Neurotransmitter Imbalance in the Brain and Alzheimer’s Disease Pathology

Article type: Research Article

Authors: Snowden, Stuart G.^{a; *} | Ebshiana, Amera A.^a | Hye, Abdul^b | Pletnikova, Olga^c | O’Brien, Richard^d | Yang, An^e | Troncoso, Juan^c | Legido-Quigley, Cristina^{a; 1} | Thambisetty, Madhav^{e; 1}

Affiliations: [a] Institute of Pharmaceutical Sciences, King’s College London, London, UK | [b] Institute of Psychiatry, Psychology and Neuroscience, Department of Old Age Psychiatry, King’s College London, Maurice Wohl Clinical Neuroscience Institute, London, UK | [c] Division of Neuropathology Johns Hopkins School of Medicine, Baltimore, MD, USA | [d] Department of Neurology, Duke University Medical School, Durham, NC, USA | [e] Clinical and Translational Neuroscience Unit, Laboratory of Behavioural Neuroscience, National Institute on Aging, Baltimore, MD, USA

Correspondence: [*] Correspondence to: Stuart G. Snowden, Institute of Metabolic Science, University of Cambridge, Pathology building level 4, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK. Tel.: +44 7708953183; E-mail: [email protected].

Note: [1] Shared senior authorship.

Abstract: Background:Cholinesterase inhibitors represent three of the four treatments for Alzheimer’s disease (AD), and target the pathological reduction of acetylcholine levels. Here we aimed to study the role of other neurotransmitter pathways in AD pathology. Objective:This study aimed to determine associations between AD pathology at both symptomatic and asymptomatic stages of disease progression, and the metabolism of a range of non-cholinergic neurotransmitters. Methods:Tissue samples were obtained from three groups, controls, AD, and ‘asymptomatic AD’ (ASYMAD), i.e., cognitively normal individuals that had significant AD neuropathology. Three brain areas were studied, the middle frontal gyrus (MFG), the inferior temporal gyrus (ITG), and the cerebellum. Results:12 of 15 metabolites involved in neurotransmitter metabolism were shown to be associated with AD pathology. Decreases in dopamine were most pronounced in the MFG with lower levels seen in the ASYMAD group compared to control (FC = 0.78, p = 2.9×10–2). In the ITG significant changes were seen in GABAergic and serotonin metabolism between control and AD patients; however, these changes were not seen between control and ASYMAD individuals. Conclusion:These results indicate that dopamine could be depleted in brains with AD pathology but intact cognition, while an imbalance of several neurotransmitters is evident in the brains of AD patients.

Keywords: Asymptomatic Alzheimer’s disease, brain, metabolomics, neurotransmitters

DOI: 10.3233/JAD-190577

Journal: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 35-43, 2019