Energy and Structure

Before we can talk about how an organism functions, we need to understand its gross organization and have the ability to visualize it. We need language to create an analogy, we need an analogy to visualize things. Recently, I had a conversation with a someone on why I view saturated fat as a superior energy substrate. But before I could explain why, I had to explain how I view the organism. Below is our conversation. This will serve as a introduction through which to interpret the rest of the of the information I write about.

(7:06:07 PM) Anonymous: so, having been looking into Peat’s work for so long and coming around to seeing his ideas as logical

(7:07:27 PM) Anonymous: this leaves me not entirely sure of some things when approaching a “low carb” diet (at least as far as macro-ratios goes)

(7:09:50 PM) Anonymous: things like how this approach relates to blood sugar, sugar=anti stress, sugar needed for T4>T3, cells running on sugar etc.

(7:11:59 PM) Edward: oh man… big question… where to start…

(7:12:03 PM) Edward: o.k. so

(7:12:24 PM) Anonymous: haha

(7:12:47 PM) Edward: If me and Dr. Peat were to agree on one thing it would be that energy and structure are interdependent

(7:13:09 PM) Edward: and quite frankly that is not a new biological concept, it is older then he is

(7:14:05 PM) Edward: however, the difference between myself and Peat is the function of structure…

(7:15:29 PM) Edward: I think that structure, which is a invention of evolution is in place to deliver energy, because I think the structure exists to support the organization of the organism

(7:16:47 PM) Edward: he looks at it a bit differently inherently if he is promoting sugar which is a primitive fuel source… in other words there is no structure needed to deliver glucose to a cell

(7:18:50 PM) Edward: does that make sense what i said so far

(7:19:01 PM) Edward: at least what we disagree on

(7:19:28 PM) Anonymous: yeah

(7:19:37 PM) Edward: I need to full screen this chat window it’s getting serious in here

(7:19:53 PM) Anonymous: i did that a little while ago ;)

(7:19:57 PM) Edward: o.k. evidence of this is the vascular system, the CNS, the lymphatic system, etc

(7:20:06 PM) Edward: at least on a big scale

(7:20:23 PM) Edward: for a single celled organism we don’t need all that

(7:20:42 PM) Edward: it is happy eating sugar

(7:21:25 PM) Edward: those systems are “structure”… in biology we say cells, tissue, organs, organ system so on when we talk about structure

(7:21:36 PM) Edward: the entire digestive system is “structure”

(7:22:23 PM) Edward: that “structure” is designed to deliver nutrients and the such to all of the cells, tissue, organs, etc… in the body

(7:23:07 PM) Edward: now obviously i argue that saturated fat is a superior energy source

(7:26:25 PM) Edward: o.k. so in the body there are the different organs, the brain, the balls, the ovaries, the muscles, the heart, etc…

(7:26:42 PM) Edward: all of these require a different energy substrate…

(7:27:02 PM) Edward: for example, your balls like citrate

(7:27:47 PM) Edward: your brain likes lactate/a bit of glucose/a bit of ketones/and some specific kinds of fat

(7:28:10 PM) Edward: the muscles at rest and during most activity burn fat

(7:28:15 PM) Edward: the heart prefers it

(7:28:58 PM) Edward: the blood… ahh the blood… the blood cells have no mitochondria

(7:29:13 PM) Edward: guess where the brains gets part of it’s lactate from

(7:29:16 PM) Edward: ?

(7:29:28 PM) Edward: The anaerobic metabolism of the red blood cells

(7:30:18 PM) Edward: the colon likes butyric acid

(7:30:33 PM) Edward: so you see each part of the body likes something different

(7:31:04 PM) Edward: how is it possible to support those fuel demands?

(7:31:44 PM) Edward: you have to have structure, the vascular system, the lymphatic system, the CNS, the GI system, etc.

