Human Study Confirms Alzheimer As A Metabolic Condition (brain Diabetes)

[haidut]

Over the last 3 years I posted quite a few studies on Alzheimer disease (AD) and have discussed it at length in the Danny Roddy podcasts. Among the most successful interventions are niacinamide and methylene blue (MB) both of which are in human clinical trials, thyroid and aspirin.
Alzheimer Disease (AD) Is Likely A Metabolic Disorder
Glucose Deprivation In The Brain Is A Causative Factor In Alzheimer's Dieases (AD)
Delirium (and Dementia/AD) Is Caused By Inability To Oxidize Glucose
Blocking PUFA Metabolism May Reverse Alzheimer Disease (AD)
Another Study Links PUFA To Alzheimer Disease (AD)
Salicylate For Alzheimers (Aspirin)
Methylene Blue Fail Alzhemiers Trial - (No It Didn't)


In a new and very important study that looks like it has been written by Peat himself (except for the estrogen part), scientists have finally provided solid human evidence that AD is a metabolic condition characterized by the inability to oxidize sugar. For women, apparently the adverse changes likely begin pre-menopause with signs of hypometabolism evident even in their early 40s.
What is particularly disturbing about this study is the complete inability of scientist to make the link between high estrogen and the induction of "starvation mode" in brain metabolism which they found in AD patients. Estrogen does this by directly increasing fatty acid oxidation and blocking glucose oxidation through the well-known Randle cycle (The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise. - PubMed - NCBI). In fact, no other hormone is known to cause this "shock state" change in metabolism, not even cortisol or adrenaline. I suppose the mantra "estrogen is low in menopause" is just too sacred for any scientist to publicly challenge...
At the very least this study should serve as evidence that the stress reaction (and its mediators estrogen, serotonin, cortisol, adrenaline, prolactin, growth hormone, NO and endorphins) is not something that should be left unopposed and the chronic rise in fatty acid oxidation is anything but benign.

Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery
Menopause triggers changes in brain that may promote Alzheimer’s | Cornell Chronicle
"...The tests revealed the women who had undergone menopause or were peri-menopausal had markedly lower levels of glucose metabolism in several key brain regions than those who were pre-menopausal. Scientists in prior studies have seen a similar pattern of “hypometabolism” in the brains of patients in the earliest stages of Alzheimer’s – and even in mice that model the disease. In addition, menopausal and peri-menopausal patients showed lower levels of activity for an important metabolic enzyme called mitochondrial cytochrome oxidase, as well as lower scores on standard memory tests. The strong contrast with pre-menopausal patients remained even when accounting that the menopausal and peri-menopausal women were older."

"...More specifically, the authors suggest that the menopausal fall in estrogen may trigger a shift to a “starvation reaction” in brain cells – a metabolic state that is beneficial in the short term but can be harmful in the long term."

 

[paymanz]

Thanks haidut,

Is there any reference showing estrogen increases FFA level?

Of curse if you meant it with this:

Estrogen does this by directly increasing fatty acid oxidation and blocking glucose oxidation .In fact, no other hormone is known to cause this "shock state" change i metabolis, not even cortisol or adrenaline.

 

[paymanz]

Also your post made me search a little bit and I found this one interesting!

Estrogen Regulation of Glucose Metabolism and Mitochondrial Function: Therapeutic Implications for Prevention of Alzheimer’s Disease

Further, while there is a 100:0 ratio of glucose to other substrates utilization in young controls, there is a 2:1 ratio in incipient AD patients compared to a ratio of 29:1 in healthy elderly controls [100].

 

[haidut]

Thanks haidut,

Is there any reference showing estrogen increases FFA level?

Of curse if you meant it with this:

There is a TON. Have you searched Pubmed or Google? Peat has also mentioned it in pretty much every article where he mentioned estrogen. Here are two studies. The second one is especially damning as it shows directly the glucose blocking effects of estrogen through the Randle cycle.
Estrogen replacement stimulates fatty acid oxidation and impairs post-ischemic recovery of hearts from ovariectomized female rats. - PubMed - NCBI
The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise. - PubMed - NCBI

 

[paymanz]

There is a TON. Have you searched Pubmed or Google? Peat has also mentioned it in pretty much every article where he mentioned estrogen. Here are two studies. The second one is especially damning as it shows directly the glucose blocking effects of estrogen through the Randle cycle.
Estrogen replacement stimulates fatty acid oxidation and impairs post-ischemic recovery of hearts from ovariectomized female rats. - PubMed - NCBI
The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise. - PubMed - NCBI

I especially want know about FFA level correlation with estrogen.

I was under the impression that FFA level is biggest factor affecting randle cycle.

Some studies show higher FFA with estrogen deficiency. Maybe estrogen lowers FFA level by stimulating beta oxidation?

 

[haidut]

I especially want know about FFA level correlation with estrogen.

I was under the impression that FFA level is biggest factor affecting randle cycle.

Some studies show higher FFA with estrogen deficiency. Maybe estrogen lowers FFA level by stimulating beta oxidation?

Did you read the second study??

 

[paymanz]

Did you read the second study??

