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Dopaminergic deficits along the spectrum of Alzheimer’s disease

Molecular Psychiatry volume 30, pages 3069–3076 (2025)Cite this article

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Abstract

Both post-mortem and in vivo data argue for dopamine dysfunction in patients with Alzheimer’s Disease (AD). However, the timing and regional progression of dopaminergic systems alterations in AD are still debated. The aim of the study was to investigate in vivo the pattern of dopaminergic changes and connectivity using DAT-SPECT imaging in patients across the AD spectrum. Fifty-nine AD patients (n = 21 AD-MCI; n = 38 AD-DEM) and a control group (CG) of n = 45 age- and sex-matched individuals entered the study and underwent 123I-FP-CIT dopaminergic imaging. The occipital binding was used as reference region to obtain single-subject binding in different brain regions. Between-group differences in 123I-FP-CIT binding in both mesolimbic and nigrostriatal dopaminergic pathways were assessed using an ANCOVA test, adjusting for the effect of center of imaging acquisition, age, and sex. Regions resulting from the voxel-wise direct comparison between AD-MCI and AD-DEM were considered as a seed of interest for a voxel-wise interregional correlation analysis. Both AD-MCI and AD-DEM patients showed dopaminergic depletion within the basal ganglia, whereas cortico-limbic regions (namely hippocampus, amygdala, anterior and middle cingulate, frontal cortex and thalamus) resulted impaired only in the dementia phase. The brain voxel-wise interregional correlation analysis showed a progressive pattern of disruption of caudate/thalamus dopaminergic connectivity to hippocampus and amygdala from AD-MCI to AD-DEM stages. This study indicates basal ganglia dopaminergic alterations and connectivity disruption in the nigrostriatal and mesolimbic systems already in early stage AD, extending to several cortico-limbic regions in dementia phases.

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Fig. 1: Voxel-wise comparisons between groups.
Fig. 2: Seed-based connectivity.

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Data availability

The datasets used and the scrips used to analyze data during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the participants in this study for their time and willingness to contribute this research. The study was partially supported by the Italian Ministry of Health with the grant RF-2018-12366209 and by #NEXTGENERATIONEU (NGEU) funded by the Ministry of University and Research (MIUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) – a multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022) to Silvia Paola Caminiti, Nicola Biagio Mercuri and Claudio Liguori; by the American Alzheimer’s Association (AARG-21-851219) and by Fondazione Roma (Rome, Italy) to Marcello D’Amelio.

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Author notes

  1. These authors contributed equally: Andrea Pilotto, Alice Galli.

Authors and Affiliations

  1. Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy

    Andrea Pilotto, Alice Galli & Alessandro Padovani

  2. Laboratory of Digital Neurology and Biosensors, University of Brescia, Brescia, Italy

    Andrea Pilotto, Alice Galli & Alessandro Padovani

  3. Neurology Unit, Department of continuity of care and frailty, ASST Spedali Civili Brescia Hospital, Brescia, Italy

    Andrea Pilotto & Alessandro Padovani

  4. Neurobiorepository and Laboratory of advanced biological markers, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy

    Andrea Pilotto

  5. Coma Science group- University of Liege, Liège, Belgium

    Arianna Sala

  6. Department of Brain and Behavioral Sciences- Univeristy of Pavia, Pavia, Italy

    Silvia Paola Caminiti

  7. Department of Physics “G. Occhialini”, University of Milano-Bicocca, Milan, Italy

    Luca Presotto

  8. Neurophysiology Unit, Sleep and Epilepsy Center- University of Rome Tor Vergata, Rome, Italy

    Claudio Liguori & Nicola Biagio Mercuri

  9. Stroke Unit, ASST Spedali Civili Brescia Hospital, Brescia, Italy

    Enrico Premi

  10. Department of Radiology and Medical Informatics- Geneva University Hospital, Geneva, Switzerland

    Valentina Garibotto

  11. Department of Psychiatry- Geneva University Hospital, Geneva, Switzerland

    Giovanni Frisoni

  12. Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy

    Agostino Chiaravalloti & Orazio Schillaci

  13. Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Rome, Italy

    Marcello D’Amelio

  14. Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy

    Marcello D’Amelio

  15. Nuclear Medicine Unit- University of Brescia, Brescia, Italy

    Barbara Paghera, Silvia Lucchini & Francesco Bertagna

  16. University Vita-Salute San Raffaele, IRCCS San Raffaele Hospital, Milan, Italy

    Daniela Perani

  17. Brain Health Center, University of Brescia, Brescia, Italy

    Alessandro Padovani

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  1. Andrea Pilotto
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Contributions

A.Pi. and A.G. performed the analysis and interpretation of data for the work and drafted the manuscript; A.S., S.P.C., C.L., A.C., V.G., GB.F., B.P., L.S., F.B., and O.S. performed the acquisition of data and revised the manuscript; E.P., M.D’A. and N.M. revised the manuscript; D.P. and A.Pa were responsible for the design and conceptualization of the study, performed data interpretation, and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Andrea Pilotto.

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Pilotto, A., Galli, A., Sala, A. et al. Dopaminergic deficits along the spectrum of Alzheimer’s disease. Mol Psychiatry 30, 3069–3076 (2025). https://doi.org/10.1038/s41380-025-02913-5

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