Graphic of brain with red, blue, and purple icons representing norephinephrine system hyperactivity, serotonin system deficits, and dopamine system dysreguation
Graphic of brain with red, blue, and purple icons representing norephinephrine system hyperactivity, serotonin system deficits, and dopamine system dysreguation

An emerging hypothesis for a cause of Agitation in Alzheimer’s Dementia (AAD)

Dysfunction in norepinephrine, serotonin, and dopamine (NSD) neurotransmitter systems may result in agitated behaviors in AAD.1,2

How might modulating these 3 neurotransmitter systems help restore balance in AAD?

Graphic of brain

Imbalance of top-down executive function and bottom-up emotional drive in AAD1-3

Graphic of brain with red, blue, and purple pathways lit up

Dysfunction of NSD neurotransmitter systems in AAD1-3

Hypothetical Neurotransmitter Systems Activity in AAD

Did you find the information on this page useful?
Resources and additional information about AAD

References: 1. Rosenberg PB, Nowrangi MA, Lyketsos CG. Neuropsychiatric symptoms in Alzheimer's disease: What might be associated brain circuits? Mol Aspects Med. 2015;43-44:25-37. 2. Wright CI, Dickerson BC, Feczko E, Negeira A, Williams D. A functional magnetic resonance imaging study of amygdala responses to human faces in aging and mild Alzheimer's disease. Biol Psychiatry. 2007;62(12):1388-1395. 3. Banno K, Nakaaki S, Sato J, et al. Neural basis of three dimensions of agitated behaviors in patients with Alzheimer disease. Neuropsychiatr Dis Treat. 2014;10:339-348. 4. Gannon M, Wang Q. Complex noradrenergic dysfunction in Alzheimer's disease: Low norepinephrine input is not always to blame. Brain Res. 2019;1702:12-16. 5. Theofilas P, Ehrenberg AJ, Dunlop S, et al. Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017;13(3):236-246. 6. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes. Neuroscience. 2007;146(1):471-480. 7. Gulyás B, Brockschnieder D, Nag S, et al. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: A post-mortem autoradiographic study. Neurochem Int. 2010;56(6-7):789-798. 8. Jacobs HIL, Riphagen JM, Ramakers IHGB, Verhey FRJ. Alzheimer's disease pathology: Pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry. 2021;26(3):897-906. 9. Lanctôt KL, Herrmann N, Mazzotta P. Role of serotonin in the behavioral and psychological symptoms of dementia. J Neuropsychiatry Clin Neurosci. 2001;13(1):5-21. 10. Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, et al. Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease. Neuropsychologia. 2005;43(3):442-449. 11. Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, De Deyn PP. Monoaminergic neurotransmitter alterations in postmortem brain regions of depressed and aggressive patients with Alzheimer's disease. Neurobiol Aging. 2014;35(12):2691-2700. 12. Lindenmayer JP. The pathophysiology of agitation. J Clin Psychiatry. 2000;61 Suppl 14:5-10. 13. Sala A, Caminiti SP, Presotto L, et al. In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer's disease phases. Alzheimers Res Ther. 2021;13(1):187. 14. Cox SML, Benkelfat C, Dagher A, et al. Effects of lowered serotonin transmission on cocaine-induced striatal dopamine response: PET [¹¹C]raclopride study in humans. Br J Psychiatry. 2011;199(5):391-397. 15. Arai H, Kosaka K, Iizuka R. Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia. J Neurochem. 1984;43(2):388-393.