In the previous post I looked at the rationale behind this multi target intervention to reverse cognitive decline along with factors relating to optimising the diet, autophagy, sleep, stress and exercise. In this post I’ll take a look at brain stimulation, optimizing homocysteine levels, C-reactive protein, albumin-globulin ratios, serum vitamin B12 levels, fasting insulin and hemoglobin A1C.
Again, this isn’t meant to be an in-depth guide but rather a brief look at the rationale behind each intervention.
For a summary of the program and the interventions used click here.
6. Brain Stimulation
The original paper was a little vague here mentioning only brain stimulation and providing a reference. Nevertheless, there are studies showing the benefits of brain stimulation through various activities. Anything that sufficiently stimulates the brain; language learning, playing games/video games, learning a new skill etc.
Bredesen’s paper cites a single source that looked at two different types of brain training or rather an experimental type of brain training set against a more conventional educational type of training which was used as an active control. Participants were subjected to a number of memory and cognitive tests both before and after. The experimental training, which consisted of “six computerized exercises designed to improve the speed and accuracy of auditory information processing” proved to be somewhat more effective than the active control, though both methods seemed to produce positive effects (1) suggesting that, perhaps, any sufficiently stimulating activity may help improve brain plasticity and a range of other markers.
Studies looking at speakers of multiple languages also found that bilingual individuals tended to develop Alzheimer’s around 5 years later than monolinguals, suggesting some benefit of speaking additional languages (2).
An extensive, and quite readable, review entitled ‘Foreign language training as cognitive therapy for age-related cognitive decline: A hypothesis for future research’ covers many studies finding that
“Numerous studies have assessed mentally-stimulating lifestyle activities by incidentally evaluating a range of cognitive activities in which the participant might engage (e.g., reading books, going to lectures, playing board games, etc.) and developing a measure of the total hours spent doing these activities, adjusted for potentially confounding factors. A common finding has been that older adults who regularly engage in intellectually stimulating exercises, such as reading newspapers and magazines, playing puzzle games, and going to museums, may delay or even reduce the occurrence of cognitive problems, including those related to dementia and Alzheimer’s disease.“(3)
With regards to languages the review goes on to say that speaking two or more languages appears to benefit the aging brain and
“Bilingual patients diagnosed with probable Alzheimer’s disease showed substantially more atrophy in temporal regions than did their monolingual counterparts, but were still able to function at the same cognitive level.” (3)
What this would seem to suggest is that even when greater levels of brain atrophy are present cognitive function is still intact in multilingual individuals.
They go on to say that even starting to learn a new language, though bilingualism may not be achieved, can still be beneficial as it stimulates many different areas of the brain that produce carry over effects pertaining to other tasks and activities. In fact, learning a foreign language may be superior to other forms of brain training because it activates so many different areas of the brain.
There also appears to be some evidence that playing video games may benefit the brain, especially for older people, but more research needs to be done (4)
7. Optimize Homocysteine levels (ideally less than 7 µmol/L)
The stated approach in the paper is ‘Take vitamin B12, methyltetrahydrofolate (biological active form of folate), pyridoxine-5-phosphate (active form of vitamin B6) and trimethylglycine (commonly known as betaine) if necessary’ in order to reduce homocysteine levels to less than 7 µmol/L
One thing I would add to this is that though the target is less than 7 µmol/L, levels of homocysteine that are too low may also present problems, too, and so I would say that the optimal window is between 4-7 µmol/L (see below)
Increased plasma homocysteine levels are associated with a number of disease states and can directly contribute to brain shrinkage, neuron death and cognitive decline (5) . Studies have shown that in people with high levels of homocysteine (>14µmol/L), the risk of Alzheimer’s almost doubled (6, 7)
Homocysteine is a non-protein amino acid that is produced during protein metabolism. It acts as an intermediate in the production of the essential amino acid methionine and the endogenous – made within the body – antioxidant glutathione. To achieve this the body requires a number of different co-factors namely the B vitamins 6, 9 and 12 (B2 and magnesium also play their part).
Now, the chemistry and issues can get quite complicated and really deserve a separate post of their own, but suffice to say, deficiencies in B 6, 9 and, perhaps most importantly, 12 can lead to higher levels of homocysteine. I’ll cover B12 deficiency in the next point.
