Promise of Novel Alzheimer’s Treatments

Last year, I blogged on a CDC report that Alzheimer’s Disease is more prevalent than previous epidemiology had acknowledged.  Last month at the Rejuv Biotech conference, I heard Chas Bountra tell us that

• Alzheimer’s Disease is currently #3 among diseases of old age
• Demographics are increasing the prevalence of AD at an inexorable rate
• Far more than cancer and vascular diseases, AD is unknown to us–medical science really doesn’t have a clue

Boutra is in a position to direct many millions of research dollars for AD, and he says he won’t go near either of the two large branches of research on the disease.  Study of (1) beta amyloid plaques and (2) tau proteins has absorbed tens of billions of research dollars over half a century, and yet there is no agreement even about what ultimately causes AD, let alone a program for cure.  So he will only fund long-shot ideas at the fringes of Alzheimer’s research.

There is no shortage of dark horses in this field.  In recent blog posts, I described two:  Tony Wyss-Coray is beginning clinical trials using plasma transfusions from young donors, and Bioviva will soon be trying gene therapy to activate telomerase.

Further along than either of these is Dale Bredesen’s innovative approach based on the sustained application of common sense.  Bredesen reports on a trial with just 10 patients, but 9 of them showed major improvement.  This was not the kind of result that you need a cognitive test to measure; the patients came out of nursing care and went back to their jobs.  He calls the program MEND, for Metabolic Enhancement for Neurodegeneration.  

Bredesen’s starting point is a model in which AD results from a change in hormonal signaling.  There is turnover of neurons throughout our lives (this alone is a relatively new acknowledgment), and late in life, the destruction of neurons outpaces the growth of new ones.  Bredesen defines AD as the tail of the distribution, in which the destruction of neurons has become so severe as to precipitate obvious cognitive decline.  He draws an analogy to osteoporosis, which is understood as a loss of the healthy balance between the creation and destruction of bone cells (osteoblasts) that renews bone tissue and keeps bones strong.  Nerve cells in the brain do not turn over as frequently as bone cells, but the principle is the same.

Body homeostasis is maintained generally by signaling with negative feedback loops.  Biology derives its robustness from  processes that are self-limiting.  But positive feedback loops act like “switches”; they can take the body from one state to another.  Beta amyloid is at the center of a positive feedback loop; it is a mis-folded protein that tends to cause more proteins to misfold, similar in dynamics to a prion, though the feedback of beta amyloid is not so direct as in prion diseases.

In the case of beta amyloid, the protein that is misfolded is called APP, for amyloid precursor protein.  Bredesen sees APP as a switch that turns AD on, and can just as well turn AD off.  It is both a signal protein and the gunk that accumulates around neurons in the Alzheimer’s brain.

The (missing) punch line

So what is the program that Bredesen has used so successfully to reverse Alzheimer’s symptoms in ten patients?  It is multi-faceted, not easily summarized, addressing multiple risk factors through multiple modalities.  The program is also personalized, as a doctor works with each patient’s particular symptoms and particular strengths, desiging a program the patient can commit to.  This is not traditional allopathic medicine, and prescription drugs play a minor role.  Bredesen describes a program for one of the 10 patients.

(1) she eliminated all simple carbohydrates, leading to a weight loss of 20 pounds; (2) she eliminated gluten and processed food from her diet, and increased vegetables, fruits, and non-farmed fish; (3) in order to reduce stress, she began yoga, and ultimately became a yoga instructor; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; [5] she took melatonin 0.5mg po qhs; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin 1mg each day; (8) she took vitamin D3 2000IU each day; (9) she took fish oil 2000mg each day; (10) she took CoQ10 200mg each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated HRT (hormone replacement therapy) that had been discontinued following the World Health Inst report in 2002; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week. [same ref above]

(Do you ever wonder about the code language used by doctors on their prescription pads, that only pharmacists can read?  “po qhs” is prescription-ese for “by mouth at bedtime”.  Methyl cobolamin is vitamin B12.)

