Thursday 30 January 2014

High Carb Diet impairs memory in young mice - ApoE4 Forum

ApoE4 Forum • View topic - E4 interaction with a High Carb Diet



E4 interaction with a High Carb Diet

Postby Juliegee » Sun Nov 17, 2013 8:11 am
Combination of apolipoprotein E4 and high
carbohydrate diet reduces hippocampal BDNF and arc levels and impairs
memory in young mice.


http://www.ncbi.nlm.nih.gov/pubmed/22836186



We've
seen plenty of studies with human subjects suggesting that a high carb
diet (HCD) leads to cognitive impairment, but this is the first (to my
knowledge) that actually studied the effect of a HCD on e4s as compared
to e3s...albeit on our mousie friends ;)



"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."

Ketosis, Carbohydrates and the Brain - Q&A | BodyRecomposition - The Home of Lyle McDonald

Ketosis, Carbohydrates and the Brain - Q&A | BodyRecomposition - The Home of Lyle McDonald



Question: I’ve been doing the CKD effectively.
However, I have a major exam on Friday. Is there any effect on limited
carbs on cognitive processes? Does limiting carbs ( 20g / day) have a
negative effect or could it retard my performance on a major exam, i.e.
MCATs, Series7, etc? Is there any study or suggestion you could give
based on your research?




Answer: First a quick definition for anyone who isn’t familiar with the abbreviation: as discussed in the Comparing the Diets Series
, a CKD refers to a cyclical ketogenic diet.  This is simply a diet
that alternates between periods of very low-carbohydrate eating
(typically 4-6 days) and very high-carbohydrate eating (1-3 days).  Dan
Duchaine’s Bodyopus, Mauro DiPasquale’s Anabolic Diet and my own Ultimate Diet 2.0 are all examples of CKD’s.  My first book The Ketogenic Diet discusses CKD’s generally in mind-numbing detail.




Now back to the question: does ketosis negatively impact on cognitive
function?  And the answer is one huge it depends.  Certainly early
studies found that, in the short-term (first 1-3 weeks),
low-carbohydrate diets tend to cause some problems.  For this reason
short-term studies (usually a week long) tend to report decrements in a
lot of things including cognitive performance.




Empirically, as well, many report fatigue, lethargy and a sort of
mental ‘fog’ until they adapt to the diet (the brain adjusts to using
ketones for fuel over those first 3 weeks).  I’d note that supplementing
with sodium, potassium and magnesium seems to go a long way towards
limiting or eliminating that feeling of fatigue.




So, for most I certainly wouldn’t recommend starting a very
low-carbohydrate/ketogenic diet right before some major test or
cognitive challenge.  Odds are it’s going to cause problems.




But what about someone who has adapted to being in ketosis. There
there tends to be huge variance.  Some people are sort of neutral to it
but I know of many who report far better brain functioning when they are
in ketosis.  I couldn’t tell you the mechanism, this is just one of
those self-reported things.  But it tends to be highly variable (and I
can’t think of any studies that have examined cognitive performance
after long-term adaptation to low-carbohydrate diets).







CKD’s add another complication, outside of some exercise research on Cyclical Ketogenic Diets and Endurance Performance
that looked only at performance, I’m unaware of any work on CKD’s and
cognitive performance.  I bring this up as some people do report changes
switching back and forth between very low and very high carbohydrate
intakes.




Quite in fact, many who find that they feel ‘great’ in ketosis feel a
bit dopey or sleepy when they switch back to high carb intakes.  This
is probably related to either blood glucose swings or a big increase in
brain serotonin (which tends to cause lethargy and fatigue) but it does
occur.




Similarly, some seem to go through at least a brief re-adaptation (in
terms of fatigue, etc.) going back from high carbs to low-carbs. 
Again, this is pretty variable, many people can switch back and forth
from one extreme to the other and don’t seem to notice anything.  I have
no idea why, just reports I’ve seen.




So back to the question, should you switch out of ketosis for your
test?  It’s a hard question to answer and you’d have to think back to
your previous switches from low- to high-carbs during the CKD.  If you
find that you’re fully adapted to ketosis and function fine mentally,
and that you get dopey going back to high-carbs, I’d probably suggest
you stay on low-carbs through the test.




If you’re one of those people who don’t seem to have ever fully
adapted to being in ketosis (they do exist), you might want to move back
to at least moderate carbs a day or two before your test.  Unfortunately, there’s just too much variability for me to give you any advice beyond that.