This is bad in itself as homocysteine is highly reactive and can, for example, cause damage to blood vessel walls, contributing to atherosclerosis etc, but what it also means is that without these co-factors homocysteine isn’t being converted into other useful substances. Conversely, this also means that very low levels of homocysteine may result in detrimentally low levels of glutathione production and other substances.
This issue is complicated further by the existence of a number of genetic predispositions that could mean that even though dietary intake is adequate faults in certain metabolic pathways lead to inefficient conversion. To get around these possible issues supplementing with the active forms of the various vitamins shows some evidence of overcoming these problems. So, instead of supplementing with folic acid, a synthetic folate precursor that needs to undergo conversion into an active form, it may be more prudent to supplement with the active form directly.
Some doctors may tell you that your level is fine even if its above 7 µmol/L, but the aim of the intervention is to optimize your levels, so even though we tend to see ranges up to 11.9 µmol/L as ‘normal’ depending on your age and sex the name of the game is about reducing it.
When discussing this issue with your doctor it may also be prudent to discuss the causes of a higher homocysteine level and they may want to do some more tests to identify possible genetic factors.
8. Increase Serum B12 to over 500 ng/L
Take vitamin B12 to raise serum levels.
As mentioned above vitamin B12 is essential for optimizing homocysteine levels, but it plays a role in many other pathways, too. It’s required for correct formation of blood cells, contributes to the synthesis of myelin -used to sheath nerve cells- and epithelial membranes as well as being directly involved in the metabolism of fatty acids, carbohydrates and proteins (8).
One of the first manifestations of vitamin B12 deficiency tends be neurological disorders which can often be overlooked as symptoms of B12 deficiency (8), with long term deficiency being linked to dementia. Indeed, the range of neurological conditions associated with a B12 deficiency is quite extensive (9)
Data on deficiency is conflicting, particularly with regards to what constitutes a healthy blood concentration. In the U.S anything less than 200ng/L (nanograms per litre) is considered deficient, but functional deficiencies may be seen around 450ng/L (8) and in Japan anything less than than 500ng/L is considered deficient (10)
Deficiencies can easily occur, with the most common reason being malabsorption due to low stomach acid, lack of intrinsic factor and certain medications. Vegetarians, vegans, people with renal and gastrointestinal diseases are also at risk.
Though a serum level of 500ng/L is a good target to aim for, high serum levels don’t necessarily translate if there are defects in the metabolic pathways that utilize vitamin B12 (8)
A better test for understanding your B12 levels and possible deficiency is a test for methylmalonic acid
“Methylmalonic acid (MMA) is considered a highly sensitive functional indicator for a Vitamin B12 deficiency. MMA is a metabolic product, the breakdown of which requires Vitamin B12. A lack of Vitamin B12 allows MMA levels to increase significantly. This also makes it possible to detect a functional B12 deficiency in which raised MMA levels and clinical symptoms of a B12 deficiency in the form of neurological and/or haematological disorders may occur despite normal serum cobalamin levels. MMA can be measured in both serum and urine. Cases of impaired renal function, however, may also manifest raised MMA, for which reason the creatinine level should also be determined to confirm sufficient renal concentration capacity. The normal range for serum MMA is 50–300 nmol/L. MMA determination is a highly sensitive test that can confirm a diagnosis even in the early stages of a B12 deficiency and is also a suitable indicator for treatment response (B12 substitution). In contrast to determination of the serum cobalamin level, which is only sufficiently sensitive in cases of alimentary B12 deficiency and disturbed enteral absorption of Vitamin B12, determination of MMA also facilitates detection of less frequent dysfunctions in the Vitamin B12 transport path and intracellular synthesis of active adenosylcobalamin. A round-table discussion in 2010 on selection of the biomarkers for determination of B12 status in continued NHANES studies concluded that determination of serum B12 and methylmalonic acid (MMA) should be recommended for further studies.” (8)
9. Reduce C-reactive protein to less than 1mg/L; albumin globulin ratio should be greater than 1.5
“Anti-inflammatory diet; curcumin; DHA/EPA; optimize hygiene “(particularly oral hygiene)
C-reactive protein (CRP) is an inflammatory marker linked to many disease states. Systemic inflammation is also thought to contribute to cognitive decline and Alzheimer’s, possibly through contributing to the onset of type 2 diabetes (T2D) with CRP being a direct predictor of T2D (11).
