Towards the Effective and Safe Treatment of Psychosis and Alzheimer’s Disease

In the U.S. alone, there are 6.2 million people living with Alzheimer’s Disease (AD), the most common form of dementia [1]. While this unfortunate reality is generally recognized by the public, a lesser-known fact is that approximately 50% of those suffering from AD also experience psychosis, characterized by delusions and/or hallucinations [1]. However, treatment of comorbid psychosis and AD is limited and often ineffective or dangerous. Antipsychotic medications are often prescribed to dementia patients also experiencing psychosis, even though such medications have been indicated to increase the risk of death in those suffering from AD [2]. Studies have suggested the abnormal hippocampal regulation of dopamine may account for the comorbidity of psychosis and AD. The hippocampus is crucial for the formation of episodic, temporal, and spatial memories [3]. It is greatly altered in AD patients, and the ventral (lower) hippocampus has been shown to play a role in dopamine regulation, which is implicated in psychosis. Notably, abnormal hippocampal function simultaneously leads to not only cognitive and memory decline but also disrupted dopamine regulation, which can cause psychosis.

Although further research is needed to clearly identify the mechanism of this comorbidity, there is evidence suggesting that amyloid-beta (AB) plaques, which are protein deposits known to aggregate in the brains of those with AD, may damage inhibitory interneurons, or neurons which inhibit the response of other neurons, resulting in hippocampus hyperactivity [2]. Notably, the loss of interneurons expressing the protein parvalbumin (PV) has been associated with both AD and psychosis [4]. Using the evidence of a connection between abnormal hippocampus activity and altered dopamine regulation, researchers proposed the hippocampus as a key site in comorbid AD and psychosis. To test this hypothesis, researchers injected ferrous amyloid buthionine (FAB) into the hippocampus of rats to model the form of AD without any clear pattern of inheritance, responsible for 95% of AD cases. The use of the FAB model was a useful experimental approach because it allowed researchers to rapidly induce key markers of AD, including the amyloid build-up, tangelement and clumping of tau proteins, loss of neurons, and pro-inflammatory activation of glial cells. Researchers then performed various behavior tests to analyze the effect of FAB treatment on various measures of AD and psychosis. They also conducted in vivo (in living rats) electrophysiology, in which the electrical activity of cells is evaluated, to measure the activity of neurons expressing dopamine [2].

Behavior tests revealed heightened locomotor activity, or increased physical activity, in FAB-treated rats compared to controls, even though the frequency of path switching in a measurement tool called the Y-maze (shaped like a Y) was decreased relative to controls [2]. The greater movement of FAB-treated rats indicates psychomotor agitation with the start of psychosis, and the reduced tendency to switch paths in the Y-maze shows impaired decision-making, working memory, and spatial memory because the rats were less able to explore different paths to encode new knowledge about their spatial surroundings. Combined, these results are consistent with the symptoms of abnormal hippocampal activity observed in Alzheimer's Disease-associated psychosis and provide further evidence to support the hypothesis that the abnormal regulation of the hippocampus may result in comorbid AD and psychosis. As expected, the concentration of the protein PV was significantly lower in the hippocampus of FAB-treated rats. The electrophysiology tests revealed enhanced firing activity of neurons in the ventral hippocampus, activating a brain region called the nucleus accumbens (NAc). The NAc plays a key role in reinforcement mechanisms and is regulated by both dopamine and glutamate, both excitatory neurotransmitters [5]. Upon activation, the NAc then releases GABA, an inhibitory neurotransmitter, which leads to increased dopamine activity in the NAc [2]. 

The results of this study suggest the treatment of comorbid psychosis and AD could involve the targeting of GABA and glutamate receptors in the dopamine signaling pathway from the hippocampus to the NAc since both are known to modulate the secretion of dopamine. Further research should investigate the roles of GABA and glutamate targeting to lead to a more effective and safe treatment for comorbid AD and psychosis. A greater understanding of these pathways may also provide insight into other neurological disorders, such as Parkinson’s Disease or amyotrophic lateral sclerosis (ALS), which also exhibit abnormal GABA or glutamate signaling [6][7].

References: 

[1] Ballard, C., Kales, H. C., Lyketsos, C., Aarsland, D., Creese, B., Mills, R., Williams, H., & Sweet, R. A. (2020). Psychosis in Alzheimer's Disease. Current neurology and neuroscience reports, 20(12), 57. https://doi.org/10.1007/s11910-020-01074-y 

[2] Perez, S. M., Boley, A. M., McCoy, A. M., & Lodge, D. J. (2023). Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease. International journal of molecular sciences, 24(8), 7196. https://doi.org/10.3390/ijms24087196

[3] Lisman, J., Buzsáki, G., Eichenbaum, H., Nadel, L., Ranganath, C., & Redish, A. D. (2017). Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nature neuroscience, 20(11), 1434–1447. https://doi.org/10.1038/nn.4661 

[4] Shu, S., Xu, S. Y., Ye, L., Liu, Y., Cao, X., Jia, J. Q., Bian, H. J., Liu, Y., Zhu, X. L., & Xu, Y. (2023). Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in Alzheimer's disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(2), 391–401. https://doi.org/10.1038/s41386-022-01435-w

[5] Chen, R., Blosser, T. R., Djekidel, M. N., Hao, J., Bhattacherjee, A., Chen, W., Tuesta, L. M., Zhuang, X., & Zhang, Y. (2021). Decoding molecular and cellular heterogeneity of mouse nucleus accumbens. Nature neuroscience, 24(12), 1757–1771. https://doi.org/10.1038/s41593-021-00938-x 

[6] Barcomb, K., & Ford, C. P. (2023). Alterations in neurotransmitter co-release in Parkinson's disease. Experimental neurology, 370, 114562. https://doi.org/10.1016/j.expneurol.2023.114562

[7] Diana, A., Pillai, R., Bongioanni, P., O'Keeffe, A. G., Miller, R. G., & Moore, D. H. (2017). Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. The Cochrane database of systematic reviews, 1(1), CD006049. https://doi.org/10.1002/14651858.CD006049.pub2