  1. Chino on
    March 16th, 2011 5:41 pm
    As much as I expected from this response.


    I am one of those people who have better concentration, focus, and
    mental/physical performance in a CKD (in my case SKD) diet. I’ve adapted
    well and also feel weak/tired as soon as I start hooking into the
    sugar.


    I would also expect, for obvious reasons, not to undertake things like exams when entering a refeed/carb-load phase.





  2. Bartjan on
    March 17th, 2011 6:39 pm
    I’ve
    read in a study (can’t find the source now) that people are able to
    concentrate better and are cognitively sharper when they are hungry.
    Which (biologically) seems logical as we need our intellect to hunt and
    we don’t need it when we just fed.


    That would suggest having few carbs would be beneficial to your cognitive abilities.

    I’d suggest the questioner doing an online IQ test while on CKD (in both
    phases) and while on a ‘normal’ diet to estimate if it has any impact
    on you.





  3. starskeptic on
    March 17th, 2011 10:53 pm
    rolf –


    you have a lot of homework to do; try reading some of Lyle’s articles on this site first…





  4. Fredrik Gyllensten on
    March 21st, 2011 12:34 pm
    Interesting
    question, and answer. I myself would probably make sure to have fasted
    for at 10-15 hours before my exam, as I seem to do best mentally then.




  5. Andrea on
    March 21st, 2011 5:37 pm



    Agree
    with Fredrik. Regardless the diet, being fasted for 12-20 hours prior
    to an exam seems to clear the head and assist with test-taking, and this
    seems especially helpful when one has to “cram” before the test.


    Just my experience, anyway…


Mixed Brain Fuel - Q&A | BodyRecomposition - The Home of Lyle McDonald

Mixed Brain Fuel - Q&A | BodyRecomposition - The Home of Lyle McDonald



Question: On a ketogenic diet, how rapidly does the
brain flip between glucose and ketones for fuel? Can it use both fuel
sources simultaneously?

So I think that answers at least part of
your question: when first starting a low-carbohydrate diet, it takes the
brain about 3 weeks to adapt to using ketones for fuel; even then it
only gets about 75% of its total fuel from them. 
At the same time, after more extended periods on the diet (perhaps
6-8 weeks), switching back and forth from a carb-based to a ketone-based
brain metabolism seems to cause most people no problems. They can sort
of drop in and out of ketosis (even throughout the day under certain
conditions) and not really notice anything one way or the other.  
Answer: The above question sort of encompasses a few
different potential things and I’m not 100% sure which you’re asking so
I’ll just cover them all.  First realize that one fuel that the brain
cannot use is fatty acids, at least not directly.  This has led to the
oft-stated belief that the brain can only use glucose. But this is
incorrect as the brain has an alternative fat derived fuel which are
ketones (or ketone bodies, the two major of which are
beta-hydroxybutyrate and acetyl-acetate).



Ketones are produced primarily in the liver (from the breakdown of
fatty acids) and exist predominantly as an alternative fuel source for
the brain (they can also be used by skeletal muscle) during periods of
low-carbohydrate availability.  This probably was originally important
during periods of complete starvation; now very low-carbohydrate diets
(defined here as any diet containing less than 100 grams per day of
carbohydrates) effectively ‘exploit’ this mechanism.



Now, on a carbohydrate based diet, the brain runs essentially on 100%
glucose since ketones are generally not produced in significant amounts
under those conditions (there are a couple of odd exceptions, one is
following very long duration endurance exercise where a post-exercise
ketosis can occur due to changes in fuel metabolism).  So what happens
when you remove most or all carbohydrates from the diet?  Does the brain
magically switch to using ketones?  For the most part, no.  Studies
done way back when show that there is an adaptation phase that may last
about 3 weeks while the brain ramps up its ability to use ketones for
fuel.



Even there, after that roughly 3 week period, the brain still only
derives about 75% of its total fuel requirements (about 400 calories per
day or thereabouts) from ketones; the other 25% come from glucose
(which the body can produce through a variety of pathways that I won’t
detail here; all of this is explained in excruciating detail in my first
book The Ketogenic Diet). 
Mind you, this is only relevant on a very low-carbohydrate diet.  Even
if the brain could still use ketones on a carb-based diet they wouldn’t
be produced in large enough amounts for it to be relevant.



