December 12, 2010
Alzheimer's Caused By Slow Trash Removal
The rate of formation of amyloid-beta in Alzheimer's disease brains is not the problem. Too slow removal of the peptide plaques in brains might be the real problem.
Neurologists finally have an answer to one of the most important questions about Alzheimer's disease: Do rising brain levels of a plaque-forming substance mean patients are making more of it or that they can no longer clear it from their brains as effectively?
"Clearance is impaired in Alzheimer's disease," says Randall Bateman, MD, assistant professor of neurology at Washington University School of Medicine in St. Louis. "We compared a group of 12 patients with early Alzheimer's disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there's an average drop of about 30 percent in the clearance rates of the group with Alzheimer's."
The measured slower rate of clearance would cause accumulation up to a level that causes disease state in about 10 years.
Scientists calculate this week in Science Express that it would take 10 years for this decrease in clearance to cause a build-up of a-beta equal to those seen in the brains of Alzheimer's patients.
This explanation might be compatible with some of the other hypotheses for Alzheimer's. For example, poorer brain blood circulation due to atherosclerosis or other blood vessel diseases could starve brain metabolism of the oxygen and sugar it needs to power the trash removal mechanisms. Also, a problem with insulin receptors similarly might starve the neurons for nutrients. Alzheimer's might be a special kind of brain diabetes disease.
Update: What is the root cause of the slow trash removal? This report does not tell us. It is an important question because the nature of the root cause may determine how hard it is to cure Alzheimer's Disease. If the root cause is a nutrient supply problem that is easier to fix than if accumulations of genetic mutations with age are the root cause. If accumulation of genetic mutations degrades the energy production machinery or plaque removal machinery in the cell then curing Alzheimer's will be a lot harder.
A rat study showed that Vitamin D plus curcumin cleared peptide plaques in rat brains. I take both supplements.
A quick web search yields some perplexing results
- amyloid accumulation may partially be due to proteasome inactivation (then amyloid itself cause further inactivation)
- curcumin and anthocyanins(e.g., from blueberries) which may prevent Alzheimer's, inhibit proteasome function
- proteasome function may be rescued by sulforaphane (broccoli, cruciferous vegetables) and carnosine.
However, proteasome inactivation may prevent cancer and neurodegenerative diseases.
"Inhibition of proteasome activity by anthocyanins and anthocyanidins"
- but, sulforaphane is anti-carcinogenic
The data clearly point in every direction.
Recall the Phase 3 trials of Flurizan in 2007-2009. It's an NSAID that had been shown to inhibit the production of amyloid in mouse models of AD. As far as the clinically relevant endpoints, Flurizan was a complete failure -- no better than placebo.
There are lots of attractive-seeming models of the biochemical basis for AD, and beta amyloid accumulation is one of the best. But it's not clear to me what its explanatory power is. There could well be other things (plural?) that determine whether the clinical syndrome develops or not. And it's the symptoms such as impaired mentation that we really care about.
Is anyone working on capturing the state of a brain at a given time, for later restoration when needed?
Like in a software operating system, where the user can restore a previous state after the system crashes.
PacRim Jim, there is hypothetical and philosophical developments on the issue. There also is an institute or group intent on such ends, iirc, though I forget their names.
The real problem with back-up solutions is the problem of continuity of identity. Is the back-up you or just someone who happens to share your memories and personality? For example what happens if you instantiate more than one copy of your backup at the same time, are you somehow both, are you just one indistinguishable or are you absent in all of the instantiated backups.
Now, until that issue is cleared, some attempts at maintaining continuity of physical existence seem a prerequisite for ensuring survival. Enhancing bodies and mind to be more physically resistant or alternatively providing heavy security for the original. As I've stated elsewhere, provided the body is made ageless, a highly advanced neural interface would allow one to communicate and experience anything with virtually zero physical risks. A self-sufficient fully automated heavily secured facility along with a body impervious to cancer, cardiovascular disease, neurodegeneration, etc would provide negligible risk of death over time. If the body could be altered to spend large times immobile(as some organisms do without seemingly adverse consequences), it could interact mainly through-vr and even with the real world mainly through say avatar-like physical bio-human droids.
Average lifespan in a disease free state with immortalized tissue designed to regenerate and minimize injuries from mere functioning would be astounding, especially in an accident crime free self sufficient fully automated facility(with similarly immortalized molecular machinery).
As regards for the issue of Alzheimer's, there have been positive articles regarding wine and resveratrol on the issue.
No kidding about the unclear data. I'm hoping in not too many years we'll have clearer signals from research on how to tune our brain metabolisms to cut Alzheimer's risk. Though there are already plenty of dietary options for decreasing Alzheimer's and dementia risk. Pretty much anything good for the cardiovascular system is good for slowing brain aging.
>>The measured slower rate of clearance would cause accumulation
>>up to a level that causes disease state in about 10 years.
10 years after what? Not after birth obviously, so the clearing mechanism was working all the way up until...? Or it really was slower at birth, and getting slower all the time?
One more observation -
Another quick web search leads me to believe that this team is looking at intracellular degradation channels, e.g., collagenases which normally break down connective tissue, but may also digest some fibrils. As far as I can tell from a quick literature read, though, the verdict is still out on whether these enzymes are cures or culprits.
BTW, proteasome inhibitors (like some flavonoids) may upregulate autophagic clearance, which, possibly, may explain why flavonoids help stave off some forms of dementia. Incredibly complicated issue.
Correction - I meant "intercellular" not intracellular
Lou, I would like to know more about intercellular trash clean-up. How much of it is done by the immune system? How much by enzymes excreted by cells? I never come across reports about this.
It is my hope that the immune system does the vast majority of trash collection. Why? The immune system is much easier to rejuvenate than all the stationary cells.
I am hoping that immune rejuvenation will:
- Cut death from cancer.
- Cut death from infections (very very likely).
- Cut decay and death from trash accumulation.
- Brighten moods by stimulating the nervous system.
There is evidence for all of these. I am hoping for really big wins from immune system rejuv.
I have been reading a lot of your posts for the past couple of days. I want to thank you very much for helping me learn so much about the AD process and clues to its reversal or at least mitigation. I do not have the disease instead I am an expert of sorts in a field which is more related to AD then I had supposed. I teach lymphology and have benefited from understanding the blood lymph relationship. You may realize of course that Cerebral Spinal Fluid is lymph. I need you to contact me soon because I am writing a book and need to know how you get so much good information so I can do the same... Please contact me at firstname.lastname@example.org .