Yes ,thank you , I read it now. I was on a phone so I didn't read it at first,sorry.

But there is mixed studies, especially in case of subcutaneous fat tissue, estrogen inhibits lipolysis here.according to some studies.

 

[Fractality]

What about other neurodegenerative diseases like progressive supranuclear palsy? My father was diagnosed with this and the behavioral symptoms are similar to Alzheimer's, so there could be parallels. My father's rapid deterioration was preceded by excessive exercise which of course raises free fatty acids.

 

[haidut]

What about other neurodegenerative diseases like progressive supranuclear palsy? My father was diagnosed with this and the behavioral symptoms are similar to Alzheimer's, so there could be parallels. My father's rapid deterioration was preceded by excessive exercise which of course raises free fatty acids.

Excessive fatty acids release has been so far confirmed in every chronic disease. So lowering them should be beneficial. I would try niacinamide and aspirin, especially since niacinamide's recent trials with Huntington, Duchenne dystrophy, Myasthenia gravis, etc.

 

[danishispsychic]

i think the first thing to think about it Alz is that is more of a syndrome than a disease. im sure a lot of people would not agree- but there are so many versions of dementia and many roads that lead to what is currently called Alz. one day, i bet that all of Ray Peats work will be used in the prevention and treatment and of course Big Pharma will try to find a way to make it their idea , as they always do . also i dont think you can rule out the DNA of it all either, the genetic markers and variants matter- but what you do about them matters more. also- it matters what crap vaccines you are pumped full of, how much metal you have/ had in your teeth and how about aspartame? how about whole generations that are gluten intolerant and dont know it- and it blocks all their b12 and what THAT does to the brain/gut ? the one doctor that tested my pregnegolone levels ( yay him and it was super low ) told me that anyone over 50 should be putting it in there morning smoothie, it is THAT important for the brain and hormones. interesting that my mother was diagnosed Alz and grew up in the depression. she told me that many days they had nothing to eat and had to pick potatoes on the side of the road to have ANY food.... starvation cannot help the situation. How about all the women who took those terrible fertility DES shots in the 60s? I am a DES daughter so naturally i am estrogen dominant.... it is a WHOLE thing. so many factors at work here .

 

[Lejeboca]

Now they are confirming that AD patients' brains lack glucose metabolism... but, in their wisdom, they propose to compensate it with ketone metabolism.

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease - ScienceDirect

Introduction: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI.
Objective: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD.
Discussion: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism
confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and
demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest
that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.

Conclusions
This cross-sectional study shows that despite widespread brain glucose hypometabolism, brain atrophy and cortical thinning, basal brainketone uptake remains normal in MCI and AD. Hence, brain energy deprivation in AD clearly appears to be specific to glucose and is a function of defective brain uptake and utilization of glucose not to lower brain glucose availability per se. The deficit in brain glucose utilization was more highly regionalized in AD and especially in MCI than were the structural changes which were widespread. These results support the need to assess whether providing more of the brain's main alternative fuel, ketones, would result in a similar increase in CMRKet as seen in younger adults (Courchesne-Loyer et al., 2016). If so, assessing whether ketogenic interventions that sufficiently compensate for the brain energy deficit could be beneficial for cognitive symptoms in MCI or AD would be warranted.

 

[Braveheart]

From my notes....PEAT ON SERATONIN KETONES ALZHEIMERS "A large carbohydrate meal increases the ratio of tryptophan to the competing amino acids, and it has been proposed that this can shift the body’s balance toward increased serotonin. In an animal study, bromocriptine, which shifts the balance away from serotonin, reduced obesity and insulin and free fatty acids, and improved glucose tolerance.............The protective, defensive reactions involving serotonin's blocking of certain types of reaction to ordinary stresses, are similar to the effects of serotonin in hibernation and in Alzheimer's disease (Mamelak, 1997; Heininger, 2000; Perry, et al., 2002). In those extreme conditions, serotonin reduces energy expenditure, eliminating all brain functions except those needed for simple survival. These parallels suggest that improving energy production, for example by providing ketones as an alternative energy source, while reducing the stress hormones, might be able to replace the defensive reactions with restorative adaptive nerve processes, preventing or reversing Alzheimer's disease"...my highlite

 

[Hans]

Eating mct oil with lots of glucose will increase ketones production, so probably no need for going keto.

 

[haidut]

From my notes....PEAT ON SERATONIN KETONES ALZHEIMERS "A large carbohydrate meal increases the ratio of tryptophan to the competing amino acids, and it has been proposed that this can shift the body’s balance toward increased serotonin. In an animal study, bromocriptine, which shifts the balance away from serotonin, reduced obesity and insulin and free fatty acids, and improved glucose tolerance.............The protective, defensive reactions involving serotonin's blocking of certain types of reaction to ordinary stresses, are similar to the effects of serotonin in hibernation and in Alzheimer's disease (Mamelak, 1997; Heininger, 2000; Perry, et al., 2002). In those extreme conditions, serotonin reduces energy expenditure, eliminating all brain functions except those needed for simple survival. These parallels suggest that improving energy production, for example by providing ketones as an alternative energy source, while reducing the stress hormones, might be able to replace the defensive reactions with restorative adaptive nerve processes, preventing or reversing Alzheimer's disease"...my highlite

He also said the ketones are emergency fuel and as such are not preferable to oxidizing glucose. So, yes, they could help restrain the serotonergic response but ideally glucose oxidation should be restored for optimal health.

