Acetylcholinergic Deficit in Alzheimer’s Disease and Treatment

There is an open-access (creative commons attribution License 2.0) article by Cummings and Sabbagh titled ‘Progressive Cholinergic Decline in Alzheimer’s Disease: Consideration for Treatment with Donepezil 23 mg in patients with moderate to severe symptomatology’ available here. In the article, the authors look at some of the evidence suggesting an acetylcholinergic deficit in Alzheimer’s Disease and examine the dose effect of the acetylcholinesterase inhibitor Donepezil. There is a nice quote about the pragmatics of focusing on acetylcholine rather than Amyloid:-

The cholinergic abnormalities seen in AD are not viewed as the cause of the disorder, but cholinergic involvement is significant because it is universal, correlates with cognitive defects, and is one of the few pathophysiologic phenomena that can be addressed with currently approved treatment options

The authors go on to summarise some of the data on Donepezil at the two main doses including one study supporting a dose effect in advanced dementia without evidence of a statistically significant difference in adverse events between doses. The authors also discuss the FDA approval of a higher dose of Donepezil as per the title although this will be significant for the USA. They discuss the evidence supporting a theoretical justification of a higher dose and specifically focus on the reduction in Acetylcholinesterase inhibition. The main part of the article focuses on a discussion of a 24-week randomised double-blind trial of Donepezil at 23 mg in people with advanced dementia. This study was part of the data set that the FDA reviewed in their assessment and in which it was thus contextualised. The analysis is brief and it would be interesting to know which outcomes were selected in the trial design and what the results were for all of these outcomes. Another interesting point is about the difference in discontinuation rates. In addition is a more detailed exploration of the physiological function of the acetylcholinesterase inhibitors in the CNS. It will be interesting to follow further research in this area.

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