(7:32:27 PM) Edward: when we look at breast milk what do we see…

(7:32:42 PM) Edward: first we see percentages of all the different saturated fat chain lengths

(7:32:54 PM) Edward: short, medium, long, very long, etc

(7:33:00 PM) Edward: and then we see protein

7:33:09 PM) Edward: a splash of lactose

(7:33:23 PM) Edward: we also see some branched chain fatty acids

(7:33:37 PM) Edward: and a very tiny tiny bit of polyunsaturated fat

(7:34:08 PM) Edward: there are no ketones in milk at least not that i am aware of… and this is the hooker

(7:34:29 PM) Edward: a baby needs ketones… if a baby does not have ketones it will either die or be retarded

(7:34:57 PM) Edward: ketones serve as a cholesterol precursor and also serve as a precursor for some of the special lipids in the brain

(7:35:31 PM) Edward: give a baby glucose instead of breast feeding and it develops tumors on the brain

(7:35:52 PM) Edward: so how does the baby get the ketones it needs

(7:36:06 PM) Edward: via “structure”

(7:36:52 PM) Edward: the liver and brain can make ketones locally and delivers them to the brain… that is structure at play (ketones are probably produced elsewhere as well)

(7:37:09 PM) Edward: so remember… structure is essentially a group of cells that perform a specialized function

(7:37:24 PM) Edward: each individual cell does not have structure not in the sense we are talking about here

(7:38:02 PM) Edward: so the ketones are delivered to each cell via structure because the individual cell itself can not do this because it serves a different function

(7:38:15 PM) Edward: same with lactate

(7:38:42 PM) Edward: babies need lactate and so does the brain… the brain itself can’t do this

(7:39:08 PM) Edward: it has to be delivered by the anaerobic metabolism of the red blood cells and locally in the brain in the astrocyctes

(7:39:34 PM) Edward: does that make sense so far?

(7:40:44 PM) Anonymous: yeah, although i’m not aware of the astrocyctes

(7:41:12 PM) Edward: oh well, there are about a dozen or more different types of cells in the brain

(7:43:53 PM) Edward: o.k. glucose is a primitive fuel source it is “anti-structure” and so are polyunsatured fats but here it we have to make perfectly clear that the polyunsaturated fats are anti-structure as a fuel source, but the brain is indeed made of polyunsatured fat… that is structure… in this case the polyunsatured fats serve electric functions

(7:43:58 PM) Edward: does that make sense

(7:44:46 PM) Edward: so as a fuel polyunsaturated fast are anti-structure but that does not mean they can not be built by the body to serve a functional/structural purpose

(7:44:50 PM) Edward: ?

(7:44:58 PM) Anonymous: yep

(7:45:04 PM) Edward: cool

(7:45:35 PM) Edward: glucose can basically be absorbed through a gradient anywhere in the body

(7:46:51 PM) Edward: if you eat it it goes in your mouth, your mouth cells, your esophagus cells, your stomach, everywhere… you can make a glucose solution and inject it in your arm and your cells will use it you can squirt some up your ass and your colon cells will use it, you can put it on your skin, etc…

(7:47:29 PM) Edward: there is absolutely no structure required for any type of cell to use it

(7:47:50 PM) Edward: so the cells are intelligent

(7:47:54 PM) Edward: “intelligent”

(7:48:06 PM) Edward: they sense their environment

(7:48:20 PM) Edward: what happens when you are queuing?

(7:49:28 PM) Anonymous: as in waiting in line?

(7:49:46 PM) Edward: yes waiting in line

(7:50:08 PM) Edward: o.k. so walk through me on this

(7:50:33 PM) Edward: what is the sort of place in the UK where you’d have to queue?

(7:52:02 PM) Anonymous: bank

(7:52:20 PM) Edward: o.k. the bank… now why would you be going to the bank?

(7:53:16 PM) Edward: bare with me on this…

(7:53:45 PM) Anonymous: you want me to pick one reason?

