Hi
I would describe the above interpretation of Rand Akasheh as TOTALLY WRONG. This is extremely important. The fundamental defect in APOE4 carriers which begins in the 20-39 year age group is decreased blood flow in same areas which later develop changes of AD. These defects in cerebral blood flow are measured by PET scans which use decrease in glucose metabolism as the measure of CBF. This understanding of defects in cerebral blood flow and that is what is being measured by glucose metabolism is of paramount importance. This is of the highest level of importance because preventing damage to cerebral flow and restoring cerebral blood flow is what prevention of AD is all about. Since the defect in CBF begins many decades before cognitive decline, there is excellent opportunity for prevention. This is what work of Zlokovic and Ai-Ling Lin is all about. Saying these changes in cerebral blood flow as measured by glucose uptake on PET scans are due to cerebral insulin resistance is to interpret what is happening as 100% wrong.
Please see my website www.alzheimer-prevention.com main discussion on home page to understand this topic of the greatest importance. This particular discussion is "Latent and Prodromal Stages in APOE4 carrier". Also "Two Hit Theory" both on home page.
HBA1c, what is ideal
Re: RE: Re: HBA1c, what is ideal
Alan, please watch Rand's excellent lecture on https://youtu.be/OKH3AE1dOb4 before criticising her work based on my very scanty note taking during her lecture. She is a respected scientist.alangreenmd wrote:Hi
I would describe the above interpretation of Rand Akasheh as TOTALLY WRONG. This is extremely important. The fundamental defect in APOE4 carriers which begins in the 20-39 year age group is decreased blood flow in same areas which later develop changes of AD. These defects in cerebral blood flow are measured by PET scans which use decrease in glucose metabolism as the measure of CBF. This understanding of defects in cerebral blood flow and that is what is being measured by glucose metabolism is of paramount importance. This is of the highest level of importance because preventing damage to cerebral flow and restoring cerebral blood flow is what prevention of AD is all about. Since the defect in CBF begins many decades before cognitive decline, there is excellent opportunity for prevention. This is what work of Zlokovic and Ai-Ling Lin is all about. Saying these changes in cerebral blood flow as measured by glucose uptake on PET scans are due to cerebral insulin resistance is to interpret what is happening as 100% wrong.
Please see my website http://www.alzheimer-prevention.com main discussion on home page to understand this topic of the greatest importance. This particular discussion is "Latent and Prodromal Stages in APOE4 carrier". Also "Two Hit Theory" both on home page.
My notes were to whet the appetite of members to understand the framework of each lecture only. The detail is in the videos.
There are many theories as to AD causation and I, as a 4/4, am not closing my mind to multiple possible options.
Everyone who is passionate about their area of interest or expertise gets my full objective and respectful attention. I would hope that our members on the whole have the same view.
I am a practising mainstream medical doctor with over 30 years of clinical experience. I have seen theories come and go as new evidence appears. And I have seen over and over how new therapies don't exactly translate into real life as they might be predicted to do from formal trials.
At the moment I am watching your theory and other theories with equal, unbiased interest.
Sent from my SM-G930F using Tapatalk
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alangreenmd
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Re: HBA1c, what is ideal
Hi Stavia,
Here are the 4 studies I quote by Reiman 2001, Reiman 2005, Thambisetty, 2010, Reiman 2004. These are all open access. All one has to do is read the studies. It is 100% clear they are measuring cerebral blood flow not insulin resistance. I will quote the section which is very brief summary of papers. The point is that understanding these studies are measuring cerebral blood flow is of extreme importance. It should be noted that 3 studies used glucose metabolism and Thembisetty study measured labeled oxygen 15.
"Cerebral Blood Flow, Hypometabolism"
"Three studies, all reporting very similar results, conducted studies of cerebral blood flow using PET scans in APOE4 carriers in middle age."
"Declining brain activity in cognitively normal APO4 heterozygotes". Reiman 2001, Used PET scan measured cerebral metabolic rate for glucose (CMRgl) in age group 50-63 over interval 2 years: "The E4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and pre-frontal cortex, basal forebrain, parahippocampal gyrus and thalamus, and these declines were significantly greater than those in the E4 non-carriers."
"Correlations between APOE4 gene dose and brain imaging measurements of regional hypometabolism, Reiman, 2005. Age group 47-68, PET scan, CMRgl: "We previously found that cognitively normal late-middle-age APOE4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia...we now find the E4 gene dose is correlated with lower CMRgl in each of these brain regions."
