WARNING re. Aricept (Donepezil)

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
User avatar
Julie G
Mod
Mod
Posts: 9187
Joined: Sat Oct 26, 2013 6:36 pm

WARNING re. Aricept (Donepezil)

Post by Julie G »

WOW. A new warning has been issued for Aricept (Donepezil.) Apparently, it can ACCELERATE cognitive decline in E4+ folks with a specific genetic variation. If you or a loved one is taking or considering this medication, get tested first. Here’s the Paper:

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.
User avatar
KatieS
Senior Contributor
Senior Contributor
Posts: 1224
Joined: Wed Mar 05, 2014 1:45 pm

Re: WARNING re. Aricept (Donepezil)

Post by KatieS »

Wondering if CC on this SNP is in any way correlated with intolerance to citicholine.
User avatar
Julie G
Mod
Mod
Posts: 9187
Joined: Sat Oct 26, 2013 6:36 pm

Re: WARNING re. Aricept (Donepezil)

Post by Julie G »

Katie, from my understanding (could be wrong,) CC is the wild type. You don't carry the risk variant and should be able to tolerate choline... per this one snip. Remind me what happens when you take Citicholine.
User avatar
KatieS
Senior Contributor
Senior Contributor
Posts: 1224
Joined: Wed Mar 05, 2014 1:45 pm

Re: WARNING re. Aricept (Donepezil)

Post by KatieS »

Just like Susan, I seem to get too hyper- excitable, occasionally even palpitations, when I take citicholine. After 3 trials, i stopped it, and now occasionally take half a Country Life choline if my diet is low (less eggs). I was wondering if having the CC has any correlation to this adverse reaction to choline. Given my reaction, I have not tried choline on my mom who is also a CC.
User avatar
Julie G
Mod
Mod
Posts: 9187
Joined: Sat Oct 26, 2013 6:36 pm

Re: WARNING re. Aricept (Donepezil)

Post by Julie G »

Choline has a known stimulant-like effect, but your experience seems extreme. Out of curiosity, I'm wondering how you do with coffee or other stimulants? How do you respond to antihistamines? You may have something else going on that amplifies this effect. FWIW, when I started citicholine, I took 250 mg AM & PM based upon advice from Gilgamesh. I didn't sleep for a week until I realized insomnia was a side effect. I dropped my second capsule and harnessed the energy burst for AM use only and now tolerate it well.
User avatar
Julie G
Mod
Mod
Posts: 9187
Joined: Sat Oct 26, 2013 6:36 pm

Re: WARNING re. Aricept (Donepezil)

Post by Julie G »

Props to Harrison who noticed that the Science Daily article accidentally linked to the wrong paper. Here's the correct one:

Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment
http://content.iospress.com/articles/jo ... /jad160562
Abstract: Background: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer’s disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer’s disease progression and donepezil therapy, and has led to contradictory results. Objectives: To determine whether BChE-K genotype predicts response to donepezil in MCI. Methods: We examined the association between BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI. Results: We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls. Conclusion: BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management. [Emphasis mine.]
User avatar
Julie G
Mod
Mod
Posts: 9187
Joined: Sat Oct 26, 2013 6:36 pm

Re: WARNING re. Aricept (Donepezil)

Post by Julie G »

Now, I'm wondering if I got the risk alleles right :?. From the paper:
The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity.

From the SNPedia link above:
The rs1803274(A) allele encodes a version of the butyrylcholinesterase enzyme known as the K variant; it may also be known as CHE*539T or BCHE*539T.
According to SNPedia, A is NOT the most frequent polymorphism. AA is denoted in brown, AG in green, and GG in blue.
chart.png
Somebody got this wrong. Can anybody clarify?
You do not have the required permissions to view the files attached to this post.
circular
Senior Contributor
Senior Contributor
Posts: 5565
Joined: Sun Nov 03, 2013 10:43 am

Re: WARNING re. Aricept (Donepezil)

Post by circular »

Boy if this doesn't serve as a hammer over researchers' heads to genotype their subjects (though I recognize it's probably expensive). I came out G,G so I guess I'm okay. Very interesting implications about all kinds of supplements and drugs that affect the cholinergic system one way or another, and in turn the cholinergic anti-inflammatory pathway. Ashwagandha, as an example of something we see recommended fairly regularly, inhibits breakdown of choline.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
Bettylacy
Senior Contributor
Senior Contributor
Posts: 121
Joined: Tue Jan 24, 2017 9:34 pm
Contact:

Re: WARNING re. Aricept (Donepezil)

Post by Bettylacy »

THis study is a reminder how important it is to test for SNPs . I'm sure more of this information will be coming out along these lines in the future. Precision individual health care through a functional approach inclusive of genetic testing is the future of medicine. I recently had 23 and me done but there was no information about APOE status. I am not familiar with Prometheus nor how to access to get more information on the specificity of SNP regarding my APOE4 or this new discovery of the BChE-K SNP. Is this info available? And how to access?


Sent from my iPad using Tapatalk
APOe 3/4; If you want to go fast go alone. If you want to go far go together. African proverb. :D
User avatar
SusanJ
Senior Contributor
Senior Contributor
Posts: 3058
Joined: Wed Oct 30, 2013 7:33 am
Location: Western Colorado

Re: WARNING re. Aricept (Donepezil)

Post by SusanJ »

Just a quick note on choline and citicholine. It's probably not because it is a stimulant like caffeine, so much as how we each metabolize it.
Screen Shot 2017-03-01 at 7.10.43 AM.png
(By Radio89 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.p ... d=20265140)

As you see above, choline metabolism can go several directions in the body. Choline dehydrogenase (CHDH), converts choline to TMG. I've found 2 snps related to the efficacy of that path:

rs12676, the T is the risk allele (NA on my 23andme, but 45% of the population has one copy and 9% have two copies of the minor T allele.)
rs9001, the A allele is one known risk for higher homocysteine (of which I'm AA)

Since Katie and I both have high homocysteine, which can be driven down by TMG supplementation, my guess is that her path to TMG is clogged like mine.

So the reality for me (and probably Katie) is that extra choline gets pushed into other parts of choline metabolism, including the path leading to an increase in acetylcholine. Hence the brain buzz (ACh is all about arousal) and heart palpitations (a little more complicated to understand, but see https://courses.washington.edu/chat543/ ... tylch.html which references atrial fibs - look for "These tractings demonstrate the effects of ACh on supraventricular cells of the heart...").

TMG is a much better option for the two of us, along with gentle amounts of choline from the diet, so our bodies can maintain choline equilibrium.
You do not have the required permissions to view the files attached to this post.
Post Reply