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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Zinc Therapy in Mild Cognitive Impairment: Cognitive Stabilization in Pharmacodynamically Responsive Patients in the ZINCAiD Trial

by
Rosanna Squitti
1,2,3,*,
Alberto Benussi
4,5,
Silvia Fostinelli
1,
Andrea Geviti
6,
Jasmine Rivolta
7,
Mariacarla Ventriglia
8,
Alessandra Micera
9,
Mauro Rongioletti
2,
Roberta Ghidoni
1,
Matteo Santilli
10,11,12,13,
Alberto Granzotto
10,11,12,13,
Alberto Albanese
14,15,
Giuliano Binetti
1,
Stefano L. Sensi
10,11,12,13,* and
Barbara Borroni
1,16
1
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy
2
Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy
3
Department of Theoretical and Applied Sciences (DISTA), eCampus University, 22100 Como, Italy
4
Neurology Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
5
Neurology Clinic, Department of Medicine, Surgery and Health Sciences, Azienda Sanitaria Universitaria Giuliano Isontina, 34148 Trieste, Italy
6
Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy
7
Neurology Unit, Department of Continuity of Care and Frailty, ASST Spedali Civili Hospital, 25123 Brescia, Italy
8
Clinical Research Center, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy
9
Research and Development Laboratory for Biochemical, Molecular and Cellular Applications in Ophthalmological Science, IRCCS–Fondazione Bietti, 00184 Rome, Italy
10
Department of Neuroscience, Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
11
Institute for Advanced Biomedical Technologies (ITAB), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
12
Centre for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
13
Neurology Institute, SS Annunziata University Hospital, 66100 Chieti, Italy
14
Department of Neurology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
15
Department of Neuroscience, Catholic University, 20123 Milan, Italy
16
Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy
 
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Authors to whom correspondence should be addressed.
Biomolecules 2025, 15(9), 1268; https://doi.org/10.3390/biom15091268
Submission received: 30 July 2025 / Revised: 25 August 2025 / Accepted: 30 August 2025 / Published: 1 September 2025
(This article belongs to the Section Chemical Biology)
Versions Notes

Abstract

Dysregulation contributes to Alzheimer’s disease (AD) pathophysiology. Zinc therapy promotes enterocyte copper sequestration, potentially reducing systemic copper. Individual biological responses may vary. Methods: 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. Findings: 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 (p = 0.030), with deterioration observed only in the Non-Responder + Placebo group (Δ = –2.72, p < 0.0001 vs. –0.71, p = 0.35 in Responders). Similar patterns were observed for CDR-Sob (interaction p = 0.017) and MMSE (trend p = 0.09). Interpretation: 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.
Keywords: clinical trial; zinc therapy; copper; mild cognitive impairment; Alzheimer’s disease clinical trial; zinc therapy; copper; mild cognitive impairment; Alzheimer’s disease

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MDPI and ACS Style

Squitti, R.; Benussi, A.; Fostinelli, S.; Geviti, A.; Rivolta, J.; Ventriglia, M.; Micera, A.; Rongioletti, M.; Ghidoni, R.; Santilli, M.; et al. Zinc Therapy in Mild Cognitive Impairment: Cognitive Stabilization in Pharmacodynamically Responsive Patients in the ZINCAiD Trial. Biomolecules 2025, 15, 1268. https://doi.org/10.3390/biom15091268

AMA Style

Squitti R, Benussi A, Fostinelli S, Geviti A, Rivolta J, Ventriglia M, Micera A, Rongioletti M, Ghidoni R, Santilli M, et al. Zinc Therapy in Mild Cognitive Impairment: Cognitive Stabilization in Pharmacodynamically Responsive Patients in the ZINCAiD Trial. Biomolecules. 2025; 15(9):1268. https://doi.org/10.3390/biom15091268

Chicago/Turabian Style

Squitti, Rosanna, Alberto Benussi, Silvia Fostinelli, Andrea Geviti, Jasmine Rivolta, Mariacarla Ventriglia, Alessandra Micera, Mauro Rongioletti, Roberta Ghidoni, Matteo Santilli, and et al. 2025. "Zinc Therapy in Mild Cognitive Impairment: Cognitive Stabilization in Pharmacodynamically Responsive Patients in the ZINCAiD Trial" Biomolecules 15, no. 9: 1268. https://doi.org/10.3390/biom15091268

APA Style

Squitti, R., Benussi, A., Fostinelli, S., Geviti, A., Rivolta, J., Ventriglia, M., Micera, A., Rongioletti, M., Ghidoni, R., Santilli, M., Granzotto, A., Albanese, A., Binetti, G., Sensi, S. L., & Borroni, B. (2025). Zinc Therapy in Mild Cognitive Impairment: Cognitive Stabilization in Pharmacodynamically Responsive Patients in the ZINCAiD Trial. Biomolecules, 15(9), 1268. https://doi.org/10.3390/biom15091268

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