"APOE epsilon 4 geneotype and longitudinal changes in cerebral blood flow in normal aging", Thambisetty, 2010. PET scan using labeled OXYGEN 15 compared regional blood flow over an 8 year period in E4 carriers older than 55 years.
Results: E4 carriers had greater regional blood flow decline compared to nonE4 carriers. The affected brain regions were the frontal, parietal and temporal cortices, those areas especially vulnerable to pathological changes in Alzheimer disease. The conclusion was "Alzheimer disease is associated with widespread decline in regional cerebral blood flow over time that precedes the onset of dementia."
In the following study, the participants were ages 20-39 carriers (heterozygotes) "Functional brain abnormalities in young adults at genetic risk for late onset Alzheimer's dementia", Reiman, 2004.
Abstract: Like previously studied patients with probable AD and late-middle-aged E4 carriers, the young E4 carriers had abnormally low rates glucose metabolism bilaterally in the posterior cingulate, parietal, temporal and prefrontal cortex. carriers of E4 gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia."
The point of all this: These PET scan specialists are measuring CEREBRAL BLOOD FLOW. If say decrease in glucose metabolism or oxygen consumption is due to insulin resistance and not due to changes in cerebral blood flow; it totally changes the understanding of the early changes that precede development of AD.
The prevention of AD in APOE4 carriers starts with understanding what are the first changes. The changes in cerebral blood flow were demonstrated in 20-39 age group in Reiman 2004 study.
Here are the 4 studies I quote by Reiman 2001, Reiman 2005, Thambisetty, 2010, Reiman 2004. These are all open access. All one has to do is read the studies. It is 100% clear they are measuring cerebral blood flow not insulin resistance. I will quote the section which is very brief summary of papers. The point is that understanding these studies are measuring cerebral blood flow is of extreme importance. It should be noted that 3 studies used glucose metabolism and Thembisetty study measured labeled oxygen 15.
"Cerebral Blood Flow, Hypometabolism"
"Three studies, all reporting very similar results, conducted studies of cerebral blood flow using PET scans in APOE4 carriers in middle age."
"Declining brain activity in cognitively normal APO4 heterozygotes". Reiman 2001, Used PET scan measured cerebral metabolic rate for glucose (CMRgl) in age group 50-63 over interval 2 years: "The E4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and pre-frontal cortex, basal forebrain, parahippocampal gyrus and thalamus, and these declines were significantly greater than those in the E4 non-carriers."
"Correlations between APOE4 gene dose and brain imaging measurements of regional hypometabolism, Reiman, 2005. Age group 47-68, PET scan, CMRgl: "We previously found that cognitively normal late-middle-age APOE4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia...we now find the E4 gene dose is correlated with lower CMRgl in each of these brain regions."
"APOE epsilon 4 geneotype and longitudinal changes in cerebral blood flow in normal aging", Thambisetty, 2010. PET scan using labeled OXYGEN 15 compared regional blood flow over an 8 year period in E4 carriers older than 55 years.
Results: E4 carriers had greater regional blood flow decline compared to nonE4 carriers. The affected brain regions were the frontal, parietal and temporal cortices, those areas especially vulnerable to pathological changes in Alzheimer disease. The conclusion was "Alzheimer disease is associated with widespread decline in regional cerebral blood flow over time that precedes the onset of dementia."
In the following study, the participants were ages 20-39 carriers (heterozygotes) "Functional brain abnormalities in young adults at genetic risk for late onset Alzheimer's dementia", Reiman, 2004.
Abstract: Like previously studied patients with probable AD and late-middle-aged E4 carriers, the young E4 carriers had abnormally low rates glucose metabolism bilaterally in the posterior cingulate, parietal, temporal and prefrontal cortex. carriers of E4 gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia."
The point of all this: These PET scan specialists are measuring CEREBRAL BLOOD FLOW. If say decrease in glucose metabolism or oxygen consumption is due to insulin resistance and not due to changes in cerebral blood flow; it totally changes the understanding of the early changes that precede development of AD.
The prevention of AD in APOE4 carriers starts with understanding what are the first changes. The changes in cerebral blood flow were demonstrated in 20-39 age group in Reiman 2004 study.
Re: HBA1c, what is ideal
Thanks Alan for your analysis of the papers quoted by Rand.
Any other members want to contribute to the discussion?
