It seems as though the once-popular assumption that amyloid beta is the root cause of Alzheimer's is only "wrong" because the clearance of amyloid plaques fails to alleviate symptoms, despite the apparent fact that amyloid clearance may delay or prevent the disease in the first place; and because immunologically induced amyloid clearance in asymptomatic individuals occasionally results in deleterious side effects. However, by applying a multifaceted approach to prevention which avoids these side-effects, and also attacking hyperphosphorylated tau (phosphotau) plaques in postdiagnostic cases via immunotherapy and induced autophagy, we might make more rapid progress. Obviously, combining these strategies with a long antidementia checklist would be prudent as well.
The big picture:
https://www.ncbi.nlm...93542-f0002.jpg
Related threads:
http://www.longecity...elopment-theory
http://www.longecity...-for-alzheimers
Papers (some are paywalled, some not):
Cessation of Neoangiogenesis in Alzheimer's Disease Follows Amyloid-beta Immunization
https://www.ncbi.nlm...cles/PMC3584312
Anti-amyloid beta to tau-based immunization: Developments in immunotherapy for Alzheimer disease
https://www.ncbi.nlm...cles/PMC4051350
Active immunotherapy for Alzheimer’s disease
https://www.ncbi.nlm...cles/PMC3560289
Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease
https://www.ncbi.nlm...pubmed/23345405
Amyloid-β Peptide Remnants in AN-1792-Immunized Alzheimer’s Disease Patients
https://www.ncbi.nlm...cles/PMC1698828
Ameliorative Effects of a Combination of Baicalin, Jasminoidin and Cholic Acid [CBJC] on Ibotenic Acid-Induced Dementia Model in Rats
https://www.ncbi.nlm...cles/PMC3577735
Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease
https://www.ncbi.nlm...cles/PMC4159618
Low vitamin K intakes in community-dwelling elders at an early stage of Alzheimer's disease
https://www.ncbi.nlm...pubmed/19027415
The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease
http://www.medical-h...(01)91307-6/pdf
Summary:
Earlier in this millenium, it was thought that the amyloid beta (AB) plaques present in postmortem Alzheimer's dementia (AD) (and often, other dementia) brains had been causal in the disease. Thus AD prevention was ostensibly a mere matter of vaccination against AB.
One of the earliest attempts was AN-1792. It succeeded handily in the reduction of hydrophobic AB ("insoluble" AB42) in the brain, accompanied by an increase in the hydrophilic form ("insoluble" AB40) in the CSF. Disaggregated AB40 (and slightly, AB42) can pass through the blood-brain barrier (BBB) for excretion.
This process appears to have worked quite well in AN-1792 and other trials, but nevertheless the symptoms of AD were only slightly suppressed. Worse, cases of meningioencephalitis were observed in some patients, presumably the result of an autoimmune response targetting normal brain tissue. In other cases, cerebral amyloid angiopathy (CAA) resulted, lining the blood side of the BBB with AB40 plaque, not unlike cholesterol plaque resulting from oxidized LDL and foam cells.
Furthermore, it has been shown in numerous studies that the presence of AB plaque in levels comparable to that observed in AD nonetheless does not imply symptomatic dementia; a more discerning phenotype of an AD brain is the plaques and tangles of phosophotau.
All of this suggests that efforts to prevent or ameliorate AD by means of AB clearance is misguided, not unlike dying one's hair in order to appear more youthful. However, as the studies above suggest, the problem may be a combination of (1) prior to the appearance of symptoms, failing to address CAA and autoimmune hyperactivation in a manner which would permit successful excretion of AB and (2) in symptomatic individuals, clearing AB without simultaneously clearing phosophotau. Progress appears to have been made toward the goal of avoiding autoimmune reactions, but otherwise these issues remain unresolved.