(7:53:48 PM) Edward: yes

(7:53:51 PM) Edward: one reason

(7:54:07 PM) Anonymous: to extract money from my account

(7:56:40 PM) Edward: this is a lose analogy

(7:56:42 PM) Edward: anyway

(7:56:56 PM) Edward: you all are standing in line

(7:57:06 PM) Edward: each person walks up gets what they need and leaves

(7:57:35 PM) Edward: what happens if you don’t stand in line? Like in Germany were they all crowd around like animals?

(7:57:57 PM) Anonymous: haha!

(7:59:22 PM) Anonymous: i guess it would be hard to discern who should be seen first by the assistant at the bank

(7:59:40 PM) Anonymous: and perhaps there would be fighting between those in line…?

(7:59:53 PM) Edward: yes, they would be all fighting for the resource they came to get

(8:00:24 PM) Edward: so some people would get their money before others and others would be waiting or pushed out of the way right?

(8:00:36 PM) Anonymous: yeah

(8:00:53 PM) Edward: congratulations you now understand why we get cancer

(8:01:17 PM) Edward: and this is why structure is so important

(8:01:42 PM) Edward: when you need something you know when you need it, you go to the bank, wait in line, and you get what you need

(8:01:54 PM) Edward: money = energy substrates

(8:02:57 PM) Edward: when you have no structure or you fill your body with a fuel that requires no structure you create an environment in the body where literally the first cell to absorb the the glucose wins at the expense of it’s sister cell

(8:03:03 PM) Edward: even if it is in the same organ

(8:03:32 PM) Edward: people who don’t wait in line and crowd around like in Germany they act like animals not civilized and chaos develops

(8:03:45 PM) Edward: this is very similar to what happens in the body

(8:04:40 PM) Edward: cancer and disease really is proof that we are made up of a group of primitive (individual) cells all working together

(8:05:27 PM) Edward: when a bunch of money drops from the sky the people scatter and fight for it, they don’t all put it in a pile and then split it equally right?

(8:05:42 PM) Anonymous: mmhmm

(8:06:03 PM) Edward: and as much as it seriously pains me to use this analogy gov’t is a good analogy to use for structure

(8:06:56 PM) Edward: obviously some gov’t are better than others and as a result each individual has a better life… some gov’t suck and then the individuals (the cells) have shitty lives

(8:07:25 PM) Edward: they starve, don’t have food, get disease

(8:07:27 PM) Edward: etc

(8:08:22 PM) Edward: does all that make sense

(8:08:23 PM) Edward: ?

(8:08:33 PM) Anonymous: yep

(8:08:42 PM) Edward: are light bulbs turning on?

(8:09:01 PM) Anonymous: lol

(8:09:04 PM) Anonymous: yeah

(8:09:44 PM) Edward: o.k. break time for a moment…

I don’t know what to title this post: follow-up

This post is going to serve as a sort of summary for the posts that I will be writing on the relationship between thyroid hormones and saturated fat. I’ve been working on ways to make things understandable and trying to develop some analogies so we can get a visual in the brain.

The first concepts I will be covering is the behavior of T3 alone, what it does to your metabolism and how it functions. I hope to dissolve some myths concerning the type of metabolism T3 promotes and why perhaps taking T3 on a low fat diet might be a mistake which can increase stress as well as making one more sensitive to stress.

From there I will work into the behavior of saturated fat alone, what it does to your metabolism, and how it functions. I hope to dissolve some myths concerning the type of metabolism that saturated fat promotes. I also hope to make it perfectly clear that there is a difference between a high saturated fat diet and a high fat diet that is high in polyunsaturated fats. And I also hope to make clear the difference between free saturated fatty acids and free polyunsaturated fatty acids.

At that point some light bulbs should be turning on and I will compare the similarities between the thyroid hormones and saturated fat. I will use that post as a jumping off point to make some predictions about things we should see in reality and the literature if this concept is true which I will follow up with examples and supporting literature.