I'll start with Cunnane's interpretation of the hypometabolism seen in the scans. Which posits another interpretation of the data.
The authors present an elegant analysis of the data
Please refer to section 2.3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478067/
Any other members want to contribute to the discussion?
I'll start with Cunnane's interpretation of the hypometabolism seen in the scans. Which posits another interpretation of the data.
The authors present an elegant analysis of the data
Please refer to section 2.3.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478067/
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alangreenmd
- Contributor
- Posts: 62
- Joined: Mon Jan 15, 2018 3:32 pm
Re: HBA1c, what is ideal
Hi Stavia,
Thanks so much for quick response and posting a paper and identify specific section to read. That was excellent as shows the reason for wrong analysis. They calculate glucose uptake and conclude glucose under utilization reflects a primary problem in glucose as opposed to primary problem in blood flow.
Please allow me to clarify the misunderstanding:
In this study the PET scan uses Oxygen 15 labeled WATER to measure cerebral blood flow. When measure water there can be no mistake that this is BLOOD.
The 4 papers posted were papers quoted by me, copied off my web site, (I have no idea what Rand used) to try and show the PET scans were about blood flow. However, 3 of those 4 papers show cerebral hypometabolism of glucose and opened the door to mis-interpretation. The glucose metabolism was used as a surrogate indirect measure of cerebral blood flow. The following study is direct measurement of water (water as in blood).
"Cerebral Blood Flow in Normal Aging", Thambisetty, 2010.
Design: "Using oxygen 15 labeled water positron emission tomography and voxel-based analysis, we compared changes in rCBF (regional cerebral blood flow) over an 8-year period between 29 nondemented APOE e4 carriers and 65 noncarriers older than 55."
Results: "widespread differences were observed in longitudinal changes in rCBF between E4 carriers and noncarriers. The predominant pattern was greater rCBF decline in E4 carriers. These differences were observed in the frontal, parietal and temporal cortices. The affected brain regions were those especially vulnerable to pathological changes in Alzheimer disease."
Conclusion: Our finding suggest that APOE e4 mediated risk for Alzheimer disease is associated with widespread decline over time that precedes the onset of dementia."
The study is part of Baltimore Longitudinal study of Aging.
It is important to keep in mind that 99.6% of treatment studies have failed in AD; suggesting very low level of understanding of basic pathogenesis.
There has been a huge body of research that has been developed in past 5 years about what causes defects in cerebral blood flow in APOE4 carriers and how to prevent and ameliorate those defects in cerebral blood flow.
The problem: if you don't understand there are defects in cerebral blood flow because you think PET scans which measure glucose hypometabolism are showing a primary defect in glucose metabolism; then just going down a rabbit hole.
I hope you will find this study using oxygen 15 labeled water persuasive that these PET scans are about cerebral blood flow.
Again thanks for posting above paper.
Thanks so much for quick response and posting a paper and identify specific section to read. That was excellent as shows the reason for wrong analysis. They calculate glucose uptake and conclude glucose under utilization reflects a primary problem in glucose as opposed to primary problem in blood flow.
Please allow me to clarify the misunderstanding:
In this study the PET scan uses Oxygen 15 labeled WATER to measure cerebral blood flow. When measure water there can be no mistake that this is BLOOD.
The 4 papers posted were papers quoted by me, copied off my web site, (I have no idea what Rand used) to try and show the PET scans were about blood flow. However, 3 of those 4 papers show cerebral hypometabolism of glucose and opened the door to mis-interpretation. The glucose metabolism was used as a surrogate indirect measure of cerebral blood flow. The following study is direct measurement of water (water as in blood).
"Cerebral Blood Flow in Normal Aging", Thambisetty, 2010.
Design: "Using oxygen 15 labeled water positron emission tomography and voxel-based analysis, we compared changes in rCBF (regional cerebral blood flow) over an 8-year period between 29 nondemented APOE e4 carriers and 65 noncarriers older than 55."
Results: "widespread differences were observed in longitudinal changes in rCBF between E4 carriers and noncarriers. The predominant pattern was greater rCBF decline in E4 carriers. These differences were observed in the frontal, parietal and temporal cortices. The affected brain regions were those especially vulnerable to pathological changes in Alzheimer disease."
Conclusion: Our finding suggest that APOE e4 mediated risk for Alzheimer disease is associated with widespread decline over time that precedes the onset of dementia."
The study is part of Baltimore Longitudinal study of Aging.
