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Cholinergic Deficiency Hypothesis in Delirium: A Synthesis of Current Evidence

¹ Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Departments of ² Neurology and ³ Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
⁴ Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts.

Address correspondence to Sharon K. Inouye, MD, MPH, Aging Brain Center, Hebrew SeniorLife, 1200 Centre Street, Boston, MA 02131. E-mail: agingbraincenter{at}hrca.harvard.edu

Abstract

Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition.

Key Words: Acetylcholine • Delirium • Delirium in older persons • Dementia • Cholinergic deficiency