血浆和游离 MMP-9 与认知的相关性，使用纵向的简易精神状态检查（Mini-Mental State Examination，MMSE）和阿尔茨海默病评估量表-认知分量表（Alzheimer's Disease Assessment Scale-Cognitive Subscale，ADAS-cog）数据。
总血浆和游离 MMP-9 水平在性别之间没有差异，但 AD 痴呆患者的总 MMP-9 水平高于 MCI 患者（β=0.06[-0.11 至-0.01]，p=0.031）。性别改变了 CSF t-tau 与总（β=128.68[55.37 至 201.99]，p<0.001）和游离 MMP-9（β=98.61[33.61 至 163.62]，p=0.003）的相关性，即总血浆和游离 MMP-9 水平越高，女性的 CSF t-tau 越高，男性的 CSF t-tau 越低。较高的游离 MMP-9 与男性的 CSF p-tau181 呈负相关（β=-14.98[-27.37 至-2.58]，p=0.018），但与女性无关。在 MCI 患者中，较高的游离 MMP-9 水平与男性的 CSF Aβ呈正相关（β=26.88[4.03 至 49.73]，p=0.022），但与女性无关。在总样本中，较高的游离和总 MMP-9 水平与女性的 MMSE 评分恶化相关（β=-2.10[-3.97 至-0.27]，p=0.027 和 β=-2.24[-4.32 至-0.18]，p=0.035），但与男性无关。较高的游离 MMP-9 与女性的 ADAS-cog 评分恶化相关（β=12.34[3.02 至 21.65]，p=0.011），但与男性无关。较高的游离 MMP-9 与女性的 ADAS-cog 评分恶化呈横向相关，但与男性的 ADAS-cog 评分恶化仅在纵向相关（β=8.98[0.27 至 17.68]，p=0.042）。
MMP-9 可能对女性的 AD 相关病理和认知变化有更不利的影响。如果得到证实，我们的研究结果可能有助于揭示导致女性 AD 易感性增加的潜在机制。
