Alzheimer's Disease: The Steps to a Solution

Lane Simonian

The key to the treatment of Alzheimer's disease is likely the following:

"The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite."

The early stages of Alzheimer's disease often begin with the overactivation of g protein- coupled receptors and receptor tyrosine kinases (last link below). Many factors can overactivate these receptors including environmental toxins, chronic bacterial, viral, and fungal infections, stress, and high glucose levels. Over-activation of these receptors leads to the formation of amyloid which when it reaches high enough levels in those with the APOE4 gene or genes can also overactivate these receptors. Anti-amyloid drugs only help APOE4 carriers and slows down the progression of the disease in these carriers closer to that of non-carriers.

The Bredesen protocol in part sought to identify the specific triggers for the disease in each individual and then develop a program to address these triggers. But there are often multiple triggers, they are often not easy to identify, and they are often not easy to "neutralize."

The next option is to inhibit processes following the overactivation of receptors (no matter what the initial causes). This includes sigma-1 receptor agonists such as Aricept/donepezil and drug candidates such as Anavex 2-73/blarcamesine and likely simufilam (sigma-1 receptor agonists reduce the release of intracellular calcium). These drugs and drug candidates can lead to temporary improvements in those with mild cognitive impairment and slow down the progression of mild Alzheimer's disease, but they do not stop the progression of the disease.

After this, one can try to inhibit NMDA receptor activation (Namenda/memantine) or points following NMDA receptor activation (multiple drug candidates). However the best solution is to combine conventional therapies which limit the formation of peroxynitrite (ONOO-) with antioxidants that scavenge peroxynitrite and reverse part of its damage. With this approach it appears that mild Alzheimer's disease can be largely stabilized for long periods of time and moderate Alzheimer's disease can be slowed down for a year or more.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729264/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362409/

https://www.science.org/doi/10.1126/scisignal.3119tr3

Lane Simonian

I thought of a simpler way to present this. Early in Alzheimer's disease, the main problem is the breakdown of acteylcholine by acetylcholinesterases. As the disease progresses, the main problem becomes declining levels of acetylcholine due to oxidation and nitration. Oxidation and nitration inhibit the transport of choline, its conversion to acetylcholine by choline acetyltransferases, and its release from muscarinic acetylcholine receptors. Direct and indirect acetylcholinesterae inhibitors can increase or maintain acetylcholine in mild cognitive impairment and mild Alzheimer's Disease and slow down oxidative stress leading to improvements or near stabilization of the disease for awhile. But to be effective over longer periods of time they need to be combined with antioxidants (although some antioxidants also inhibit acetylcholinesterase activity). For later stages of the disease, you need to combine antioxidants with treatments that inhibit NMDA receptor activation and/or inhibit one or more of the points after NMDA receptor activation (some antioxidants also do this, too).

The following quote summarizes the value of this approach:

"Inactivation of the mAChR [muscarinic acetylcholine receptors] by the LMW [low molecular weight] endogenous inhibitor is likely to be a factor in the continual decline of Alzheimer's patients, even those taking acetylcholinesterase inhibitors. Natural antioxidants and pyrophosphate analogs may improve the effectiveness of acetylcholinesterase inhibitors and prove useful in the treatment and prevention of Alzheimer's disease since the muscarinic acetylcholine receptor is required for memory, and decreased cholinergic function is a critical deficit in Alzheimer's disease."

Probably the best antioxidants for the treatment of Alzheimer's disease are panax ginseng or aromatherapy with certain essential oils (like rosemary, bay laurel, clover, lemon balm, lavender, rose, lemon, and orange). These treatments are not without possible side effects (such as insomnia, stomach problems, and higher blood pressure for awhile at least for panax ginseng and increased agitation, anxiety, and higher blood pressure for some of the more stimulating essential oils). I also don't know if there are risk combining these antioxidants with either Aricept (or other acetylcholinesterase inhibitors) or with Namenda (memantine). What I am almost certain of though is that these treatments are more effective and safer than the current drugs being considered for Alzheimer's disease.

mommyandme (m&m)

Thank you!

Marta

”more effective and safer “ - has there been a head to head trial?

Lane Simonian

To a certain extent, yes. The panax ginseng trial was an open label so the comparision has limitations. Nevertheless those with mild Alzheimer's disease improved in cognition on panax ginseng, whereas those on acetylcholinesterase inhibitors or anti-amyloid drugs decline. The side effects for ginseng were claimed to be mild.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

Lane Simonian

Here are the specific numbers:

Indirect acetylcholinesterase inhibitor and direct antioxidant

Panax ginseng (high dose group/9.5 grams) baseline MMSE 21.4 48 weeks 22 96 weeks 24.7

Panax ginseng (low dose group/4 grams) baseline MMSE 22 48 weeks 25.7 96 weeks 23.7

Direct acetylcholinesterase inhibitor and indirect antioxidant

Aricept baseline MMSE 22 52 weeks 21.2 78 weeks 20.3

https://www.researchgate.net/publication/6494106_Donepezil_in_Alzheimer%27s_Disease_What_to_Expect_after_3_Years_of_Treatment_in_a_Routine_Clinical_Setting

Lane Simonian

Marta, were you the member who moved to Sequim and helps dementia patients and their families? If you are ever interested Sequim has one of the best apothecary stores in the world.

My father worked for twenty years as a seasonal ranger naturalist in Olympic National Park (mostly at Kalaloch) so I am quite familiar with this beautiful part of the country.