It is important to keep in mind that 99.6% of treatment studies have failed in AD; suggesting very low level of understanding of basic pathogenesis.
There has been a huge body of research that has been developed in past 5 years about what causes defects in cerebral blood flow in APOE4 carriers and how to prevent and ameliorate those defects in cerebral blood flow.
The problem: if you don't understand there are defects in cerebral blood flow because you think PET scans which measure glucose hypometabolism are showing a primary defect in glucose metabolism; then just going down a rabbit hole.
I hope you will find this study using oxygen 15 labeled water persuasive that these PET scans are about cerebral blood flow.
Again thanks for posting above paper.
Re: HBA1c, what is ideal
Well Alan, there’s you, a pathologist posting your website to try to gin up business and attempting to come across as the inveterate authority instead of embracing respectful dialogue and totally ignoring the years of discourse we’ve conducted on this website... (Moderators is this okay? I quote the community guidelines: “Respect. All posts and private messages should be courteous. Disagree with ideas, not people. You may not attack, insult, undermine, or belittle anyone. This broad prohibition extends beyond other members and this community to the world at large. Humility. Refrain from posturing as an expert or relying on your professional status to make your point. Support your opinions with personal or clinical experience, your physician’s perspective, and/or published medical research. Avoid overreaching – we are most credible when we focus on our own personal experiences, Kindness. Some here are suffering. Look for the best in one another, and speak with empathy and generosity. Trust. Ulterior financial interests complicate our interactions. Do not self-promote or advertise.”)”alangreenmd wrote:I would describe the above interpretation of Rand Akasheh as TOTALLY WRONG.
It’s not what you’re saying Alan, it’s how you’re saying it my friend.
Let me start over, Alan there’s you, a pathologist trying to gin up business, and then there’s the research which since the 2008 paper Alzheimer's Disease is Type 3 Diabetes-Evidence Reviewed https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/ has bolstered the hypometabolism theory.
I'll bite.Stavia wrote:Any other members want to contribute to the discussion?
From the conclusions in this 2017 paper Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer's Disease https://www.frontiersin.org/articles/10 ... 00118/full
The paper discusses vascular effects but cites IR first then vascular impairment:"all but certain that brain IR plays a major role in AD pathogenesis”
There's also this paper Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease https://www.ncbi.nlm.nih.gov/pubmed/26967215Vascular function is tightly coupled to insulin signaling, and central to this relationship is endothelial dysfunction, which manifests through deficient vasodilation and improper vasoconstriction throughout the body in the setting of IR (Hsueh et al., 2004; Quiñones et al., 2004; Cersosimo and DeFronzo, 2006)….
…Recently, the term “vascular contribution of cognitive impairment and dementia” (VCID) has been coined to capture this heterogeneity.
There is emerging evidence showing that IR and diabetes have significant implications in VCID. It is well known that cerebral blood flow is decreased in diabetic patients (Jellinger, 2007). Cerebral small vessel disease (CSVD) is the cause of approximately 20% of strokes and the underlying etiology for many of the other pathologies previously mentioned (Lammie et al., 1997; Cai et al., 2015). Importantly, CSVD is aggravated by diabetes….
There's also the research of Dr Ed Geotzl, MD, Harvard Medical School trained, currently associated with USCF. Dr Geotzl has numerous other papers including, Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease.Mullins, R. J.,Mustapic, M.,Goetzl, E. J.,Kapogiannis, D.; Hum Brain Mapp. 2017 Jan 21, unfortunately they don’t seem to be publicly available for free, but Dr Dale Bredesen has often referenced Dr Geotzl’s research with exosomes as showing that basically everybody who has Alzheimer’s Disease has insulin resistance in the brain, whether or not they have it peripherally.“However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, [Insulin Degrading Enzyme] and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here.”
