Monday, July 27, 2015

Letter to the editor: who to believe on Alzheimer's?

Also in this week's C&EN, an interesting letter on Alzheimer's: 
“Alzheimer’s Next Chapter” by Lisa Jarvis highlights the lack of consensus regarding the primary mechanism of neurodegeneration in Alzheimer’s disease (C&EN, June 1, page 11). This is a significant problem because understanding the causal mechanism of a disease process provides a rational platform for drug development. 
Unfortunately, the Alzheimer’s field is dominated by two exclusive ideological factions—tauists and βaptists. In our opinion, this situation has impaired the search for effective pharmacotherapies. The myopic focus on the amyloid-β plaques and neurofibrillary tangles is dangerous and frankly unwarranted, since the presence of protein anomalies does not necessarily indicate pathogenic significance. 
In this regard, it is noteworthy that some evidence suggests that the tangles and plaques are of secondary pathophysiological importance. Regardless, the failure to adequately consider alternative mechanisms can prematurely narrow the field of hypothesis testing. 
Initial studies in the field of Alzheimer’s disease neuropathogenesis identified nerve terminal dysfunction and defective mitochondrial bioenergetics coupled to oxidative stress as early consequences of Alzheimer’s. Whereas some might consider these to be outdated parameters, the resulting changes in central nervous system neurotransmission represent a plausible basis for the cognitive deficits that characterize the disease. 
Based on the probable complexity of Alzheimer’s neuropathogenesis, it is clear that the molecular process of Alzheimer’s disease neurodegeneration is highly complex and, as Genentech’s Carole Ho points out, the most effective approach will likely involve combination therapy. 
Richard M. LoPachin
Bronx, N.Y. 
Terrence Gavin
New Rochelle, N.Y.
I don't understand Alzheimer's biology well enough to have an opinion on this letter, other than to say that I wish that C&EN would offer some sort of third-party explanation to go along with these letters. I guess the problem with my desire is that someone with enough Alzheimer's biology experience to have an informed opinion is going to be either a "tauist or a βaptist."

There's this strange aspect of the letters to the editor at C&EN to act as an outpost of Medical Hypotheses. It's both interesting (always makes for great reading) and question inducing, but still I feel it needs more context from a trusted source.

UPDATE: A respected reader writes in to ask which letters to C&EN I am referring to. Here are a few:
All of these are really interesting, but (as I have said) it'd be great to get some sort of expert opinion to accompany them. Overthinking it, I'm sure. 


  1. CJ: Thanks for the candor when you mention that .."I don't understand Alzheimer's biology well enough to have an opinion on this letter." None of us do. It is my gut feeling that everyone who are working on it does not know it either! Right or wrong people do get funded and when it comes to proposing some novel ideas or concept for treating AD. Treating Rheumatoid Arthritis sometime back was difficult until we had Disease-Modifying Drugs (DMARDs). Knowing how complicated RA was in the past, I see a similar outcome for AD. Just a matter of trying it out in clinical setup!

    1. " "I don't understand Alzheimer's biology well enough to have an opinion on this letter." None of us do."

      I used to have a pretty good handle on it, but I've forgotten most of what I knew.

  2. paging lane simonian

  3. Thanks for "paging me", otherwise I would not have seen this insightful and very important piece.

    Eleven years of studying this disease as a not scientist has lead to an important conclusion:

    It does not matter how much hyperphosphorylated tau, amyloid oligomers or amyloid plaques a person has in their brain as long as oxidants are being scavenged. Thus two people may have similar levels of each of these--one without Alzheimer's disease and one with Alzheimer's disease.

    When the oxidant peroxynitrite stops being scavenged, hyperphosphorylated tau is permanently nitrated which inhibits neurotransmissions and the transport of nutritents. When amyloid oligomers are nitrated they are converted into amyloid plaques. Amyloid plaques absorb copper and zinc which prevents (or limits) the further production of hydrogen peroxide.

    The pathways leading to oxidative stress, amyloid, and hyperphosphorylated tau are intertwined. All begin with the overactivation of g protein-coupled receptors (or the direct activation of g proteins) and the subsequent activation of phospholipase C. The then release of intracellular calcium leads to the production of amyloid oligomers whereas the then activation of protein kinase C leads to the production of peroxynitrites. Either pathway can lead to the hypeprhosphorylation of tau.

    If you inhibit the pathways that lead to the formation of oligomers, plaques, or hyperphosphorylated tau you may slow down the progression of the disease early on, but if you focus on removing the oligomers, plaques, or hyperphosphorylated tau you have done little to treat the disease. If you prevent the formation of peroxynitrites, scavenge them, and reverse part of their oxidative and nitration damage (among other things oxidation and/or nitration inhibit the synthesis and release of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, reduce antioxidant levels in the brain, restrict blood flow and limit the transport of glucose in the brain which can lead to apathy, wandering, and delusions, prevent the regeneration of neurons in the hippocampus, can lead to hallucinations via the overactivation and then deactivation of NMDA receptors, and lead to the death of neurons) then you can not only inhibit the progression of Alzheimer's disease you can partially reverse it.

    The best peroxynitrite scavengers are methoxyphenols because the methoxy group increases the donation of hydrogen atoms and electrons from phenols (ONOO- + 2h+ + 2e-=NO2- +H20). Water is a de-nitrating agent and hydrogen donation also partially reverses oxidation. Small-scale clinical trials using the methoxyphenol eugenol in rosemary essential oil via aromatherapy (Jimbo, et al. 2009) and the methoxyphenol syringic acid and ferulic acid in panax ginseng (Heo, 2011) have resulted in the partial reversal of Alzheimer's disease.

    Once the paradigm shifts from amyloid and hyperphosphorylated tau as the cause of Alzheimer's disease to oxidation and nitration as the cause of Alzheimer's disease, then the path to the effective treatment of the disease becomes wide open.

    1. An addition: the overactivation of receptor tyrosine kinases can also lead to Alzheimer's disease.