Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer’s Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects
http://content.iospress.com/articles/jo ... /jad160373
APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.
From SNpedia, the snip is rs1803274. The risk allele appears to be AA and (possibly AG) Together, they seem to affect roughly 40% of the population so this is not a small group. My version of 23andMe does report for this gene. They use the C and T alleles. C typically corresponds with G and T with A. In this case, T would be the risk allele.
Perhaps I'm overthinking it, but this feels a bit understated given the blurry boundary between MCI and AD. Here’s the PR:
Donepezil, a medication that is approved to treat people with Alzheimer's disease, should not be prescribed for people with mild cognitive impairment without a genetic test. UCLA School of Nursing researchers discovered that for people who carry a specific genetic variation -- the K-variant of butyrylcholinesterase, or BChE-K -- donezpezil could accelerate cognitive decline.
Donepezil was tested as a possible treatment for mild cognitive impairment in a large, federally funded study published in 2005, but it was not approved by the FDA. Still, doctors have often prescribed the drug "off-label" -- meaning that it is not approved for that specific disorder -- for their patients with mild cognitive impairment.
The MOA (mechanism of action) of Donzepezil is described by Wikipedia:
Donepezil binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This results in an increased acetylcholine concentrations at cholinergic synapses.
This leads me to wonder if increasing acetylcholine levels via other means such supplementing with citicholine or even eating foods high in choline could be detrimental for APOE-ɛ4 and BCHE-K* positive subjects. Lots of unanswered questions.