Merry Christmas, tradherpete and all,
You already know what I think!
Alzheimer’s is a mystery with 2 prominent clues for detectives wishing to solve its “crime” element:
First, there’s physical evidence: the presence of amyloid beta. - That’s like a hammer at the scene of the crime. It’s there but we can’t account for its presence…is it the cause of death, the murder suspect, the murder weapon, or the motive, or just an innocent bystander?
Second, there is this incredible pattern which science doesn’t appear to be including in reasoning the solution to the puzzle/ mystery.
The first thing a detective would do when trying to determine sequence of events at multitudes of “serial kills” (in this case, AD) would be to look for a pattern used by the “killer” or “killers”. Is it random or can we narrow the “suspects” down based on the victims’ circumstances?
Yeah, we’ve been over this before. Whatever causes Alzheimer’s must not only impair brain function (cause of death) but must also have a selection chauvinism for females to the tune of 2:1 when compared to males (gender calibrated at birth, sorry, no identity proclivity games here, can’t fool Mother Nature).
Science/Big Pharma got this wrong for 30 years by looking at the physical finding and trying to pin the blame on it and make it the cause. Bosh!
Detectives and deductive reasoning will get closer: work backwards from the “victims” - MUCH LARGER CLUE than the high drama surrounding amyloid beta…(if Amyloid Beta is the Lee Harvey Oswald of CNS victims, then, Biogen is Jack Ruby, and the FDA and the Alz advocacy groups are the Warren Commission - it’s THAT obvious).
Ask yourself the litmus question when considering cause of disease as a drug-able target for treatment/cure MOA in AD:
Would this account for the gender disparity?
P. Gingivitis and other bacteria would be candidates in my book if the sponsors of the trials testing the drugs which treat these (bacteria/viruses) can show the correlation between females carrying the bacterium/virus (plural, if there are many brain infections causing the inflammation) TWICE as often as their age correlated male counterparts. Everything I have read suggests that women, in general, practice superior dental hygiene to males as a habit. If not superior, at least equal to males, which would give this “suspect” a reasonable/plausible “alibis” for not being the culprit in these serial crimes…we can’t account for them being in 2/3’s of the victims’ mouths/systems at the time when Alzheimer’s begins to develop in brains and that predates the manifestation by decades. Really? An infection taking that long to become virulent?
Contemplate the soundness of the timing…people can have p. Gingivitis throughout life, even young adults/middle age, both genders…why do predominantly old females manifest neuronal death/impairment and dementia at twice the rate of older males after an infection which needed to be increasing plaque buildup for decades?
Get that answer and you get the prize (unless you’re Biogen…in which case the “prize” for discovering the Holy Grail of CNS diseases turned out to be loss of share price, loss of employees (looking at you Sandrock, and coming layoffs), expert neurologists denouncing your drug’s efficacy on the national stage, Congress and Fed govt (US) investigating your approval path, lot of bad press - scandals for FDA - Medicare, Medicaid walking away like it’s a live grenade…hell, even the VA turned this down - someone in Vegas got rich betting AGAINST Biogen. Warren Buffett dumped the stock, Europe and Japan declined (not even politely) and it now looks as though Biogen will NOT be able to carry out the confirmatory ph 4 because they can’t get 1600 participants willing to pay - and that’s at half price.
Yes, LLY is announcing their intent to apply for approval of another plaque remover, as is Roche, but that’s to increase current share price. They have no intention of filing - that’s the second half of the 1-2 punch and is for suckers…it (filing and approval) drains the gains made off the announcement(!) to file)).
You can’t get to dementia from gum disease, sorry CRTX, you’re about to hang an Innocent Man.
As for SAVA’s MOA - filamin A malfunction causing amyloid plaque build up from misfolded proteins, let’s have the gender connection. What causes females to have this expressed at a staggeringly higher rate in old age when compared with males or young folks? I find nothing that can lawfully implicate, let alone convict, the filamin A.
As for the Sigma 1 receptor, we have already discussed the fact that the most potent inhibitor of the S1R, on the planet, is progesterone. Since there is a correlation between females using contraceptive pills (beginning in the 1970’s widespread, so females around age 20 average in 1970’s would now be women in their 70’s) and the current population afflicted with Alzheimer’s. Contraceptive pills contained much higher doses of the hormones when they began (orders of magnitude) versus today’s BCP’s.
Add the correlation between countries who approved use of “the pill” and today’s Alzheimer’s population and one can see a perfect map overlay of where our “killer” was at the time of the crime.
Add in the fact that countries which never approved use of “the pill” have statistically significant lower AD rates today.
Include the knowledge that countries where diets are rich in turmeric (India and Southeast Asia) have lower rates of AD today as well - significant. It’s noted that turmeric inhibits progesterone.
Compounding evidence: Women who have had five or more pregnancies are at increased risk for AD. Fact. But, pregnancies happen when you are young… and progesterone is produced to thicken the uterine lining, endometrium, as a nurturing environment for the embryo to best develop into a fetus.
So, when pregnant, a woman’s progesterone level rises from 1.2 ng/mL to 300+ ng/mL. During the pregnancy, a woman could have her S1r’s inhibited for 9 months. Five or more of these extended periods, where S1r is substantially inhibited, appears to increase the risk of Alzheimer’s later in life. So, shutting down the S1r for extended periods multiple times during childbearing ages can be the culprit at the right place and the right time to create the conditions for proteins to misfold and demonstrate increased cognitive impairment later.
That’s not just a random pile of facts or coincidences and it’s certainly not magic or conspiracy. But, it does help explain a correlation between the S1r and the gender difference of Alzheimer’s population we see right now.
Then, turn your attention to chromatin and look for gender discrimination there. Outta time for now - you got this!
Can’t promise that S1r agonists will cure AD but if so, the gender “mystery” will have been solved (to my satisfaction). With other treatments - just not seein’ it.
Healthy, happy, prosperous, 2022 to all.
Wish that Benny were here to usher in a new year with us.
A 12/31 11pm toast to the AVXL demons, rascals, and merry makers - aces, all! will be offered and in memory of those we lost.
Raise a glass wherever you are in solidarity:)
And, at midnight, drink to those whose afflictions might see some relief in the coming year(s) as soon as possible
2022 - a better year for all, I hope
Cheers!
Biostock
PS: FTR, I know, it’s not a crime scene nor detective series, and they are all just biotechs doing trials and trying to develop drugs which pass trials which is a tricky business (got that tattooed) and promise I will be very careful, once and F’r All!:)