 

[haidut]

Now they are confirming that AD patients' brains lack glucose metabolism... but, in their wisdom, they propose to compensate it with ketone metabolism.

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease - ScienceDirect

Introduction: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI.
Objective: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD.
Discussion: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism
confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and
demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest
that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.

Conclusions
This cross-sectional study shows that despite widespread brain glucose hypometabolism, brain atrophy and cortical thinning, basal brainketone uptake remains normal in MCI and AD. Hence, brain energy deprivation in AD clearly appears to be specific to glucose and is a function of defective brain uptake and utilization of glucose not to lower brain glucose availability per se. The deficit in brain glucose utilization was more highly regionalized in AD and especially in MCI than were the structural changes which were widespread. These results support the need to assess whether providing more of the brain's main alternative fuel, ketones, would result in a similar increase in CMRKet as seen in younger adults (Courchesne-Loyer et al., 2016). If so, assessing whether ketogenic interventions that sufficiently compensate for the brain energy deficit could be beneficial for cognitive symptoms in MCI or AD would be warranted.

Sad. But the good news is that there are several human studies with both plain niacinamide and nicotinamide riboside and I have high hopes that at least one of them will show the same robust benefit shown in earlier animal trials - complete reversal of AD symptoms in mice.

 

[Lejeboca]

Sad. But the good news is that there are several human studies with both plain niacinamide and nicotinamide riboside and I have high hopes that at least one of them will show the same robust benefit shown in earlier animal trials - complete reversal of AD symptoms in mice.

Thanks for the pointer to niacinamide (NAM) studies!

Just for the record: I found that one such a human trial is scheduled to finish by March 2019.

Nicotinamide as an Early Alzheimer's Disease Treatment - Full Text View - ClinicalTrials.gov

In it, the experimental group is fed 1500mg of niacinamide 99%, which is close to the mice study of "the equivalence of about 2 g of nicotinamide for humans".

In Nicotinamide Forestalls Pathology and Cognitive Decline in Alzheimer Mice: Evidence for Improved Neuronal Bioenergetics and Autophagy Procession , it is referenced that "NAM enhances glycolysis and may reduce the accumulation of abnormal protein aggregates and glycation end products associated with neurodegenerative disorders (Hipkiss et al., 2009)." and discussed that "When 3xTgAD neurons were treated with NAM, they exhibited elevated levels of the antioxidant glutathione. Thus, in addition to maintaining cellular NAD+ levels, NAM may protect neurons against AD-related proteotoxicity by elevating endogenous antioxidant defenses."

 

[Braveheart]

So the 1000 mg niacinamide I'm taking for my Actinic Keratosis might help prevent Alzheimers...love it when a supplement can do double duty...Is there anything B3 can't do?

 

[haidut]

Thanks for the pointer to niacinamide (NAM) studies!

Just for the record: I found that one such a human trial is scheduled to finish by March 2019.

Nicotinamide as an Early Alzheimer's Disease Treatment - Full Text View - ClinicalTrials.gov

In it, the experimental group is fed 1500mg of niacinamide 99%, which is close to the mice study of "the equivalence of about 2 g of nicotinamide for humans".

In Nicotinamide Forestalls Pathology and Cognitive Decline in Alzheimer Mice: Evidence for Improved Neuronal Bioenergetics and Autophagy Procession , it is referenced that "NAM enhances glycolysis and may reduce the accumulation of abnormal protein aggregates and glycation end products associated with neurodegenerative disorders (Hipkiss et al., 2009)." and discussed that "When 3xTgAD neurons were treated with NAM, they exhibited elevated levels of the antioxidant glutathione. Thus, in addition to maintaining cellular NAD+ levels, NAM may protect neurons against AD-related proteotoxicity by elevating endogenous antioxidant defenses."

Yep, that' the one I had in mind. The company Chromadex that pushes nicotinamide riboside (NR) is getting all sorts of trials under way including one for AD. I am hoping that the human study with plain niacinamide will complete and get published before those NR trials finish so the public can see that plain niacinamide is not something to scoff at, and in fact has benefits (SIRT inhibition) that NR does not.

 

[haidut]

So the 1000 mg niacinamide I'm taking for my Actinic Keratosis might help prevent Alzheimers...love it when a supplement can do double duty...Is there anything B3 can't do?

...and melanoma prevention too. Google for "nicotinamide melanoma Australian study".

 

[Braveheart]

...and melanoma prevention too. Google for "nicotinamide melanoma Australian study".

Thank you...was following that study...they mention four months...I have been wondering if that dose can be taken indefinitely ...it has improved my AK a lot already after one month ...not sure but seems to affect my weight?...but skin looks great...smooth and big pores all gone etc