10 replies to this topic

[reason]

Alzheimer's disease is the name given to the end state of rising amyloid levels in the brain: it is the stage at which the patient has a lot of amyloid and is severely impacted by it. But we will all suffer increased levels of amyloid to some degree, and we will all be negatively affected by it to some degree. This is similarly the case for the other protein aggregate involved in Alzheimer's disease, tau, that precipitates into tangles in brain tissue. Rising levels are a shared manifestation of aging, it is just that some people arrive at the pathological level much earlier. One of the objectives of repair based treatments that fix damaged clearance mechanisms or remove protein aggregates from tissues is to make this difference irrelevant - everyone should undergo the therapies every so often, and then no-one would have to worry about a future involving degeneration of the mind:

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of (Aβ) plaques. For these "NFT+/Aβ−" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex).

Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time.

Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies.

Link: http://dx.doi.org/10...0401-014-1349-0

View the full article at FightAging

[Turnbuckle]

The solution to tauopathy might very simple--

 

 

Furthermore, these results suggest that nicotinamide may also be effective against other tauopathies, which share many common pathological features with the tau pathology seen both in AD and in the 3xTg-AD mice. In summary, the results presented here suggest that nicotinamide has potential as a novel, safe, and inexpensive AD therapy, either alone or in combination with Aβ-lowering therapies.

 

http://www.jneurosci...8/45/11500.long

 

 

 

There is an ongoing study. This six year trial was supposed to be completed in July, but results have not yet been reported.

 

 

Detailed Description:

 

The goal of this proposal is to show that, nicotinamide (NA), a B3 vitamin, is safe and effective for the treatment of patients with mild to moderate Alzheimer's disease (AD). NA is known to block the ability of certain proteins to regulate other proteins by removing their acetyl groups. Recent evidence has demonstrated that inhibitors such as NA prevent nerve cell degeneration in models of Huntington's disease (HD), Parkinson's disease and Lou Gehrig's disease (or ALS). Despite these beneficial effects in many different animal models, there have been no studies to date using these inhibitors in AD. In some of our recent studies we found that the potent inhibitor, NA, significantly improves learning and memory in transgenic mice that develop AD. NA treatment also resulted in striking changes in tau, a protein that abnormally accumulates in AD. NA has been extensively used in clinical studies over the last 40 years and is generally safe and well-tolerated. As NA is a safe and readily available vitamin supplement, our recent results provide a strong argument for a study of NA in patients with AD. We therefore propose to treat 50 patients with mild to moderate AD with either NA (1500 milligrams twice a day) or an identical but inactive drug (placebo) for 24 weeks. At 6 week intervals we will assess functions such as learning and memory, and ability to carry out daily activities as well as caregiver reports using standardized tests. We will also perform spinal taps at the beginning and end of the study to measure the level of abnormal tau protein in the cerebrospinal fluid. Blood tests will periodically be done to assess liver function and complete blood counts. The results of this study may provide the basis for a more extensive study of NA for the treatment of mild to moderate AD.

 

 

 

[Daniel Cooper]

Turnbuckle - My father has some sort of age related dementia.  It may be Alzheimer's and it may not.  It has been slowing progressing but is getting noticeably worse.

 

I'm very interested in trialing him on Nicotinamide.  Looks like the study dose is 1500mg twice a day.

 

Currently he is on no flush niacin which I assume is inositol hexaniacinate.  I'm wondering if I should discontinue the no flush niacin and replace it with nicotinamide or if I should add the nicotinamide on top.  Any thoughts?

 

 

Edited by Daniel Cooper, 09 November 2014 - 03:20 AM.

[Turnbuckle]

Niacin and derivatives have been looked with the idea of improving cerebral blood flow and memory. The study in post 2 suggests that nicotinamide effects tau protein and thus gets at the root cause, but until the results are published, we won't know. And even then we won't know which form of niacin is best. I took 3 grams of niacin for decades but then stopped as I was worried about reports of liver damage. More recently I've begun taking it again, now spacing it out once every three days to recover the flush, which may have some impact on cholesterol. My dose is now 2 grams of niacin and 1 of nicotinamide (niacinamide), taken together.

 

As for inositol hexaniacinate vs nicotinamide, I can't say, but it looks from various papers that different forms have different though overlapping effects.

