Squitti Rosanna, Benussi Alberto, Fostinelli Silvia, Geviti Andrea, Rivolta Jasmine, Ventriglia Mariacarla, Micera Alessandra, Rongioletti Mauro, Ghidoni Roberta, Santilli Matteo, Granzotto Alberto, Albanese Alberto, Binetti Giuliano, Sensi Stefano L, Borroni Barbara
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.
Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy.
Biomolecules. 2025 Sep 1;15(9):1268. doi: 10.3390/biom15091268.
Dysregulation contributes to Alzheimer's disease (AD) pathophysiology. Zinc therapy promotes enterocyte copper sequestration, potentially reducing systemic copper. Individual biological responses may vary.
ZINCAiD was a 24-week, randomized, double-blind, placebo-controlled phase II trial assessing zinc therapy in individuals with mild cognitive impairment (MCI) due to AD (EudraCT No.: 2019-000604-15; registered on 26 March 2020). Participants were randomized 2:1 to receive elemental zinc (135 mg/day for 12 weeks, then 65 mg/day) or placebo. Ceruloplasmin was measured at predefined intervals for safety monitoring, blinded to the investigators. Post hoc, "Zinc Responders" were defined by ≥20% reduction in ceruloplasmin at week 12. The primary cognitive endpoint was the Cognitive Composite 2 scale (CC2); secondary endpoints included MMSE and CDR-Sob.
Of the 48 participants randomized, 9 discontinued, primarily due to unrelated clinical deterioration; 39 had complete ceruloplasmin data. Two serious adverse events occurred in the Placebo group. Mild gastrointestinal symptoms occurred in eight participants, with only four leading to dropout. In the primary zinc vs. placebo analysis, no significant differences emerged in cognitive outcomes. A post hoc exploratory analysis stratified participants by pharmacodynamic response: 12 individuals with MCI due to AD (31%) met the criteria for "Zinc Responder," defined by ≥20% reduction in serum ceruloplasmin at week 12. Only Zinc Responders maintained cognitive stability over 24 weeks, whereas the combined group of Zinc Non-Responders and placebo-treated participants showed a significant decline. For the composite cognitive score (CC2), the interaction between visit and response group was significant ( = 0.030), with deterioration observed only in the Non-Responder + Placebo group (Δ = -2.72, < 0.0001 vs. -0.71, = 0.35 in Responders). Similar patterns were observed for CDR-Sob (interaction = 0.017) and MMSE (trend = 0.09).
Zinc therapy stabilized cognition in a pharmacodynamically defined MCI subgroup. These exploratory findings suggest serum ceruloplasmin as a feasible biomarker of target engagement. Larger trials are needed for confirmation.
失调参与了阿尔茨海默病（AD）的病理生理过程。锌疗法可促进肠细胞对铜的螯合，可能会降低全身铜水平。个体的生物学反应可能存在差异。
ZINCAiD是一项为期24周的随机、双盲、安慰剂对照II期试验，评估锌疗法对AD所致轻度认知障碍（MCI）个体的疗效（欧盟临床试验编号：2019-000604-15；于2020年3月26日注册）。参与者按2:1随机分组，分别接受元素锌（第12周前每天135毫克，之后每天65毫克）或安慰剂。在预定时间间隔测量铜蓝蛋白以进行安全性监测，研究人员对此不知情。事后，“锌反应者”定义为在第12周时铜蓝蛋白降低≥20%。主要认知终点是认知综合2量表（CC2）；次要终点包括简易精神状态检查表（MMSE）和临床痴呆评定量表-总和版（CDR-Sob）。
48名随机分组的参与者中，9人退出，主要原因是与研究无关的临床病情恶化；39人有完整的铜蓝蛋白数据。安慰剂组发生了两起严重不良事件。8名参与者出现轻度胃肠道症状，只有4人因此退出。在锌与安慰剂的主要分析中，认知结果没有显著差异。事后探索性分析根据药效学反应对参与者进行分层：12名AD所致MCI个体（31%）符合“锌反应者”标准，定义为第12周时血清铜蓝蛋白降低≥20%。只有锌反应者在24周内保持认知稳定，而锌无反应者和接受安慰剂治疗的参与者组合显示出显著下降。对于综合认知评分（CC2），访视与反应组之间的交互作用显著（P = 0.030），仅在无反应者 + 安慰剂组中观察到恶化（Δ = -2.72，P < 0.0001，而反应者为 -0.71，P = 0.35）。CDR-Sob（交互作用P = 0.017）和MMSE（趋势P = 0.09）也观察到类似模式。
锌疗法在药效学定义明确的MCI亚组中稳定了认知。这些探索性发现表明血清铜蓝蛋白是一种可行的靶点参与生物标志物。需要更大规模的试验来证实。
