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Depression and Synaptic Zinc Regulation in Alzheimer Disease, Dementia with Lewy Bodies, and Parkinson Disease Dementia

Lookup NU author(s): Dr Clive Ballard, Professor Alan ThomasORCiD, Professor John O'Brien, Dr Dag Aarsland


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Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. Methods: We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. Results: Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (beta = -0.351, df = 93, t = -3.318 p - 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (beta = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (beta = -0.433, df = 37, t = -2.924, p = 0.006). Conclusion: Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target.

Publication metadata

Author(s): Whitfield DR, Vallortigara J, Alghamdi A, Hortobgyi T, Ballard C, Thomas AJ, O'Brien JT, Aarsland D, Francis PT

Publication type: Article

Publication status: Published

Journal: American Journal of Geriatric Psychiatry

Year: 2015

Volume: 23

Issue: 2

Pages: 141-148

Print publication date: 01/02/2015

Online publication date: 14/05/2014

Acceptance date: 09/05/2014

ISSN (print): 1064-7481

ISSN (electronic): 1545-7214

Publisher: Elsevier


DOI: 10.1016/j.jagp.2014.05.001


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Funder referenceFunder name
Brains for Dementia Research
Medical Research Council and Brains for Dementia Research
Newcastle University
NIHR Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust
Medical Research Council
109Alzheimer's Society
136BUPA Foundation through the Alzheimer's Society