[resveratrol_guy]

A totally different approach to reversing tauopathy (or more generally, inducing microtubule protection (and (re)construction?)) is ADNP nasal spray (activity-dependent neuroprotective protein). (The video presentation is a bit juvenile, but if you do the research, this compound was quite effective in specific brain diseases in animals and humans. Allon Therapeutics pursued a related compound (davunetide), but went bankrupt after a key trial failed. It's a shame because the schizophrenia trial in the video suggests that the ADNP team lead by Illana Gozes were on the road to tauopathy reversal in alzheimers. Sounds like a job for TeamLTR or some other pharacological dumpster diver to pick up and run with.)

 

Relevant papers:

 

Microtubules (tau) as an emerging therapeutic target: NAP (davunetide)

 

The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins

 

Edited by resveratrol_guy, 19 November 2014 - 05:50 PM.

[resveratrol_guy]

There is an ongoing study. This six year trial was supposed to be completed in July, but results have not yet been reported.

 

This doesn't look good; clinicaltrials.gov says it hasn't heard anything from the team since 12/2013. Here is the home page of the lead researcher at the University of California at Irvine. Whoever is sophisticated about such research, please email him and let us know what's up. (I don't practice in his field, and don't want to risk exhausting what might be very little patience for such inquiries.)

 

Yes, the trial will "fail" because you can't send people to the vitamin shop for a $5 supplement that substantially cures dementia; that would be antipharmocratic. But it would be nice to get a peak at the raw data first, before it's massaged to create said failure. Of course, it might actually fail. Either way, can anyone here help us get a status report? This is way too important to ignore.

 

Turnbuckle scored a home run by presenting this issue, from a relevancy standpoint. But... does it work, and what's the proper niacin/niacinamide ratio, especially in light of liver risk?

[Turnbuckle]

 

There is an ongoing study. This six year trial was supposed to be completed in July, but results have not yet been reported.

 

This doesn't look good; clinicaltrials.gov says it hasn't heard anything from the team since 12/2013. Here is the home page of the lead researcher at the University of California at Irvine. Whoever is sophisticated about such research, please email him and let us know what's up. (I don't practice in his field, and don't want to risk exhausting what might be very little patience for such inquiries.)

 

Yes, the trial will "fail" because you can't send people to the vitamin shop for a $5 supplement that substantially cures dementia; that would be antipharmocratic. But it would be nice to get a peak at the raw data first, before it's massaged to create said failure. Of course, it might actually fail. Either way, can anyone here help us get a status report? This is way too important to ignore.

 

Turnbuckle scored a home run by presenting this issue, from a relevancy standpoint. But... does it work, and what's the proper niacin/niacinamide ratio, especially in light of liver risk?

 

 

 

This is not the first human study.

 

Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline

 

Results: Energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks (95% confidence intervals) for incident AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3 (0.1 to 0.6), 0.3 (0.1 to 0.7), 0.6 (0.3 to 1.3), and 0.3 (0.1 to 0.7) adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p for linear trend = 0.002 in the adjusted model). In an adjusted random effects model, higher food intake of niacin was associated with a slower annual rate of cognitive decline, by 0.019 standardised units (SU) per natural log increase in intake (mg) (p = 0.05). Stronger associations were observed in analyses that excluded participants with a history of cardiovascular disease (ß = 0.028 SU/year; p = 0.008), those with low baseline cognitive scores (ß = 0.023 SU/year; p = 0.02), or those with fewer than 12 years' education (ß = 0.035 SU/year; p = 0.002)

 

Conclusion: Dietary niacin may protect against AD and age related cognitive decline.

 

 

 

Also of interest--Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

[resveratrol_guy]

Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline

 

Results: Energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks (95% confidence intervals) for incident AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3 (0.1 to 0.6), 0.3 (0.1 to 0.7), 0.6 (0.3 to 1.3), and 0.3 (0.1 to 0.7) adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p for linear trend = 0.002 in the adjusted model). In an adjusted random effects model, higher food intake of niacin was associated with a slower annual rate of cognitive decline, by 0.019 standardised units (SU) per natural log increase in intake (mg) (p = 0.05). Stronger associations were observed in analyses that excluded participants with a history of cardiovascular disease (ß = 0.028 SU/year; p = 0.008), those with low baseline cognitive scores (ß = 0.023 SU/year; p = 0.02), or those with fewer than 12 years' education (ß = 0.035 SU/year; p = 0.002)

 

Conclusion: Dietary niacin may protect against AD and age related cognitive decline.

