Bending the Curve of Alzheimer's Disease

Lane Simonian

Acetylcholine is a critical compound needed for the retrieval of memory.  The breakdown of acetylcholine by acetylcholinesterases is a problem early in Alzheimer's disease, but as Alzheimer's disease progresses acetylcholinesterase activity declines thus limiting the effectiveness of acetylcholinesterase inhibitors.  The problem shifts from the breakdown of acetylcholine to decreasing levels of acetylcholine itself.  A critical factor in this decline is the oxidation or nitration of choline transport systems, choline acetyltransferases (an enzyme which converts choline into acetylcholine), and the release of acetylcholine through muscarinic acetylcholine receptors.  As the disease progresses then, the importance of scavening the nitro-oxidant peroxynitrite and reversing part of its damage becomes increasingly critical.

Acetylcholinesterase inhibitors lead to temporary improvements in cognition that can be maintained for about a year.  After that acetylcholinesterases perform only slightly better than a placebo.  On the other hand, compounds that scavenge peroxynitrite largely stabilize Alzheimer's disease over long periods of time.  The first link shows the general difference between transient cognitive improvements and disease modification (i.e. near stabilization over long periods of time).  The subsequent links show peroxynitrite scavengers that accomplished the latter.

https://www.e-tjp.org/viewimage.asp?img=TaiwanJPsychiatry_2020_34_4_152_303679_f2.jpg

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/ (Chinese herbs plus conventional therapy)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/ (Korean red ginseng/panax ginseng: Figure Two)

http://www.arianapharma.com/wp-content/uploads/2019/03/ANAVEX2-73_CTAD_2018_Presentation_v2.pdf (Anavex 2-73/blarcamesine: p. 17).

Crushed

Lane Simonian wrote:

.  On the other hand, compounds that scavenge peroxynitrite largely stabilize Alzheimer's disease over long periods of time.  The first link shows the general difference between transient cognitive improvements and disease modification (i.e. near stabilization over long periods of time).  The subsequent links show peroxynitrite scavengers that accomplished the latter. 

https://www.e-tjp.org/viewimage.asp?img=TaiwanJPsychiatry_2020_34_4_152_303679_f2.jpg

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/ (Chinese herbs plus conventional therapy)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/ (Korean red ginseng/panax ginseng: Figure Two)

http://www.arianapharma.com/wp-content/uploads/2019/03/ANAVEX2-73_CTAD_2018_Presentation_v2.pdf (Anavex 2-73/blarcamesine: p. 17).

Just repeating more silly stuff
eg
  
 A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease.
 
Open label studies are garbage
open retrospective studies are garbage   

the  Anavex Phae 3 trial is not published yet

"  Anavex is expecting that top-line data from the Phase 2b/3 clinical trial, called Anavex 2-73-AD-004 (NCT03790709), will be available in the second half of 2022, according to a press release." 

  
  More importantly the Anavex  trial deals only with cognitive SYMPTOMS  so claims about  DISEASE PROGRESSION are unwarranted

Brief Summary:

Phase 2b/3 48-week study to evaluate the effects of ANAVEX2-73 on cognition and function after 48 weeks of daily treatment. Additional outcome measures include refined measures of sleep, behavioral and psychological symptoms typically observed in AD, changes in daily functioning of participants and changes in caregiver burden, as well as changes in quality of life measures of both, patients and caregivers during treatment with ANAVEX2-73

To remind everyone  there is a fundamental difference between Alzheimer's DISEASE and Alzheimer's   SYMPTOMS   It is entirely possible to have improvement in Alzheimer's symptoms without affecting the progression of the underlying disease.  

Lane's claims are worthy of a Nobel Prize if there was any "proof of effect"  on the disease progression.  

 



  

  

Lane Simonian

These are some good points, Crushed.  I want to take a closer look at the symptoms versus causes debate.

One of the symptoms of Alzheimer's disease is memory loss.  Acetylcholine is critical to the retrieval of short-term memory.  If a memory is permanently lost, then it cannot be recovered, but if a memory cannot be accessed then there is a possibility that it can be recovered.  The latter seems to be the case in Alzheimer's disease.

Now what is the cause of memory loss in Alzheimer's disease or in other words what causes the decline in acetylcholine?  Early in the disease that decline is primarily caused by high levels of acetylcholinesterase activity which breaks down acetylcholine.  This enzyme requires calcium.  Both acetylcholinesterase inhibitors and Anavex 2-73 inhibit the release of intracellular calcium.  Intracellular calcium also plays a role in the formation of amyloid and in oxidative stress.  But over time both acetylcholine levels and the release of intracellular calcium decline in Alzheimer's disease, thus reducing acetylcholinesterase activity.  Acetylcholinesterase inhibitors are treating an early cause of memory loss in Alzheimer's disease, but it is mostly a transient cause.  That is why after a year or so, the effects of acetylcholinesterase inhibitors begin to decline so that they start performing only slightly better than a placebo.

The primary cause of Alzheimer's disease begins to shift to the loss of acetylcholine.  Oxidation and nitration inhibit the transport of choline, the production of acetylcholine, the release of acetylcholine from muscarinic acetylcholine receptors, and the regeneration of neurons.  It also contributes to the death of both neural progenitors and fully formed neurons.  All of this makes it impossible for someone with Alzheimer's disease to access many of their memories.

One caveat is that the regeneration of neurons appears to only occur in the hippocampus.  Acetylcholine in the hippocampus is tied to various type of memories including object recognition, remembering places, facial recognition, and repetitive memory (numbers, the alphabet, one's name, etc.).  Memories tied partially or fully to the frontal cortex such as memories of recent past events and the ordering of information are less effected by treatments restoring acetylcholine levels because the dead neurons have not been replaced.

Disease modifying (not curing) treatments are possible in which some improvements in certain types of memory at least are possible.  Improvements in cognition can also lead to less tangible improvements such as better quality of life, more alertness and awarenes and fewer behavioral problems (such as anxiety and delusions).  In addition, antioxidant treatments can also affect these other aspects of Alzheimer's disease  by similar routes as they affect cognition.