Then I will write posts on longevity, metabolic rate, disease, and dovetail all of these concepts together. I was struggling with either wanting to write one large article or a series. I decided on writing a series because it will allow me to manage my time a little better with my work schedule. Plus I am getting ready to transfer to a hospital in Connecticut so with that pending move there might be some delays here and there. But the delays will give you a chance to start digging around yourself and poke holes in things that I may have overlooked. It is important to be vigilant. I have been very thorough in looking to find exceptions but I am only one person, and the literature is massive, and maybe you will look  at things a little differently. And that is o.k., all we are after is answers to questions, and questioning assumptions.

Finally, always look for exceptions. It leads to great questions.

I don’t know what to title this post


A few years ago I started looking at the mechanisms through which T3 works. In my brain when I’m developing a model in my head, it needs to resemble a gently moving mobile; you know those things over a baby crib. It has to make sense, it has to look beautiful. I’ve always pictured everything in nature almost as a fractal.

I had noticed in some personal experiments that T3 reminded me of eating butter. A lot of the same symptoms T3 seemed to solve where the same symptoms butter seemed to solve. Things like that make me incredibly curious.

When you are looking at hormones it becomes tempting to read so much about the positive benefits of one hormone that you convince yourself that actually taking that hormone is a good idea. It is easy to look at the positive benefits of a substance and quickly forget to ask the question what is causing a flux in this particular hormone to begin with?

It is very easy to forget the flux and the balance. I picture in my head a glass full of different colored dyes all remaining separate yet blended together at their edges in beautiful gradients.

Even more important is that when you look at hormones, you can’t just look at the flux of different hormones to understand them. One hormone is always pushing or pulling another through a cascade. To really get down to the understanding of hormones and their function, you have to get down to the microscopic level where organization starts. What is it about multicellular organisms that makes all of the cells organize, what makes them work together, how do they know where to go? How does a blood cell know it is a blood cell, how does muscle cell know it belongs in your muscle instead of your brain. How come your toenails grow straight out instead of curling under and growing back into your toe? How come sperm cells know to attach to the egg instead of attaching to an epithelial cell?

Everyday curious minds are working on solving these mysteries. It is fascinating how much we know really. Utterly staggering. Almost every question I’ve ever cared to ask at one point or another has been studied in some form or fashion, or at least part of the question has been studied.

These days what we are lacking most of all are creative people who can move objects in space in their brains. These days people are super concerned with data points instead of prediction power. Prediction power is the ultimate test for any theory. And as I’ve said many times if you don’t have prediction power or if your model can’t predict an exception then it’s time to go back to the drawing board.

You have to constantly back check everything from the microscopic to the macroscopic. You can never be too careful in coming to conclusions. Especially when it comes to your own health.

As I said, it made me incredibly curious when I noticed that T3 solved the same problems butter seemed to solve. So I began looking for a connection. I have a lot of posts I’m supposed to be writing and for now they will be put on hold. From here on out I will be focusing on writing about the connection between T3 and butter.

T3 and UCPs

Lanni, a., Moreno, M., Lombardi, A., & Goglia, F. (2003). Thyroid hormone and uncoupling proteins. FEBS letters, 543(1-3), 5–10. doi:10.1016/S0014-5793(03)00320-X

Thyroid hormone (TH/T3) exerts many of its effects on energy metabolism by affecting gene transcription. However, although this is an important target for T3, only a limited number of T3-responsive genes have been identified and studied. Among these, the genes for uncoupling proteins (UCPs) have attracted the interest of scientists. Although the role of UCP1 seems quite well established, uncertainty surrounds the physiological function of the recently discovered UCP1 analogs, UCP2 and UCP3. The literature suggests that T3 affects both the expression and the activity of each of these UCPs but further studies are needed to establish whether the mechanisms activated by the hormone are the same. Recently, because of their larger range of expression, much attention has been devoted to UCP2 and UCP3. Most detailed studies on the involvement of these proteins as mediators of the effects of T3 on metabolism have focused on UCP3 because of its expression in skeletal muscle. T3 seems to be unique in having the ability to stimulate the expression and activity of UCP3 and this may be related to the capacity of T3 to activate the integrated biochemical processes linked to UCP activity, such as those related to fatty acids, coenzyme Q and free radicals.

