The Mediterranean Diet: Food for our Brains, but Research Served up that Leaves you Empty


Of course, we all tend to believe that the Mediterranean Diet must do some good for us and our brains in some way somehow.

Today we came across a study which seems to want to provide some basis for us eating in accord with such a regimen.

Sadly, however, this research does not add to any knowledge about the manner in which this kind of diet has impact upon us…and, although published in a Neurology journal, seems to rely more on statistical massaging of data rather than on any actual reliance upon knowledge of the brain, which they seem to be inclined to measure.

But, as we shall see, this study, despite itself .might give us an opportunity to remark on a few interesting aspects of the situation into which they rather blindly…should we say “double blindly” stumble. And indeed it will lead us to both Microglia and to Estrogen’s role in the Brain.

This research from Scotland shows that those seniors who were in their 70s, and who were also, according to their own self report of eating happens, low consumers of the Mediterranean Diet (MeDi) had significantly greater decrease in total brain volume over a 3-year period than those who regularly adhered to this type of diet. Of course, they end up with not even a “shot in the dark” as to what Total Brain volume differences might suggest.

As we look at their study down below we can see that there is a gorilla in the room’ and that is the APOE4 genomic difference with which their two studied groups begin their participation in the research.

To compound this, there were also no significant differences between the groups in changes in gray matter volume or cortical thickness.

So we have no choice but to read the researcher’s minds and surmise that somehow the difference in “total” volume ought to rely on the white matter of the brain. This itself, as a measure of anything that can be usefully articulated in the brain is as vague and lacking in meaning as the design and methods of the study.

It is notoriously a fact that this kind of total volume measure tells us practically nothing insofar as it could mean practically anything. This point is made nicely in this recent study, whose title speaks for itself:

Brain Changes Speak Volumes About Normal Aging and Dementia

It is well-known, however, that APOE4 is implicated very strongly in white matter structure and function..and that this can lead to countless other neuro-cognitive problems than just Alzheimer’s progression.

The impact of ApoE alleles on age-related myelin breakdown

“ApoE4 alleles decrease while ApoE2 alleles increase age at onset. Human and non-human primate data suggest that in middle age, the structural integrity of myelin sheaths begins breaking down with an accelerating age-related trajectory most evident in the brain’s later-myelinating association regions. This results in a progressive “disconnection” of widely distributed neural networks that may underlie the age risk factor for AD.”

Age-related differences in white matter integrity and cognitive function are related to APOE status.

doi: 10.1016/j.neuroimage.2010.08.052

“APOE ε4 has a significant impact on the trajectory of age-related cognitive functioning in older adults. Possible mechanisms are discussed that could account for the associations between ε4, diffusion, and cognitive function, including the influence of ε4 on neural repair, oxidative stress, and the health of myelin-producing oligodendroglia.”

This does not of course stop these researchers from avoiding any such consideration or analysis of their data…and they rush on to touting their study with the Medical Paparazzi…presumably to justify their funding…and their jobs… with a headline as follows:

“Mediterranean-Style Diet Linked to Higher Total Brain Volume”

The say, ‘Past research has linked this type of diet to many benefits, including better cognitive function and reduced risk for stroke and dementia. It has also recently been associated with increased cortical thickness and to larger brain volume in older patients.”

The Mediterranean Diet calls for fruit, vegetables, cereals, legumes, and olive oil in high quantities, moderate amounts of fish, and a low intake of red meat.

Interestingly, an increased consumption of fish or lower consumption of red meat did not drive this finding, “suggesting that other components of the MeDi or, possibly, all of its components in combination are responsible for the association,” write the investigators.

Now, while we tend to “believe” in the virtues of this type of diet, this study raises as many questions as it answers. For example, there was no difference in the baselines at the beginning of the three year period between the two groups in total brain volume despite their alleged reporting of having eaten in accord with that regimen during the past. So what do we make of that???? That the difference in diets only began to be operative when the study began in their older age? Or what? (in fact…oddly enough that is a remotely possible factor to be taken into account)

What they do report is that most of the demographic characteristics were similar, the high-adherence group had significantly more carriers of the APOE ε4 risk allele than did the low-adherence group (33.2% vs 24.4%, respectively; P = .03).

Now this APOE4 gene is indeed known to be a ‘risk factor” for Alzheimer’s and so, if a researcher knowns nothing except the epidemiological statistics, that is all they are concerned about.

However, if we look at this gene,we see that APOE4 is a class of apolipoprotein that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.

Interestingly, those who found themselves in the high Mediterranean diet group actually had higher APOE4 genes and were at higher risk for Alzheimers..but of course they were at higher risk, as we can see, in regard to much much more.

In peripheral tissues, APOE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism in an isoform-dependent manner. In the central nervous system, In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.

For example even within the brain, which is presumably where the research has some sort of very blurry eyed focus, this gene is one which determines how our neurosteroids interact with our Microglia.

Of course microglia are key player in the etiology and manifestations of Alzheimer’s, but is their role in hundreds of other aspects of neural functioning that is ..or at least should have been considered by the authors of this research.

Microglia Function in Alzheimer’s Disease

Estrogens, Neuroinflammation, and Neurodegeneration.

“Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells.”

They tell us that” Estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease” And as we know that Alzheimer’s is a great risk as females age than for males as they age.

We also know that estrogen is a potent neuroprotectant..and that, as estrogen levels drop in women, the risk to Alzheimer’s is made every higher, with the youthful levels of Estrogen managing a protective function till after menopause.