So I think that answers at least part of
your question: when first starting a low-carbohydrate diet, it takes the
brain about 3 weeks to adapt to using ketones for fuel; even then it
only gets about 75% of its total fuel from them.  This scans pretty well
with what many experience on the diet, they don’t feel fantastic for
the first 2-3 weeks of the diet (while they are adapting). Some of that,
mind you, is related more to mineral intake than anything else (early
studies found that sufficient intake of sodium, potassium and magnesium
eliminated all of the fatigue and lethargy that occurred on very low
carbohydrate diets).



But there is a related question that often comes up which has to do
with switching back and forth between fuels (this is especially relevant
for some cyclical ketogenic diets such as what’s described in The Ketogenic Diet or in my Ultimate Diet 2.0). 
Here I am unaware of any research on the topic and most of what I have
to say is just based on empirical evidence, what people have reported
over the 15+ years they’ve been giving me feedback.



Certainly early in the diet there is often a period where the
alternation of high and low carbs often causes some people distress,
they get the same headaches and issues going from high-carbs back to
low-carbs for a couple of weeks.  Probably just a function of
‘interrupting’ the adaptation to ketone metabolism in the brain and
there might be some rationale to doing 2-3 straight weeks of a ketogenic
diet prior to inserting refeeds or carb-loads.



At the same time, after more extended periods on the diet (perhaps
6-8 weeks), switching back and forth from a carb-based to a ketone-based
brain metabolism seems to cause most people no problems. They can sort
of drop in and out of ketosis (even throughout the day under certain
conditions) and not really notice anything one way or the other. 
Interestingly, even after extended periods off of a low-carbohydrate
diet, most people don’t report the same early adaptation phase that they
went through the first time on the diet; they go back onto a ketogenic
diet and don’t notice anything.



This suggests to me that there is some type of long-term and/or
almost permanent change in the brain in terms of its ability to use
ketones for fuel with long-term exposure to them.  Again, I have exactly
zero research to back this up; it’s just an observation.  But even
there you’d still expect to see the same basic 75/25 split, just with an
easier switching back to ketone metabolism after that initial
adaptation phase.



Hope that answers your question.

Monday 27 January 2014

Tobacco Products: Nicotine has a negative impact on the developing adolescent brain..

Snus News & Other Tobacco Products: Nicotine has a negative impact on the developing adolescent brain..



October 24, 2007 - The
nicotine in tobacco products poses a significant danger of structural
and chemical changes in developing brains that can make teens more
vulnerable to alcohol and other drug addiction and to mental illness,
according to Tobacco: The Smoking Gun, a new white paper released
today by The National Center on Addiction and Substance Abuse (CASA) at
Columbia University (Joseph A. Califano, Jr., chairman and president of
CASA) and commissioned by The Citizens’ Commission to Protect the
Truth, a group of all former U.S. Secretaries of Health, Education, and
Welfare and of Health and Human Services, all former U.S. Surgeons
General, and all former Directors of the Centers for Disease Control and
Prevention.

The Commission asked CASA to assemble the scientific
evidence of the impact of nicotine on the adolescent brain, conduct
original analyses of data from the National Survey on Drug Use and Health (NSDUH)
on the relationship between teen smoking, alcohol and illegal drug
abuse and addiction and mental health, and issue a report on its
findings.CASA’s original analysis of data from the NSDUH finds that
teens who smoke are nine times likelier to meet the medical criteria for
past year alcohol abuse or dependence and 13 times likelier to meet the
medical criteria for abuse and dependence on an illegal drug than teens
who don’t smoke.The CASA analysis also found that among teens ages 12
to 17, twice as many smokers as nonsmokers suffered from symptoms of
depression in the past year. Teens who reported early initiation of
smoking were more likely to experience serious feelings of hopelessness,
depression and worthlessness in the past year.The report also notes
that smoking at a young age is related to panic attacks, general anxiety
disorders and post-traumatic stress disorder.

Reference: Tobacco: The Smoking Gun, Lauren Duran, 212-841-5260, Tobacco: The Smoking Gun, lduran@casacolumbia.org Sulaiman Beg, 212-841-5213,sbeg@casacolumbia.org , The National Center on Addiction and Substance Abuse at Columbia University.10/23/2007.



Sunday 12 January 2014

Caffeine restores forgotten memories- further...(19) SuppVersity

(19) SuppVersity - Caffeine restores forgotten memories- further...