Nicotine, BAT thermogenesis, UCPs

Nicotine uncouples the mitochondria via UCP1 (uncoupling protein 1, or thermogenin). It upregulates BAT thermogensis (brown adipose tissue) and increases in BAT thermogenesis is associated with increased longevity. I could see nicotine, aside from butter, promoting longevity. 

Mattson, M. P. (2010). Perspective: Does brown fat protect against diseases of aging? Ageing research reviews, 9(1), 69–76. doi:10.1016/j.arr.2009.11.004

The most commonly studied laboratory rodents possess a specialized form of fat called brown adipose tissue (BAT) that generates heat to help maintain body temperature in cold environments. In humans, BAT is abundant during embryonic and early postnatal development, but is absent or present in relatively small amounts in adults where it is located in paracervical and supraclavicular regions. BAT cells can “burn” fatty acid energy substrates to generate heat because they possess large numbers of mitochondria in which oxidative phosphorylation is uncoupled from ATP production as a result of a transmembrane proton leak mediated by uncoupling protein 1 (UCP1). Studies of rodents in which BAT levels are either increased or decreased have revealed a role for BAT in protection against diet-induced obesity. Data suggest that individuals with low levels of BAT are prone to obesity, insulin resistance and cardiovascular disease, whereas those with higher levels of BAT maintain lower body weights and exhibit superior health as they age. BAT levels decrease during aging, and dietary energy restriction increases BAT activity and protects multiple organ systems including the nervous system against age-related dysfunction and degeneration. Future studies in which the effects of specific manipulations of BAT levels and thermogenic activity on disease processes in animal models (diabetes, cardiovascular disease, cancers, neurodegenerative diseases) are determined will establish if and how BAT affects the development and progression of age-related diseases. Data from animal studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity and age-related diseases. Examples include: diet and lifestyle changes; specific regimens of mild intermittent stress; drugs that stimulate BAT formation and activity; induction of brown adipose cell progenitors in muscle and other tissues; and transplantation of brown adipose cells.

Yoshida, T., Yoshioka, K., Hiraoka, N., & Kondo, M. (1990). Effect of nicotine on norepinephrine turnover and thermogenesis in brown adipose tissue and metabolic rate in MSG obese mice. Journal of nutritional science and vitaminology, 36(2), 123–30. Retrieved from

To clarify whether nicotine stimulates the sympathetic nervous system (SNS) and thermogenesis in brown adipose tissue (BAT) and whether it promotes the resting metabolic rate (RMR), with resulting mitigation of obesity, we measured norepinephrine (NE) turnover (an indicator of SNS activity), guanosine-5’-diphosphate (GDP) binding (a thermogenic indicator), oxygen consumption in BAT, and RMR in monosodium-L-glutamate (MSG) obese and saline control mice after 2 weeks treatment with nicotine. Nicotine significantly increased NE turnover, GDP binding, oxygen consumption in BAT, and RMR, and significantly reduced body weight in MSG obese mice as well as in control mice without affecting food intake. These results suggest that nicotine stimulates NE turnover and thermogenesis in BAT, and promotes RMR, all of which contribute to the mitigation of obesity.

Romestaing, C., Piquet, M.-A., Bedu, E., Rouleau, V., Dautresme, M., Hourmand-Ollivier, I., … Sibille, B. (2007). Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutrition & metabolism, 4, 4. doi:10.1186/1743-7075-4-4 

BACKGROUND: Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. METHODS: 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. RESULTS: MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25-28% vs standard). CONCLUSION: Long term high saturated fat feeding led to increased “peripheral” fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH.

