Loading discussion content. Please wait...
Younger-Onset AD or Other Dementia
Maybe I have finally figured this disease out
I have been trying to figure out Alzheimer's disease for nearly twenty years. It comes down to this very simple observation:
"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."
Every treatment that slows down the production of peroxynitrite slows down the progression of Alzheimer's disease, but only those treatments which scavenge peroxynitrite and reverse part of the damage it does to the brain largely stabilizes Alzheimer's disease over long periods of time.
Here is a good example, Aricept/donepezil slows down oxidative stress by inhibiting the release of intracellular calcium and Namenda reduces oxidative stress by inhibiting NMDA receptors but both work much better with compounds that also scavenge peroxynitrite and repair part of the damage that it does to the brain:
"MMSE change in groups with or without herbal medicine. a Patients with Alzheimer’s disease had a transient improvement in cognitive function with conventional therapy (CT), but declined to a level similar to no treatment after 18 months. CT supplemented with herbal medicine (CT + H) provided additional benefit. The effect from herbal medicines became more pronounced over time. Expected decline of MMSE were calculated by formula produced from previous data. b In subgroup analysis, patients with moderate AD (red lines) were initially more responsive to both CT + H and CT therapies than mild AD (blue lines) patients. Over the course of treatment, CT + H outperformed CT therapy, a substantial deceleration in cognitive decline being observed in patients with moderate AD, while a long-term stabilization effect being observed in the patients with mild AD. MMSE denotes mini-mental state examination."
A number of other examples of this exist. For instance, compounds in panax ginseng that not only slow down the production of peroxynitrite but also scavenge it and reverse part of its damage led to improvements in cognitive function at 24 weeks that were sustained for two years. Anavex 2-73 which like Aricept inhibits peroxynitrite formation by reducing the release of intracellular calcium, but unlike Aricept acts as a direct antioxidant largely stabilized cognitive function for three years. The evidence for other treatments that do the same thing is more short-term but includes aromatherapy and GV-971 (a drug derived from brown algae).
The multiple failures in Alzheimer's drug development was not due to the intractable nature of the disease, it was due to efforts that nibbled around the edges of the disease rather than attacking its core.
Lane, I have a different perspective. I believe that the key to preventing and treating Alzheimers is reducing the over-activation of microglia immune cells, which produce in excess reactive oxygen species (ROS), including peroxynitrite and nitric oxide. It is more effective to prevent ROS formation, rather than try to treat it after it is already doing its damage to DNA and brain cells.
In 2015, Dr Aigner in Austria showed that montelukast reduced microglia swelling and over-activation in aging wild type rats. The FDA clinical trial at Emory University and the Health Canada Intelgenx clinical trial should determine before the end of 2023 if montelukast is an effective treatment for Alzheimers and other dementias related to aging and inflammation.
The oxidative stress and neuroinflammation hypotheses of Alzheimer's disease actually go hand and hand. Oxidative stress contributes to the activation of microglia and the activation of microglia causes more oxidative stress.
Our results show that proteinous DAMPs [damage-associated molecular patterns] modified by peroxynitrite more potently amplify inflammation via TLR4 activation than the native DAMPs, and provide first evidence that such modifications can directly enhance innate immune responses via a defined receptor.
Toll-like receptors in turn activate microglia which as you note produce more oxidants such as peroxynitrite.
There are all sorts of inflammatory mediators that can help trigger Alzheimer's disease. If one is present such as gingipains or leukotrienes and you inhibit it or its actions (montelukast, for instance, inhibits leukotriene receptors), you have a good chance of at least significantly slowing down Alzheimer's disease in that group of patients. But if it is not present, the drug will likely not work.
The best treatments for Alzheimer's disease slow down the production of oxidants, scavenge oxidants, and reverse part of the damage that they do. If you do only the first, you only slow down the progression of the disease. If you do the second and third, you only slow down the progression of the disease. If you do all three, you likely largely stabilize the disease for long periods of time.
can you explain how you arrived at that regime of medicine
what do you think of steriods to treat inflamation
thank you Paul
Great question, Paul, and welcome here. I started studying Alzheimer's disease in 2004 when my aunt and cousin were in the late stages of the disease and my mother was in the early stages of the disease. I found that the one thing all Alzheimer's patients have in common is that they all have high levels of calcium in their brain. It took me three years to trace what causes high levels of calcium and what this lead to. Eventually I put together a chart that was much like this one (ONOO- is peroxynitrite).
In 2007, I came across the following article and began to give my mother rosemary to smell each day (via direct inhalation aromatherapy).
After about a month, my mother asked "why have you been giving me this to smell for every day for a month." Her sense of time improved. She also recognized her home again, remembered her name, she stopped having delusions, and was more alert and aware. Her short-term memory got slightly better and she became a little bit more lucid.
I began looking for other natural products that were scavengers for peroxynitrite, although I found them after my mother had passed away from heart failure. One of the best appears to be panax ginseng.
The problem with most anti-inflammatories including steroids is that they act after peroxynitrite formation, although they can further reduce peroxynitrite formation.