The amyloid hypothesis on trial

There is a conceptual framing for this hypothesis: that beta-amyloid plaques are akin to the garbage left in the stadium after a big match. The garbage itself is not the cause or raison d'etre of the stadium and its activity, yet it is a negative and fixable side-effect of the main event. I'm sure those who support the tao-hypothesis or some of the other more fringe hypotheses would be in favor of such an explanation.

It's not simply that drugs have failed time and again for Alzheimers. It's a very hard disease to come up with a treatment for. Here are some challenges:

1) It's a hard disease to detect in the earliest stages, where preventative/slowing drugs would have the most effect. If your drug slows decline by 30% but you start using the drug after 60% of the decline has already occurred, your effect size will be much smaller.

2) The blood-brain-barrier is a strong obstacle in our anatomy that prevents the passage of many potentially useful small or large molecules from general circulation into the brain.

3) Our early-stage disease models, things from petri dishes to mice, are less effective for choosing winners in this disease in particular. Maybe due to the complexity of the human neurology, though TBH I'm not sure why this is.

4) Even if you reduce beta-amyloid or other biomarkers, if you can't slow the disease progression/symptoms, then why is your drug useful? It's much harder to provide the slowing or reduction of cognitive decline than it is to simply clean up the beta-amyloid plaques. 4) is a specific case of the general use of "biomarkers" or "surrogate endpoints" - you need to measure SOME outcome, it's hard to do for cognitive diseases, so you find something measurable and look at that, though the linkage to symptoms is not totally clear in many cases.

I thought we'd cleared this up on HN last week with 'Alzheimer's risk 10 times lower with herpes medication' https://news.ycombinator.com/item?id=17540094

and subcosmos's comment "Right on the heals of the recent publication that shows that beta-amyloid in the brain specifically wraps around HerpesViral particles in order to prevent them from spreading!" (1st comment on the above).

There seems evidence the amyloid is a body defence against viral infection, mostly herpes 6&7.

I just read in the NYT about an amyloid-clearing drug called BAN2401 that just reported results of Phase 2 trials (which test the safety and efficacy of a drug). The article starts by singing the praises of the drug, which substantially reduces amyloid scores. However, it then cautions that the drug's ability to slow down cognitive decline was small.

This supports the OP: amyloid may not be the culprit. In a phase 3 trial, the drug may not pan out.

source: nyti.ms/2JWjznT

I've read some interesting news about how people giving people with Alzheimer given a regular dose of coconut oil, maybe due to also some findings about how this could be related to a type 3 diabetes, maybe the lack of ketones in the blood, maybe the brain needs alternative energy sources, or the fat provided by those foods provides a nutrient pathway that is currently dormant or unblocks the neuronal damage in their brain. I'm not any kind of expert, but I've been reading about people who gained some benefit / therapeutic value from doing that. Saw someone post this which was interesting, https://www.ncbi.nlm.nih.gov/pubmed/24244584 so the claim is, maybe damaged metabolism using glucose, and the body needing to switch to ketone, but if someone has a compromised metabolism, say being insulin resistant, this practically shuts down ketone distribution, it also can be found to have heart implications for the future, but if the brain switches to needing fatty acids, and insulin prevents this, it might help understand how Alzheimer progresses and gets worse over time.

Recent and related: https://news.ycombinator.com/item?id=17444214.

Also, this submission was in response to https://news.ycombinator.com/item?id=17617054.

It all sounds very interesting, and I can totally believe that it might not be amyloid plaques that are the cause. I also believe we should fund multiple lines of study. BUT, I also had this odd feeling of deja vu while reading it, and eventually I realized that it sounded like some of the early HIV-skeptics, when the HIV hypothesis had been around for years but no effective treatments had been found yet.

This is a really great article outlining the current state of research in the field. It'd be nice to pin canonical articles like this every time a disease is discussed.

Are there any good Twitter Lists for Alzheimer's research?

Too many companies want to cure a disease with a drug. It is understandable since a drug can be patented and the company can make a profit. Unfortunately this means that diseases that do not require a drug never get cured.... Unless you name is Dr Dale Bredesen. Dr Bredesen has a methododoly instead of a drug to reverse Alzheimer. He has published about it and reverses Alzheimer in 9 out 10 patients and is currently doing new studies with a larger number of patients. TL;DR go to bed at 10 PM, do stress management, exercise a little, eat well and take supplements (blood tests determine which ones), and take a couple of other substances that our body needs, Alzheimer's disappears in less than 4 months.