 

 

 

Also of interest--Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

 

 

So based on Table 2 of the niacin study, it's evident that niacin defficiency has a pretty strong correlation to the development of AD. However, it's equally clear that once the RDA is met, there is essentially no further risk reduction obtainable by increasing intake any further. I do find it somewhat remarkable that the 4th quintile (almost-highest intake) experiences a risk resurgence. I don't think this is a statistical aberration, based on the number of participants (815). Instead, I think it reflects the likelihood that the 4th quintile contains heavy overeaters, whereas the 5th quintile contains healthy people who supplement niacin at levels generally beyond what can be obtained dietarily. In any case, based on the large sample size, I would say that the study proved: (1) niacin defficiency increases the risk of AD by 100-200% but (2) apart from taking a daily multivitamin, niacin supplementation is dead on arrival as an AD preventative. Niacinamide (or nicotinamide, which Wiki implies as its official preferred synonym), however, is an open question.

 

The second paper is much more interesting, if frustrating for the lack of a clear dose-effect relationship. A few key points:

 

1. "Restoration of NAD+ content in mitochondria with liposomal NAD+ prevents neuronal injury" -- Liposomal NAD+? Sounds like a potentially promising alternative to nicotinamide itself, which might have more isolated effects, in particular cognitive effects due to crossing the BBB.

 

2. "Nicotinamide (NIC) prevents the loss of mitochondrial membrane potential during oxygen glucose deprivation (OGD)... Even during periods of free radical injury in human blood lymphocytes, nicotinamide may block necrotic death through pathways that limit excessive PARP activity that can consume essential NAD+ stores." -- So it sounds like it would support the development of cancer, particular the anoxic/Warburg variety? (Maybe that's the price of preventing brain atrophy.)

 

3. "Exposure to elevated concentrations of nicotinamide can inhibit the function of rat pancreatic beta-cells, decrease DNA content of adult rat pancreatic islet cells, and induce cell death in fetal rat pancreatic islet cells. Nicotinamide also has been shown to result in the release of choline that may precipitate neuronal injury when levels of choline become excessive. Furthermore, excessive exposure to nicotinamide may lead to autointoxication and precipitate disorders such as Parkinson’s disease... As a result, one must approach therapy with nicotinamide with caution, since nicotinamide may have detrimental effects with cellular aging that appear to be concentration dependent" -- Sounds like dose calibration would be difficult indeed. Decreased DNA content of pancreatic cells sounds like DNA destruction due to oxidative stress; the pancreas is about the last place I would want to mess up my DNA.

 

All in all, unfortunately, it sounds like this stuff is way too complicated to touch; I basically quit reading after that became clear. However, especially for the sake of ameliorating AD symptoms, perhaps NADH plus c60oo would be a better alternative.

 

 

 

 

 

 

 

 

Edited by resveratrol_guy, 29 November 2014 - 01:30 AM.

[Turnbuckle]

 

So based on Table 2 of the niacin study, it's evident that niacin defficiency has a pretty strong correlation to the development of AD. However, it's equally clear that once the RDA is met, there is essentially no further risk reduction obtainable by increasing intake any further. 

 

 

The average niacin equivalents in the four groups ranged from 24 to 60 mg, which is very low (in spite of being above the RDA except for some in the first quintile), and I suspect there is little justification in breaking these groups into more than two. The only statistically significant finding was that the first group had several times the incidence of the others. It is likely that with no niacin, the majority of the population would develop cognitive defects, but even with several times the RDA, there will be a minority with metabolism deficiencies that will require drug-like doses--grams instead of milligrams. Abram Hoffer has long made a similar contention about niacin and schizophrenia. So when you say it's clear that there is no further risk reduction obtainable by increasing intake further, you are making that assessment by looking at 5 points grouped near the zero on a scale that goes out 50 times further when supplements are used.

[Turnbuckle]

 

Yes, the trial will "fail" because you can't send people to the vitamin shop for a $5 supplement that substantially cures dementia; that would be antipharmocratic. But it would be nice to get a peak at the raw data first, before it's massaged to create said failure. 

 

 

 

This is "Enduramide," an OTC niacinamide product. Since it's sustained release and the dose is 3 grams/day, it will probably show the same liver toxicity that sustained release niacin shows. In which case the safety study will fail.

Edited by Turnbuckle, 29 November 2014 - 02:45 PM.

[resveratrol_guy]

Both good points, but I still look forward to hopefully seeing the data from the trial. As a result of your information here, my attention has shifted to nicotinamide riboside (radically different from nicotinamide) as a potential antidementia agent (and more). Thanks, Turnbuckle and StevesPetRat.

 

Edited by resveratrol_guy, 30 November 2014 - 01:44 AM.