3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.3.3 The Cholinergic Hypothesis cognition
1 min read1 figure
Written by Resident Doctor Committee · Published
Pathways and function
The cholinergic hypothesis links the cognitive impairment of Alzheimer's disease to reduced acetylcholine transmission from the basal forebrain to the cortex and hippocampus.
The nucleus basalis of Meynert projects to the cortex, and medial septal and diagonal band neurons project to the hippocampus.
Acetylcholine supports arousal and selective attention and favours hippocampal encoding over retrieval, so its loss impairs attention and new learning.
Evidence and limits
Post-mortem studies found reduced cortical and hippocampal choline acetyltransferase, the enzyme that makes acetylcholine, in step with dementia severity.
Scopolamine, a central muscarinic blocker, impairs attention and new learning but does not reproduce progressive pathology.
Cholinergic loss contributes alongside amyloid, tau and inflammation rather than starting the disease, and it also occurs in Lewy body and Parkinson's disease dementia.
Cholinesterase inhibitors
Donepezil, rivastigmine and galantamine preserve the acetylcholine that surviving terminals release. Benefit is symptomatic and modest, about 2 to 3 points on the Alzheimer's Disease Assessment Scale cognitive subscale.
Benefit is limited because fewer terminals remain and postsynaptic networks also degenerate.
Site | Adverse effects |
|---|---|
Peripheral muscarinic | Gastrointestinal upset, urinary urgency, weight loss |
Cardiac vagal | Bradycardia, heart block, syncope |
Airway | Bronchoconstriction, so caution in asthma |
Central | Insomnia, vivid dreams, agitation |
Rivastigmine patches can reduce gastrointestinal effects.
Treating drug-induced urgency with oxybutynin is a prescribing cascade that may oppose the cognitive benefit.
Cumulative antimuscarinic burden from prescribed and over-the-counter drugs is associated with delirium, cognitive impairment and mortality.