Agreement: I Agree Body: Dear Editor Cholinergic Pathway Responding to the 16 April article, BMJ 2026;393:s719, on Alzheimer’s drugs which states that independent Cochrane review has concluded drugs targeting amyloid β proteins do not produce clinically meaningful positive effects, we suggest a more positive perspective. Amid dementia research teams, carers, patients and investors disappointment, public media reaction to the Cochrane review almost invariably omits any reference to therapy that has been available for thirty years. Cholinergic therapy was partly prompted by a BMJ report (Br Med J,1978; 2:1457-1459) on cholinergic correlates of cognitive and pathological indices in Alzheimer’s disease, and yet most of our acquaintances today have no idea that there is any treatment for Alzheimer’s and related dementias. A pharmacological approach for treating dementia, cholinergic medication provides improvement in cognitive and behavioural symptoms. As medical research scientists, investigating the role of the cholinergic system in dementia for decades, we highlight research developments which match the Cochrane recommendation to “focus on other pathways”. Significant developments towards improving the outcome of cholinergic medication are evident in the most recent published reports or reviews on the cholinergic system and dementia: Targeting different cognitive disorders - Symptomatic benefit following cholinergic therapy varies according to diagnosis of Alzheimer's disease, Dementia with Lewy bodies and Vascular Dementia, with the Lewy body conditions responding more positively. Impacting non-cognitive symptoms - behavioural aspects respond to cholinergic therapy, and medications for other conditions which have incidental anticholinergic side effects may induce both cognitive and other psychological symptoms. Comparing drugs - responses can vary for available cholinesterase enzyme inhibitors (donepezil, rivastigmine, and galantamine), and for their combination with the glutamate antagonist drug memantine. Targeting the CNS - with significantly more muscarinic M1 receptors in the brain compared with most other organs, drugs targeting this cholinergic receptor point to alternative acetylcholine-enhancing actions. Limiting side effects - apart from CNS selective drugs, strategies that help to limit gastrointestinal side effects for current cholinergic drugs include the use of anti-nausea agents, and transdermal or intranasal drug delivery. Natural product potential - drug discovery can depend on the unparalleled structural diversity and biological relevance of phytochemicals; promising controlled trial evidence of plant medicine benefitting Alzheimer’s patients includes the botanicals Ginkgo biloba and sage, Salvia officinalis, both with cholinomimetic activity. These complement plant alkaloid cholinesterase inhibitors such as galantamine, physostigmine and huperzine (a licensed prescribed drug for dementia in China). Moving on from cholinergic pharmacotherapy, deep brain stimulation of the cholinergic basal forebrain (Septum and Nucleus Basalis of Meynert) is under investigation for memory improvement and slowing cognitive decline. Numerous other pathways extend to targeting aberrant proteins such as tau, different neurotransmitters, and inflammatory mechanisms. In the meantime, cholinergic therapy is, at the very least, one open for new opportunity and optimism. Elaine Perry and Robert Perry, Newcastle University Professors Emeriti of Neurochemical Pathology and Clinical Neuropathology, No competing Interests: Yes The following competing Interests: Electronic Publication Date: Tuesday, April 21, 2026 - 13:24 AI use: No, I have not used AI Highwire Comment Subject: Alzheimer’s drugs targeting amyloid do not produce clinically meaningful effects, concludes Cochrane review Workflow State: Released Full Title: Re: Alzheimer’s drugs targeting amyloid do not produce clinically meaningful effects, concludes Cochrane review Highwire Comment Response to: Alzheimer’s drugs targeting amyloid do not produce clinically meaningful effects, concludes Cochrane review Check this box if you would like your letter to appear anonymously:: Last Name: Perry First name and middle initial: Robert H Email: robert.perry@ncl.ac.uk Address: Newcastle University Occupation: Emeritus Professor Other Authors: Professor Elaine Perry Affiliation: Newcastle University BMJ: Additional Article Info: Rapid response