C-reactive protein in itself isn’t a bad thing but raised levels can denote that there is some ongoing issue with inflammation somewhere in the body.
Periodontal disease has been linked to higher levels of CRP due to low level infection causing chronic inflammation (12) and so a regimen of improved oral hygiene was prescribed to some participants of the study.
Curcumin, a substance derived from turmeric, has been shown to have a number of beneficial effects in the body (13) including
” …lowering of plasma triglyceride values, lowering of salivary amylase levels, raising of salivary radical scavenging capacities, raising of plasma catalase activities, lowering of plasma beta amyloid protein concentrations, lowering of plasma sICAM readings, increased plasma myeloperoxidase without increased c-reactive protein levels…” (14)
Curcumin also boosts special caretaker proteins known as heat shock proteins which have several beneficial and protective properties (15)
Omega 3 fatty acids are also beneficial in several ways and act as anti inflammatory agents. In addition, it’s thought that omega 3 fatty acids are essential for healthy brain function and a number of studies seem to support this idea (16)
Albumin, the most abundant protein in blood plasma, is produced in the liver and is important for transporting many substances around the body. It both delivers nutrients and carries away harmful waste products amongst other things and is considered to be an antioxidant (17, 18) Globulins are produced in the liver and by the immune system. They have a range of functions including fighting invading pathogens.
Albumin tends to be quickly removed when damaged and this could also mean that there are systemic issues causing damage within the body, too much sugar causing damage to proteins through a process known as glycation, for example. It also results in less albumin being available to shuttle important nutrients.
Ratios of albumin to globulin normally fall within 0.8-2.2; low ratios tend are linked with disease states and inflammation (though excessively high ratios can be bad, too) ideally it should be be above 1.5.
In the study, Dr Bredesen made it a point for participants to improve their oral hygiene as there is evidence that periodontal disease is directly linked to several disease states and systemic inflammation, which is a contributary factor in Alzheimer’s and cognitive decline (19). Periodontal disease has also been linked to higher levels of beta amyloid in the brain (20)
Curcumin can be taken as a supplement or simply added to food in the form of turmeric. Evidence suggests that combining it with piperine (found in black pepper) greatly increases its absorption and bioavailability (13)
The conversion of omega 3 to the anti inflammatory EPA and DHA may be blocked by the presence of omega 6 fatty acids (omega 3 and omega 6 use the same conversion pathway). In order to get around this it’s probably better the supplement with EPA and DHA, from a good source, directly.
Improve oral hygiene, via flossing, brushing and more regular visits to the dentist. Have a dentist check for periodontal disease and address as necessary.
9. Lower Fasting Insulin and Hemoglobin A1C Levels
Fasting insulin should ideally be less than 7mIU/L and hemoglobin A1c less than 5.5%. This can be achieved through optimizing the diet.
The relationship between type 2 diabetes and AD is supported by range of studies, (21) with evidence even suggesting that there is a positive reinforcement of the two within the brain as beta amyloid appears to block insulin receptors in the brain leading to insulin resistance (as above).
Insulin resistance, as the name suggests, is when the body becomes resistant to the effects of insulin. This means that cells cannot receive essential nutrients like amino acids, glucose etc.
When cells become resistant to insulin one of the first things the body does is to ramp up the production of insulin resulting in a higher levels in the blood. With cells less responsive to glucose uptake there will be correspondingly high levels of glucose in the blood, too. Having excess glucose in the blood is less than ideal as it can be highly reactive and tends bind with other molecules causing damage and making them less effective. Albumin, for example, is particularly sensitive to glycation – the addition of sugar residues.
A measure of the level glucose in the blood is how much glycated hemoglobin, known as HbA1c, there is.
As already mentioned optimizing the diet and reducing added and simple sugars will go a long way to keeping insulin and therefore HbA1c levels down.
Exercise is also a great way to boost insulin sensitivity, too.
In the next part I’ll cover hormone levels, optimizing gut health, reducing amyloid in the brain and cognitive enhancement with supplements.
If there’s anything here that you would like explained in greater detail please leave a comment and I’ll try to address it.