7 hours ago ·
Caffeine restores forgotten memories- further evidence for caffeines anti-dementia effects

For some, it's the tradition of steeping tealeaves to brew the perfect cup of tea. For others, it's the morning shuffle to a coffee maker for a hot jolt of java. Then there are those who like their wake up with the kind of snap and a fizz usually found in a carbonated beverage.

Regardless of the routine, the consumption of caffeine is the energy boost of choice for millions to wake up or stay up. Now, however, researchers at the Johns Hopkins University have found another use for the stimulant: memory enhancer.

Michael Yassa, assistant professor of psychological and brain sciences in the Krieger School of Arts and Sciences at Johns Hopkins, and his team of scientists found that caffeine has a positive effect on long-term memory in humans. Their research, published by the journal Nature Neuroscience, shows that caffeine enhances certain memories at least up to 24 hours after it is consumed.

"We've always known that caffeine has cognitive-enhancing effects, but its particular effects on strengthening memories and making them resistant to forgetting has never been examined in detail in humans," said Yassa, senior author of the paper. "We report for the first time a specific effect of caffeine on reducing forgetting over 24 hours."

The Johns Hopkins researchers conducted a double-blind trial; which participants who did not regularly eat or drink caffeinated products received either a placebo or a 200-milligram caffeine tablet five minutes after studying a series of images. Salivary samples were taken from the participants before they took the tablets to measure their caffeine levels. Samples were taken again one, three and 24 hours afterwards.

The next day, both groups were tested on their ability to recognize images from the previous day's study session. On the test, some of the visuals were the same as from the day before, some were new additions and some were similar but not the same as the items previously viewed. More members of the caffeine group were able to correctly identify the new images as "similar" to previously viewed images versus erroneously citing them as the same.

The brain's ability to recognize the difference between two similar but not identical items, called pattern separation, reflects a deeper level of memory retention, the researchers said.

"If we used a standard recognition memory task without these tricky similar items, we would have found no effect of caffeine," Yassa said. "However, using these items requires the brain to make a more difficult discrimination -- what we call pattern separation, which seems to be the process that is enhanced by caffeine in our case."

The memory center in the human brain is the hippocampus, a seahorse-shaped area in the medial temporal lobe of the brain. The hippocampus is the switchbox for all short-term and long-term memories. Most research done on memory -- the effects of concussions in athletics to war-related head injuries to dementia in the aging population -- are focused on this area of the brain.

Until now, caffeine's effects on long-term memory had not been examined in detail. Of the few studies done, the general consensus was that caffeine has little or no effect on long-term memory retention.

The research is different from prior experiments because the subjects took the caffeine tablets only after they had viewed and attempted to memorize the images.

"Almost all prior studies administered caffeine before the study session, so if there is an enhancement, it's not clear if it's due to caffeine's effects on attention, vigilance, focus or other factors. By administering caffeine after the experiment, we rule out all of these effects and make sure that if there is an enhancement, it's due to memory and nothing else," said Yassa.

According to the U.S. Food and Drug Administration, 90 percent of people worldwide consume caffeine in one form or another. In the United States, 80 percent of adults consume caffeine every day. The average adult has an intake of about 200 milligrams -- the same amount used in the Yassa study -- or roughly one strong cup of coffee or two small cups of coffee per day.

Yassa's team completed the research at Johns Hopkins before his lab moved to the University of California-Irvine at the start of this year.

"The next step for us is to figure out the brain mechanisms underlying this enhancement," he said. "We can use brain-imaging techniques to address these questions. We also know that caffeine is associated with healthy longevity and may have some protective effects from cognitive decline like Alzheimer's disease. These are certainly important questions for the future."

www.suppversity.com -- based on press release

Monday 6 January 2014

A Genetic Approach to the ApoE4 Puzzle | ALZFORUM

A Genetic Approach to the ApoE4 Puzzle | ALZFORUM

For decades, scientists have wondered how ApoE4, the strongest genetic risk factor for Alzheimer’s disease, influences pathology. They know the allele affects cells and tissues in many ways, but which actually lead to AD? Researchers led by Asa Abeliovich at Columbia University, New York, outline a new approach to answer the question in the July 24 Nature online. They compared transcriptomes of healthy ApoE4 carriers to those of LOAD patients who do not carry this gene, and found common patterns of gene expression. Genes regulating endocytosis and the processing of the amyloid β precursor protein (APP) stood out, hinting that ApoE4 primes the brain for APP-related changes that lead to AD, suggested the authors. “The data jibe with longstanding human and mouse data showing that ApoE4 enhances brain amyloid pathology,” wrote Samuel Gandy, Mount Sinai Medical Center, New York to Alzforum in an email. “It is heartening to think that after 20 years of ApoE4 linkage to AD, there are new exciting leads that might offer an explanation.” However, he noted some caveats (see full comment below).