Stavia referenced Dr Cunane’s work, He holds a PhD in Physiology at McGill University in 1980, followed by post-doctoral research on nutrition and brain development in Aberdeen, London, and Nova Scotia, senior Canada Research Chair at the Research Center on Aging. His current research uses brain imaging techniques to study changing brain fuel metabolism and cognitive function during aging. Some of his papers:
Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease, 2016, https://www.ncbi.nlm.nih.gov/pubmed/26766547
Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937039/
Brain fuel metabolism, aging, and Alzheimer's disease 2011 https://www.ncbi.nlm.nih.gov/pubmed/21035308
And there's Amy Berger, who holds a master’s degree in human nutrition, is a Certified Nutrition Specialist (CNS) and certified Nutritional Therapy Practitioner, in 2016 she wrote Insulin resistance and reduced brain glucose metabolism in the aetiology of Alzheimer’s disease https://insulinresistance.org/index.php ... le/view/15 where she wrote:
I'm sure there's more.“There is a significant link between Alzheimer’s disease and impaired fuel metabolism in the brain, with disturbed cerebral glucose metabolism being an invariant pathophysiological feature of AD.23 (23.Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies. Prog Neurobiol. 2013;108:21–43. http://dx.doi.org/10.1016/j.pneurobio.2013.06.004) The defining metabolic signature of AD is a decrease in the cerebral metabolic rate of glucose (CMRglu). This may be the primary underlying cause of neuronal degeneration and death: at its heart, AD is an energy crisis in the brain. It is the death of neurons via starvation, as they have lost the capacity to effectively harvest energy from glucose.”
-Theresa
ApoE 4/4
ApoE 4/4
Re: HBA1c, what is ideal
"TOTALLY WRONG". Perhaps strong words in a disease where we still lack definitive answers in process and treatment.alangreenmd wrote:I would describe the above interpretation of Rand Akasheh as TOTALLY WRONG.
As a moderator, I want to point out that you continue to shoot down other hypotheses under discussion in strong terms even though I have previously asked you to tone it down.
Yes, I understand your hypothesis, but until research studies have shown your suggested treatment is successful, then your take is also still a hypothesis.
Our guidelines (please read them if you haven't), say to disagree respectfully. Yelling "TOTALLY WRONG" is not disagreeing respectfully and the fact you have an "MD" behind your name might give some people a sense of imprimatur that you are "correct." Join the discussion, point out where you disagree, but don't posture that you are always right and other researchers are "TOTALLY WRONG".
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Orangeblossom
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Re: HBA1c, what is ideal
What do you think is causing the blood flow problems, rather than a problem with glucose?alangreenmd wrote:Hi Stavia,
Thanks so much for quick response and posting a paper and identify specific section to read. That was excellent as shows the reason for wrong analysis. They calculate glucose uptake and conclude glucose under utilization reflects a primary problem in glucose as opposed to primary problem in blood flow.
Please allow me to clarify the misunderstanding:
In this study the PET scan uses Oxygen 15 labeled WATER to measure cerebral blood flow. When measure water there can be no mistake that this is BLOOD.
The 4 papers posted were papers quoted by me, copied off my web site, (I have no idea what Rand used) to try and show the PET scans were about blood flow. However, 3 of those 4 papers show cerebral hypometabolism of glucose and opened the door to mis-interpretation. The glucose metabolism was used as a surrogate indirect measure of cerebral blood flow. The following study is direct measurement of water (water as in blood).
"Cerebral Blood Flow in Normal Aging", Thambisetty, 2010.
Design: "Using oxygen 15 labeled water positron emission tomography and voxel-based analysis, we compared changes in rCBF (regional cerebral blood flow) over an 8-year period between 29 nondemented APOE e4 carriers and 65 noncarriers older than 55."
Results: "widespread differences were observed in longitudinal changes in rCBF between E4 carriers and noncarriers. The predominant pattern was greater rCBF decline in E4 carriers. These differences were observed in the frontal, parietal and temporal cortices. The affected brain regions were those especially vulnerable to pathological changes in Alzheimer disease."
Conclusion: Our finding suggest that APOE e4 mediated risk for Alzheimer disease is associated with widespread decline over time that precedes the onset of dementia."
The study is part of Baltimore Longitudinal study of Aging.
It is important to keep in mind that 99.6% of treatment studies have failed in AD; suggesting very low level of understanding of basic pathogenesis.
There has been a huge body of research that has been developed in past 5 years about what causes defects in cerebral blood flow in APOE4 carriers and how to prevent and ameliorate those defects in cerebral blood flow.
The problem: if you don't understand there are defects in cerebral blood flow because you think PET scans which measure glucose hypometabolism are showing a primary defect in glucose metabolism; then just going down a rabbit hole.
I hope you will find this study using oxygen 15 labeled water persuasive that these PET scans are about cerebral blood flow.
Again thanks for posting above paper.