Here they tell us that this APOE4 is a key factor in the ability of estrogen to modulate Microglia phenotype status…and indeed, with microglia, we know that they are responsible for the monitoring of neurogenesis and the control of cells that need to be phagocytosed and eliminated. In that way all neuronal function is modulated via the action of the microglia ..hopefully this normal maintenance can go on when they are not in an inflammatory mode but in that mid ground mode of merely being “ramified microglia”.

The APOE4 genotype alters the response of microglia and macrophages to 17beta-estradiol.

As this study writes, “Post-menopausal women with AD who express at least one APOE4 gene have more severe neuropathology and worsened cognitive scores than their non-expressing counterparts.” 17beta-estradiol down-regulates inflammation as part of its neuroprotective role,

“Our data,” they say, ” indicate that the APOE genotype may be a critical component in assessing the effectiveness of 17beta-estradiol’s action and may impact the neuroprotective role of 17beta-estradiol and of hormone replacement therapy on brain function when the APOE4 gene is expressed.

“The genotype specific effect was not restricted to brain macrophages since peritoneal macrophages from APOE4 ovariectomized mice also demonstrated a significant difference in 17beta-estradiol responsiveness”

Yet, even to get to playing with their data, the researchers seem to rather casually dismiss the fact that this was not a likely factor in their results because there were no traces (by which measure???) of any difference in ncreased Alzheimer directed changes in the sample

They say, “In our sample, the APOE e4 allele (Alzheimer disease risk allele) frequency was higher in those who adhered more to the MeDi. None of our sample had been diagnosed with Alzheimer disease so disease progression was unlikely having an influence on diet.”

However, honestly, this is almost a comical response in its glibness.   Apolipoprotein E (APOE) is not strictly tied to Alzheimer’s at all. The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer’s disease (AD) in a variety of ethnic groups. But of course ApoE4 is not a determinant of the disease – at least a third of patients with AD are ApoE4 negative.

“Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations.” But AD is rare among them. There is growing evidence that suggests that this may be due to their low cholesterol levels
Of course as we can suspect from the function of the APOE4 gene, it is not branded with label, Alzheime’rs Risk”…and “A recent study showed ” that high serum total cholesterol may be an independent risk factor for AD and some of the effect of the apoE σ4 allele on risk of AD might be mediated through high serum cholesterol.”

So the question least in evaluation of these results and perhaps advancing further in our awareness of what the Diet regimen might actually have done…is whether or not or why the elevated APOE4 levels in the Med Diet group might have contributed to their less diminution in brain volume?

What we are left with here is the likely fact it may have well be that those who reported being on some sort of Mediterranean diet…prior to their recruitment for the study and their filling out of the questionnaires….had found in their previous years , to some degree in association with their elevated APOE4 genomic profile that they had better begin to watch their diet, whether because of cardiovascular or other manifestations of the elevated APOE4.

It is well known that people with the APOE4 allele have elevated serum cholesterol. With the medical professions hyper zealous attempts to admonish us about keep cholesterol serum levels low, it is highly probably that those with the APOE4 allele, even if they did not have any Alzheimer’s or were only on the way towards such a fate that would not be determined by the kinds of testing done in this research anyway, had already been duly warned time and again and had, as one of their options for some of them, altered their diet to something like the Med Diet, and so that would easily account for the signficant difference in the starting points of the two groups selected.

Now actually have no idea what their total brain volume looked like three or four years prior to the study, perhaps they had already managed to control its diminution by having been on that diet.

But it would not be at all surprising, as they both groups they might have found that their incidence of untoward aspect of brain structure and function was increased as their hormonal levels, and especially their estrogen levels dropped further.

So over the three years of the study it might well have been the continued diet which, especially in those most prone to microglial inflammation via both the drop in Estrogen and the presence of the APOE4 gene…who benefited more than those in the other group.

As always seems to be the case, the microglia are there at the center of every “storm” that arise in our brain and its ‘minding” functions. And lest we forget those astrocytes, we should note that they themselves are key producers of, of all things, cholesterol in the brain and they also depend for their proper function on APOE and the APOE4 allele is associated with an dysfunction of the astrocytes..

Impaired Autophagy in APOE4 Astrocytes

Here the researchers discover just how all of these aspects of brain must be considered in relation to each other. Those astrocytes with that known risk factor for Alzheimer’s, the ApoE4 allele eliminate amyloid plaques less effectively than the corresponding ApoE3 astrocytes.

“These findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired astrocytes function results from that ApoE4 and that among other things, the impaired autophagy that has already been assessed is related to ineffective clearance of the amyloid plaques.”

There is much more to discover about how the kind of diet, which has been the initial impetus for this post,  may affect our health and well being..but it certainly cannot be discovered without studies that truly base themselves on a deeper understanding of the brain and its minding than this one. We only have raised a few of the questions which any truly valuable study ought to be able to address in its design and data discovery.

This Med Diet study which we discuss today does not provide us with much “food for thought”. More fat than substance in this one.

#alzheimers #brain #diet #anti-aging #longevity #aging #neuroscience


  1. well i eat salmon from norway, just a little before going to bed.. and if i wake up early a little then.. What that does for the brain.. its incredible.. i would love to know more what its doing. So far we have three modes of action. Its keeping the glials from being less inflammatory somehow, maybe by controlling arachodonic acid. Then it increases serotonin apparently. But you can actually simulate a little of what omega 3 does, by taking iboprofen and a serotonin simulator… but its nowhere near the same


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