“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bioenergetics coupled to oxidative stress as early consequences of Alzheimer’s. Whereas some might consider these to be outdated parameters, the resulting changes in central nervous system neurotransmission represent a plausible basis for the cognitive deficits that characterize the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
Terrence GavinI 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."
New Rochelle, N.Y.
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:
- There was the titanium in sunscreen one, just a couple weeks back.
- There was the cancer carcinogenesis letter.
- Here's one on regenerating tissue from July.
- And then the one about using ultrasound in Alzheimer's research/therapies?