Re: HBA1c, what is ideal
I wouldn't mind going both routes. I personally feel better on a carb restricted, healthy fat diet with lots of greens and veggies. But also I would love to incorporate any suggestions that would increase blood flow to my brain. I typically have low blood pressure, with systolic under 100. Does that seem problematic? Any other suggestions from other members? Thanks in advance.
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alangreenmd
- Contributor
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- Joined: Mon Jan 15, 2018 3:32 pm
Re: HBA1c, what is ideal
Hi OrangeBlossom,
Thanks for asking great question.
Yesterday Julia posted paper by Robert Mahley. In the last 10 pages Robert Mahley presents his his own theory, none of which I happened to agreed with; but on page 4, while still in introduction mode he answers your question. The following is quote from Robert Mahley. This quote very succinctly expresses the essence of the current leading theory of AD.
"ApoE is known to exhibit isoform-specific effects on blood-brain barrier (BBB) integrity in mouse models (Bell et.al., 2012) In ...transgenic mice, apoE4 expression increases the BBB's susceptibility to injury by activating the proinflammatory cytokine cyclophilin A in pericytes and triggering the NF-kB/matrix metalloprotinase 9 pathway. Interestingly, BBB breakdown is independent of AB. The subsequent neuronal damage that occurs appears to result from the leakage of blood-derived proteins--including immunoglobulin G, thrombin, and fibrin--into the brain."
The critical reference is Bell, 2012. "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A, Bell...Zlokovic. This paper is probably the most important paper in current leading AD theory as regards development of AD in APOE4 carriers. Note that Julia posted the Robert Mahley paper and Robert Mahley quotes the above entire passage under topic heading, "Direct Effects of ApoE in Causing Neuropathology.
The 2012 Bell...Zlokovic paper was a mouse study. All these same finding were later confirmed in 2015 Zlokovic study in which examined brains from E3, not AD, E3 with AD, E4 with AD. The same finding shown in the mice as regards breakdown of cerebral blood microcirculation and BBB were in AD brains, with AD E4 brains having more than E3 AD brains.
So short answer of what causes the blood flow problem: APOE4 forms weak bond with LRP1. The weak bond with LRP1 then triggers the pathway described by Robert Mahley above. Note the most import cell mentioned is "pericyte". The target of MMP9 is tight junctions between cells of BBB. MMP9 is enzyme which dissolves proteins. All explained in Bell, 2012.
If question is what does glucose have to do with all of this the answer is as follows: elevated glucose causes elevated mTOR and elevated mTOR accelerates the reactions.
Thanks for asking great question.
Yesterday Julia posted paper by Robert Mahley. In the last 10 pages Robert Mahley presents his his own theory, none of which I happened to agreed with; but on page 4, while still in introduction mode he answers your question. The following is quote from Robert Mahley. This quote very succinctly expresses the essence of the current leading theory of AD.
"ApoE is known to exhibit isoform-specific effects on blood-brain barrier (BBB) integrity in mouse models (Bell et.al., 2012) In ...transgenic mice, apoE4 expression increases the BBB's susceptibility to injury by activating the proinflammatory cytokine cyclophilin A in pericytes and triggering the NF-kB/matrix metalloprotinase 9 pathway. Interestingly, BBB breakdown is independent of AB. The subsequent neuronal damage that occurs appears to result from the leakage of blood-derived proteins--including immunoglobulin G, thrombin, and fibrin--into the brain."
The critical reference is Bell, 2012. "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A, Bell...Zlokovic. This paper is probably the most important paper in current leading AD theory as regards development of AD in APOE4 carriers. Note that Julia posted the Robert Mahley paper and Robert Mahley quotes the above entire passage under topic heading, "Direct Effects of ApoE in Causing Neuropathology.
The 2012 Bell...Zlokovic paper was a mouse study. All these same finding were later confirmed in 2015 Zlokovic study in which examined brains from E3, not AD, E3 with AD, E4 with AD. The same finding shown in the mice as regards breakdown of cerebral blood microcirculation and BBB were in AD brains, with AD E4 brains having more than E3 AD brains.
So short answer of what causes the blood flow problem: APOE4 forms weak bond with LRP1. The weak bond with LRP1 then triggers the pathway described by Robert Mahley above. Note the most import cell mentioned is "pericyte". The target of MMP9 is tight junctions between cells of BBB. MMP9 is enzyme which dissolves proteins. All explained in Bell, 2012.
If question is what does glucose have to do with all of this the answer is as follows: elevated glucose causes elevated mTOR and elevated mTOR accelerates the reactions.