Bredesen’s results

The good news is that AD was dramatically reversed, especially in its early stages, with a low-cost program that does not require superhuman life style changes.  This worked in 9 cases out of 10, and the 10th case was advanced AD.  The bad news is that crafting an individualized program for the patient requires a doctor with broad knowledge both of medicine and of the patient’s history and temperament, as well as blood tests and cognitive tests.  Patience.  This is likely to be expensive and difficult to replicate in modern, assembly-line medicine where doctors are fungible cogs in a health care factory.  But then, perhaps the bad news isn’t bad–it’s pointing in the direction of the future of medicine.

Ultrasound

This is just vibration, but at a higher frequency than human ears can hear.  Ultrasound is commonly used (at low intensity) as an imaging tool

Prof. Jürgen Götz and Gerhard Leinenga of the Clem Jones Centre for Ageing Dementia Research, Queensland, Australia have pioneered the use of ultrasound at higher intensity to break up the beta amlyloid plaques in the brain, with dramatic benefits in mice.  Mice normally don’t get AD, but they can be genetically engineered to come down with AD reliably.  It was these mice that the Queensland doctors worked with, and in most mice they were able to clear up the plaques.  There is still controversy (after 40 years) whether amyloid plaques actually cause AD or whether they are a symptom or side-effect.  So it was important to verify that the mice showed actual memory improvements, and not just better results on the diagnostic tests.  The next step is to get experience in larger animals, before the first human trials.  [Read more from Medical News Today]  [In-depth nterview with Norman Swan.  The episode also includes an interview with Saul Vileda of Stanford about planned plasma transfusion experiments in Alzheimer’s patients.]

 

Alzheimer’s as an Immune Disorder

A promising line of research regards AD as an immune attack on nerve cells that producers amyloid plaques as a side-effect.  It is not the neurons byt glial cells, the “in-between” cells in the brain, that trigger the immune attack.  In active brains with lots of nerve firings, the glial cells are kept in check, while inactive neurons allow the neighboring glial cells to turn themselves into immune provocateurs.

This is a link between decline of the immune system with age, increase in inflammation, and AD.  Strong circumstantial support for this perspective comes from the fact that anti-inflammatories such as NSAIDs and curcumin offer some of the best protection against Alzheimer’s risk that we currently have available.

Conversely, the healthy immune system attacks amyloid beta and breaks it up.  Biogen Corp purchased a drug based on antibodies produced by healthy humans that attacks A-beta.  Just this year, a new drug called Aducanumab, aka BIIB037, was reported to be effective in reversing cognitive decline in small, initial trials with human trials–not just mice.

 

DFMO and Arginine

Arginine is one of the 20 amino acids used to build proteins, and it has been found that the AD brain consumes inordinate quantities of arginine.  This begs the question whether arginine is part of the problem or part of the body’s natural solution.  Carol Colton and her Duke Univ lab are betting on the latter.  DFMO=difluoromethylornithine is a drug that blocks arginase, the enzyme that breaks down arginine.  In case that’s too many negatives for you: more DFMO means more arginine.  DFMO has already been approved as a cancer treatment, and now it has been tested in mice, and found to both decrease plaques and improve cognitive performance. [News article, Research article]

Another protein component called taurine was found last year to be beneficial for the mice genetically engineered for susceptibility to AD.  Taurine was added to their drinking water in quantities huge by human standards, equivalent to more than 2 ounces per day of pure taurine.  But improvements in cognitive performance were dramatic.  Results were reported from the Korean lab of YoungSoo Kim.   

 

Current “best practices”

There are currently 5 FDA-approved drugs for AD, but all of them provide symptomatic relief only, and work only for a few months.  None is able to slow progression of the disease.  [Read more from Carl Sundquist]  Last year, there was a breathless announcement by Eli Lilly about early successes with a new drug called solanezumab, but later results deflated the bubble.

 

What you can do to lower your long-term risk of AD

• Regular and sufficient sleep
• Anti-inflammatories: NSAIDs, fish oil, curcumin=turmeric
• Weight control
• Mental and emotional engagement
• Yoga and meditation
• Vigorous exercise
• mega-doses of Vitamin D
• Melatonin at bedtime
• DHEA, Vit B12 and SAMe, especially for people with MTHFR genetic risk
• Low carb diet
• CoQ10

Fortunately, the greatest risk factors for AD are the same as for other diseases of old age, so there are broad benefits from the above program.  General risk factors are cholesterol levels in the blood, insulin resistance, and inflammation.