Studies of humans, mice, and cultured cells suggest that ApoE4 impairs Aβ degradation and clearance, and encourages inflammation and endocytosis, which create even more Aβ (see Castellano et al., 2011; Koistinaho et al., 2004; Zhu et al., 2012; and He et al., 2007). However, it is unclear if all or any of these effects cause AD, result from it, or even relate to the disease, said co-first author Herve Rhinn. He and colleagues wanted to figure out what changes occur first as a way of getting closer to the root causes of the disease.

To do that, Rhinn and co-first author Ryousuke Fujita looked for transcript alterations in the cerebral cortex of postmortem brains from 185 healthy people grouped by ApoE status. The analysis revealed more than 8,000 genes that were expressed differently in people who carried the ApoE4 allele compared to those with ApoE2 or E3. Of those hits, 215 turned up in a separate analysis comparing expression in 86 LOAD patients and 67 age-matched controls, all without ApoE4. These genes may be key to AD risk endowed by ApoE, suggested the authors.

image
Genetic overlap among aging, ApoE4, and LOAD.

Image courtesy Herve Rhinn and Nature

Curiously, the ApoE4 pattern barely overlapped with that seen when the researchers compared gene expression among 64 older (age 85 and up) and 56 younger brains (age 75 or less). This suggested to the authors that ApoE and aging—the major risk factor for late onset AD (LOAD)—contribute to the disease via separate mechanisms (see figure below). The implication is that “different genetic forms or subtypes of Alzheimer’s disease may have specific underlying mechanisms and respond differently to treatment,” wrote Vivek Swarup and Daniel Geschwind of the University of California, Los Angeles, in an accompanying editorial.

To find out what mediated the differences in expression, the researchers applied a systems biology approach called differential co-expression analysis (DCA), which weighs results based on co-regulated genes (see ARF related news story). This identified 20 "master regulators" of the 215 genes. Researchers had previously associated the top hit, the zinc-binding protein RNF219, with cognitive performance, lipid metabolism, and brain ventricular volume. Another candidate—the synaptic vesicle protein SV2A—helps regulate neuronal endocytosis. Scientists had previously tied several of the regulators, including APBA2, ITM2B, and FYN, to the processing and intracellular trafficking of APP. Fyn kinase has also been linked to Aβ toxicity via tau (see ARF related news story).

To test whether these 20 genes bring about ApoE4’s effects, Rhinn and colleagues used small hairpin RNAs to knock down several individually in mouse N2a neuroblastoma cells and gauge how the cells reacted to added human recombinant ApoE4. This treatment spurred production of Aβ40 and Aβ42 in wild-type N2a cells, but not when the genes were knocked down.

The researchers then took a closer look at RNF219 and SV2A. Knocking down either prevented ApoE4 from boosting β–secretase 1 (BACE1) processing of APP, which it does in wild-type cells by promoting co-localization of BACE1 and APP in endosomes. Levetiracetam, an SV2A inhibitor used to treat epileptic seizures, also reduced Aβ production in N2a cells as well as in neurons induced from human fibroblasts donated by ApoE4 carriers. Together, these results suggest that RNF219 and SV2A mediate ApoE4’s effects on APP processing, concluded the authors.

Previous studies suggested that levetiracetam lowers neuronal hyperactivity and improves cognition in J20 mice. Interestingly, other anti-epileptic drugs, which have no affinity for SV2A, failed to achieve the same result (see ARF related news story). “We think levetiracetam works by reducing Aβ,” Abeliovich told Alzforum. “Our work reframes existing data, and suggests that hitting this target [SV2A] could be disease-altering,” he said. Michela Gallagher, Johns Hopkins University, Baltimore, Maryland, who previously reported that levetiracetam improved memory in people with mild cognitive impairment (see ARF related news story), agreed. “This report has potential therapeutic implications in support of SV2A as a target to prevent LOAD, at least in ApoE4 carriers,” Gallagher wrote to Alzforum in an email (see full comment below). She pointed out that benefits of levetiracetam extend to mice and humans that do not carry ApoE4, so the drug could help a broader population.