It looks like AD pathology evolves as follows: (1) AB accretion damages the tight junction (TJ) seal between the cerebrovascular endothelium and white/gray matter, permitting backflow of toxins (including previously cleared AB) and inhibiting oxygen and nutrient delivery, (2) hyperneovascularization evolves as an ongoing response to the damage, (3) the increasingly incompetent new TJs create a positive feedback loop with AB deposition, (4) rising toxicity levels create phosphotau, and (5) phosphotau inihibts normal tau from performing its memory tasks and also activates further AB pathology in a positive feedback loop involving ectopic repetitive cell cycle reentry (CCR) culminating in neuronal death.
So this is why AB immunotherapy fails to alleviate postdiagnostic AD, even though it largely succeeds in AB clearance, even well into the disease process: hyperpermeable TJs are cropping up everywhere. It's rather like collecting garbage throughout a city where all the fences are ripped open: things appear cleaner, but the city is still dysfunctional because garbage and stray animals continue to flow uninhibited around the neighborhood. Worse, CAA inhibits the healing of TJs.
But I think it was a mistake to give up so easily, because we can quite possibly eliminate the CAA, allowing the TJs to heal. Vitamin K2 and endothelial rejuvenators (MitoQ/c60oo, raw cacao, olive oil, etc.) would perhaps accomplish this, especially because low vitamin K has been linked (above) to accelerated Alzheimer's. (It also turns out to have more direct involvement with AD prevention, involving Gas6.) Perhaps this is also the reason that aspirin goes a long way toward AD prevention, but only before symptoms emerge, at which point the phosphotau feedback loop has been activated, preventing AB excretion and eliminating the prophylactic value of aspirin.
In other words, AD prevention has little to do with the suppression of AB production or even clearance from the brain; it's more related to AB excretion, which implicitly requires vascular maintenance as indicated above. Immunotherapy can assist to the extent of delivering embedded AB to the BBB for disposal, courtesty of the microglia (brain immune cells). If you're asymptomatic, then there are substances that can help you remain that way, even in the interminable delay between now and evetual FDA approval of an AB vaccine: consume substances which (1) clear AB (EGCG, lipidated curcumin such as Longvida, and many others described on Longecity) and (2) prevent the emergence of CAA (MitoQ etc.as above). It also wouldn't hurt to pursue a ketogenic diet, thereby preventing diabetes types 2 (systemic) and 3 (cerebral), cancer, and adrenal dysregulation all at once. And definitely read the CBJC paper above.
But what if you already have AD, in which case the amyloid hypothesis is definitively "wrong" in the sense that AB clearance will not affect prognosis? In this case, absent any approved phosphotau immunotherapy (clinical trials are ongoing), you could do the above for AB excretion in addition to upregulating autophagy. Wogonin, rapamycin analogs, nilotinib, and other compounds might be useful here, although dosing is a sensitive issue on account of hyperautophagy killing too many normal neurons in the same manner that nilotinib causes cancer cells to digest themselves. You would likely also need to repair the TJ by means of mononuclear mesenchymal stem cell therapy (or whole bone marrow reinjection, which is widely available from competent osteopaths and various quack doctors alike), ideally after minimizing the plaques to the extent possible through supplements.
So what's the future of AD immunotherapy? Probably nothing, at least in developed countries, because the most effective prevention opportunity is obviously in young people, which means that the results won't be evident for decades. There is some chance, however, that a therapeutic (i.e. postdiagnostic) vaccine will be available for existing patients several years from now. (Of course, look to banana republics for early availability following successful trials in tightly regulated countries.) The latest techniques seem to involve "biolistics" (biological ballistics): the injection of DNA plasmids which encode for various AB epitopes directly into cells via reversible electroporesis (gene gun). If I understand the approach, this technique should provide an autorenewing continual low level exposure of AB antigens to the immune system, sustaining longterm immunity which reminds the microglia to bind with and fragment large tau and AB aggregates, thereby facilitating clearance and ultimately excretion. Given the failure of monoclonal antibody trial in the paper above, the AB plasmid approach may be more fruitful.
Other insights and contradictory arguments are invited. Evidence talks.
Edited by resveratrol_guy, 16 February 2015 - 02:06 PM.