Di Paola, M., & Lorusso, M. (2006). Interaction of free fatty acids with mitochondria: coupling, uncoupling and permeability transition. Biochimica et biophysica acta, 1757(9-10), 1330–7. doi:10.1016/j.bbabio.2006.03.024 

Long chain free fatty acids (FFA) exert, according to their actual concentration, different effects on the energy conserving system of mitochondria. Sub-micromolar concentrations of arachidonic acid (AA) rescue DeltapH-dependent depression of the proton pumping activity of the bc1 complex. This effect appears to be due to a direct interaction of AA with the proton-input mouth of the pump. At micromolar concentrations FFA increase the proton conductance of the inner membrane acting as protonophores. FFA can act as natural uncouplers, causing a mild uncoupling, which prevents reactive oxygen species production in the respiratory resting state. When Ca(2+)-loaded mitochondria are exposed to micromolar concentrations of FFA, the permeability of the inner membrane increases, resulting in matrix swelling, rupture of the outer membrane and release of intermembrane pro-apoptotic proteins. The characteristics of AA-induced swelling appear markedly different in mitochondria isolated from heart or liver. While in the latter it presents the canonical features of the classical permeability transition (PT), in heart mitochondria substantial differences are observed concerning CsA sensitivity, DeltaPsi dependence, reversibility by BSA and specificity for the activating divalent cation. In heart mitochondria, the AA-dependent increase of the inner membrane permeability is affected by ANT ligands such as adenine nucleotides and atractyloside. AA apparently causes a Ca2+-mediated conversion of ANT from a translocator to a channel system. Upon diamide treatment of heart mitochondria, the Ca2+/AA-induced CsA insensitive channel is converted into the classical PT pore. The relevance of these observations in terms of tissue-specific components of the putative PTP and heart ischemic and post-ischemic process is discussed.

ApoE4: This is your brain on ApoE4

At least until the CHO breaks you…

Dennis, N. a, Browndyke, J. N., Stokes, J., Need, A., Burke, J. R., Welsh-Bohmer, K. a, & Cabeza, R. (2010). Temporal lobe functional activity and connectivity in young adult APOE varepsilon4 carriers. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 6(4), 303–11. doi:10.1016/j.jalz.2009.07.003

BACKGROUND: We sought to determine if the APOE epsilon4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults. METHODS: Twenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE epsilon4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed. RESULTS: In the absence of demographic or performance differences, APOE epsilon4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas epsilon4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices. CONCLUSIONS: These results suggest that the APOE varepsilon4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult epsilon4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer’s disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.

Evans, S., Gray, M. A., Dowell, N. G., Tabet, N., Tofts, P. S., King, S. L., & Rusted, J. M. (2013). APOE E4 Carriers show prospective memory enhancement under nicotine, and evidence for specialisation within medial BA10. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 38(4), 655–63. doi:10.1038/npp.2012.230

There is evidence to suggest that the APOE ɛ4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ɛ4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18-30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ɛ4 carriers, but not in ɛ3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ɛ4 carriers. These differences in early visual processing may contribute to the behavioral findings. Activity in medial BA10 (previously implicated in PM) differentiated ɛ4 from ɛ3 carriers. One BA10 subregion showed greater deactivation in ɛ4 carriers during PM trials. Activity in other BA10 subregions was modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ɛ4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ɛ4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally specific subregions.

Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., … Mackay, C. E. (2009). Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proceedings of the National Academy of Sciences of the United States of America, 106(17), 7209–14. doi:10.1073/pnas.0811879106

The APOE epsilon4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE epsilon4-carriers and 18 matched noncarriers (age range: 20-35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased “default mode network” (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in epsilon4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in epsilon4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE epsilon4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.

Mondadori, C. R. A., de Quervain, D. J.-F., Buchmann, A., Mustovic, H., Wollmer, M. A., Schmidt, C. F., … Henke, K. (2007). Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Cerebral cortex (New York, N.Y. : 1991), 17(8), 1934–47. doi:10.1093/cercor/bhl103

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer’s disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas epsilon2 and epsilon3 carriers increased activity. This smaller neural investment of epsilon4 carriers into learning reappeared during retrieval: epsilon4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE epsilon4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.