Scott Small, also at Columbia University, pointed out that the data support a hypothesis, summarized in his review written with Gandy, that any defect that keeps APP and BACE1 in endosomes will increase Aβ production and drive pathology (see Small and Gandy, 2006).

Other experts cautioned that the paper was still speculative, and required more exploration. “It will be interesting to see if the function of SV2A and RNF219 described here in cell culture can be reproduced in AD animal models,” wrote Lars Ittner, University of New South Wales, Sydney, Australia, to Alzforum via email (see full comment below). Ittner pointed out that how these ApoE4-driven changes relate to tau remains to be seen. Gandy cautioned that in other cultured neural cells, ApoE4 does not modify APP sorting or processing (see Biere et al., 1995).

Abeliovich plans to test if and how the other hits from this DCA study influence disease progression. In addition, he will extend this analysis beyond ApoE4 to other risk variants identified in genome-wide association studies for AD, and apply the method to Parkinson’s disease (see ARF related news story).—Gwyneth Dickey Zakaib.

References:

Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A. Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease. Nature. 2013 July 24. [Epub ahead of print] Abstract.
Swarup V, Geschwind DH. From big data to mechanism. Nature. 2013 July 24. [Epub ahead of print] Abstract

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Comments on this content

  1. I read this paper with keen interest yesterday, but also found myself uneasy with the recombinant ApoE cell treatments as noted by Sam Gandy. Following my reading of his comments today, I took another look at that paper with a different view, asking if these points diminished my initial enthusiasm. I arrived at the conclusion that even if all of the recombinant ApoE treatment studies were removed from the paper as potentially artifactual, the conclusions of the authors still stand on the basis of the differential co-expression analyses and the experiments with the human induced neuronal cultures.More

Comments on Primary Papers for this Article

  1. Apart from aging itself, apolipoprotein E (Apo-E) polymorphic alleles are the primary genetic determinants of risk for sporadic late onset Alzheimer disease (LOAD). Rhinn et al. have uncovered a candidate effector pathway for Apo-E4 on amyloid beta precursor protein (APP) endocytosis and metabolism contributing to LOAD. In addition to advancing biological understanding, the report has potential therapeutic implications in support of Sv2a as a target to prevent LOAD, at least in ApoE4 carriers. Would the Sv2a inhibitor used to suppress altered APP processing in APOE4-positive human induced neurons (hiNs) have in vivo efficacy in that population? More

    While that remains to be seen, it is important to note that targeting Sv2a has shown beneficial effects in aging, MCI patients, and AD models apart from ApoE4. This is true for our (Bakker et al., 2012) and a second prior study using levetiracetam cited by the authors (Sanchez et al., 2012). 

    The AD mouse model used by Sanchez et al. is devoid of ApoE4 but showed improved cellular, network, and behavioral outcomes specific for mice with hAPP overexpression after treatment with the Sv2a ligand levetiracetam (see also Spiegel et al., 2013 for further evidence of a therapeutic benefit in a rodent model, absent ApoE4). Hyperactivity leading to network dysfunction is a common feature of these preclinical models. As Rhinn and colleagues noted, our report using low dose levetiracetam in amnestic mild cognitive impairment (MCI) ascribed therapeutic benefit to effective reduction of hippocampal hyperactivity. We have since completed additional cohorts of MCI patients under the same protocol (totaling N=54). In the aggregate MCI study population, 43 percent of the genotyped subjects were APOE4 carriers. The signature of hyperactivity localized within the hippocampal formation was not restricted to APOE4 carriers but was evident in carriers and non-carriers alike. 

    The notion that this condition contributes to disease progression is supported by a close association between the magnitude of hippocampal hyperactivity in MCI with the severity of structural atrophy in key AD related areas of the brain (Putcha et al., 2011). It is also notable that hippocampal hyperactivity is seen pre-symptomatically in early-onset AD (Quiroz et al., 2010) as well as in asymptomatic APOE4 carriers and in aMCI, irrespective of E4 carrier status. Hence, drugs that target Sv2a could be beneficial therapeutically in the broader context of prodromal AD, while not being limited to the ApoE4 population.
    View all comments by Arnold Bakker