Moreau, P.-H., Bott, J.-B., Zerbinatti, C., Renger, J. J., Kelche, C., Cassel, J.-C., & Mathis, C. (2013). ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice. Behavioural brain research, 243, 1–5. doi:10.1016/j.bbr.2012.12.043

The APOE-ɛ4 allele is associated with increased cognitive decline during normal aging and Alzheimer’s disease. However, several studies intriguingly found a beneficial effect on cognition in young adult human APOE-ɛ4 carriers. Here, we show that 3-month old bigenic hAPP-Yac/apoE4-TR mice outperformed their hAPP-Yac/apoE3-TR counterparts on learning and memory performances in the highly hippocampus-dependent, hidden-platform version of the Morris water maze task. The two mouse lines did not differ in a non-spatial visible-platform version of the task. This hAPP-Yac/apoE-TR model may thus provide a useful tool to study the mechanisms involved in the antagonistic pleiotropic effects of APOE-ɛ4 on cognitive functions.

Rusted, J. M., Evans, S. L., King, S. L., Dowell, N., Tabet, N., & Tofts, P. S. (2013). APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. NeuroImage, 65, 364–73. doi:10.1016/j.neuroimage.2012.10.010

The APOE e4 allele, which confers an increased risk of developing dementia in older adulthood, has been associated with enhanced cognitive performance in younger adults. An objective of the current study was to compare task-related behavioural and neural signatures for e4 carriers (e4+) and non-e4 carriers (e4-) to help elucidate potential mechanisms behind such cognitive differences. On two measures of attention, we recorded clear behavioural advantages in young adult e4+ relative to e4-, suggesting that e4+ performed these tasks with a wider field of attention. Behavioural advantages were associated with increased task-related brain activations detected by fMRI (BOLD). In addition, behavioural measures correlated with structural measures derived from a former DTI analysis of white matter integrity in our cohort. These data provide clear support for an antagonistic pleiotropy hypothesis–that the e4 allele confers some cognitive advantage in early life despite adverse consequences in old age. The data implicate differences in both structural and functional signatures as complementary mediators of the behavioural advantage.

ApoE4: Combination of apolipoprotein E4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice

The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment.

Maioli, S., Puerta, E., Merino-Serrais, P., Fusari, L., Gil-Bea, F., Rimondini, R., & Cedazo-Minguez, A. (2012). Combination of apolipoprotein E4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice. Journal of Alzheimer’s disease : JAD, 32(2), 341–55. doi:10.3233/JAD-2012-120697

ApoE4: High carbohydrate diets and Alzheimer’s disease

Alzheimer’s disease (AD) is a common, progressive, neurodegenerative disease that primarily afflicts the elderly. A well-defined risk factor for late onset AD is possession of one or more alleles of the epsilon-4 variant (E4) of the apolipoprotein E gene. Meta-analysis of allele frequencies has found that E4 is rare in populations with long historical exposure to agriculture, suggesting that consumption of a high carbohydrate (HC) diet may have selected against E4 carriers. The apoE4 protein alters lipid metabolism in a manner similar to a HC diet, suggesting a common mechanism for the etiology of AD. Evolutionarily discordant HC diets are proposed to be the primary cause of AD by two general mechanisms. (1) Disturbances in lipid metabolism within the central nervous system inhibits the function of membrane proteins such as glucose transporters and the amyloid precursor protein. (2) Prolonged excessive insulin/IGF signaling accelerates cellular damage in cerebral neurons. These two factors ultimately lead to the clinical and pathological course of AD. This hypothesis also suggests several preventative and treatment strategies. A change in diet emphasizing decreasing dietary carbohydrates and increasing essential fatty acids (EFA) may effectively prevent AD. Interventions that restore lipid homeostasis may treat the disease, including drugs that increase fatty acid metabolism, EFA repletion therapy, and ketone body treatment.

Henderson, S. T. (2004). High carbohydrate diets and Alzheimer’s disease. Medical hypotheses, 62(5), 689–700. doi:10.1016/j.mehy.2003.11.028