In part one I took a look at diet, stress, sleep, exercise and autophagy. In part two I looked at brain stimulation, optimizing homocysteine levels, C-reactive protein, albumin-globulin ratios, serum vitamin B12 levels, fasting insulin and hemoglobin A1C.
Here I’ll be tackling optimizing hormone levels, gut health and ways to reduce beta-amyloid in the brain finishing up with a look at cognitive enhancement.
Each one of these points could easily fill a sizable volume and so the idea here is to give some explanation of the rationale behind each intervention above and beyond the limited information provided in the original paper by Dr Bredesen.
Again, if you have any questions or suggestions please leave a comment below and I’ll try to address it.
10. Optimize Hormone Balance
Optimize free thyroxine (FT4) and free triiodothyrocine (FT3), estradiol, testosterone, progesterone, pregnenolone, cortisol
Thyroxine (T4) and triiodothyronine (T3), the added F denoted above tells us that it is free, are hormones secreted by the thyroid gland.
They are involved in almost every metabolic process in the body; from body temperature, to metabolic rate, growth, protein production, heart rate etc.
A number of studies have shown that hypothyroidism (too little T3 and T4 is produced) and hyperthyroidism (too much is produced) are both linked to Alzheimer’s disease
“Proposed mechanisms to explain the observed association between thyroid dysfunction and AD risk have included a direct adverse effect of thyroxine depletion on cholinergic neurons, adverse effects of excessive levels of thyroid hormone, and vascular-mediated mechanisms. The important role played by the thyroid hormone in the development and maintenance of the basal forebrain cholinergic neurons involved in AD has been demonstrated in animal studies. Several in vitro and in vivo studies have also shown that thyroid hormone regulates the gene expression of amyloid precursor protein (APP); in neuroblastoma cells, triiodothyronine (T3) has been demonstrated to repress APP promoter activity and regulate APP processing and secretion. An in vivo study found that a hypothyroid state enhanced the expression of APP gene product in mouse brains. These findings suggest that low CNS -central nervous system- thyroid hormone levels may contribute to the development of AD by directly increasing APP expression and consequently, Aβ peptide and β-amyloid levels. Indeed, a small case control study showed increased rT3 levels and an increased rT3 to rT4 ratio in the CSF of AD patients, suggesting the presence of abnormal intracerebral thyroid hormone metabolism and brain hypothyroidism.” (1)
Aside from the possible contribution to cognitive decline and Alzheimer’s, having an under or over active thyroid or other issues with your thyroid can lead to several disease states.
Estradiol and Progesterone
There is a clear link between estrogen decline following menopause and increased risk of developing Alzheimer’s. The estrogen estradiol, often referred to as E2, is thought to play a critical role in memory formation, neuron protection and the prevention of beta amyloid build-up through a number of mechanisms (2, 3)
The idea of supplementing the missing hormones, however, hit a snag with the results from the Women’s Health Initiative study, a study of more than 160,000 women. Around 27,000 postmenopausal women, aged 50-79 at enrollment, went on to receive either conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) or just CEE alone as part of the Women’s Health Initiative Memory Study (WHIMS) (4). The results were disheartening, to say the least, showing an increased risk of heart disease, stroke, pulmonary embolism, and breast cancer in the CEE+MPA trial and increased stroke risk and no benefit for heart disease in the CEE-only trial. What’s more both arms also showed an increased risk of Alzheimer’s (5)
The results were disappointing, to say the least, and the study was drawn to a close early due to increased risk of heart disease, stroke, pulmonary embolism, and breast cancer in the CEE plus MPA trial and an increased risk of stroke and no benefit in terms of heart disease. Most worryingly there was a significant increased risk of Alzheimer’s in the CEE plus MPA trial and a slight increase in risk for the CEE alone (6).
In recent years, however, the findings of the study have been questioned, not least because the outcome of the trials stand in stark contrast to numerous studies that show clear benefits of E2. Issues were raised about a number of aspects of hormone therapy, the method of administration; oral, transdermal or vaginal, the formulation; CEE vs E2 and whether treatment should provide a continuous dose or be cyclic to mirror the natural hormone cycle (7, 3).
Another important aspect is the timing of the therapy. Many of the women in the WHIMS study began treatment years after menopause which most likely contributed to the negative effects seen. Two more recent studies, the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Vs Late Intervention Trial with Estradiol (ELITE) study (Medpage article) suggest that early intervention may be more beneficial.
Just as estrogens are neuroprotective in women so, too, are androgens in men. The idea that testosterone naturally declines with age is widespread even amongst scientists, but this isn’t necessarily true (8, 9). Decreases in testosterone are most likely caused by a number of factors that accrue with age.
Androgens promote neural growth and regeneration, synaptic function, protect against neuron loss and help to regulate beta-amyloid accumulation (3)
Produced from cholesterol, pregnenolone is the precursor for many other hormones, including progesterone, testosterone, estrogen, aldosterone, cortisone etc.
As a key ingredient for neurosteroid synthesis low levels could play a role in neurodegenerative diseases (10)
Cortisol is a hormone produced by the body in response to stress. As with many substances in the body the chemistry can be immensely complicated and the full relationship between cortisol and Alzheimer’s has yet to be resolved, however,
“Cortisol plasma concentration was found to be increased in AD; nevertheless, the role of cortisol in the pathogenesis of AD remains the subject of controversy. In AD subjects who had higher cortisol levels in the early stage of the disease, an accelerated progression of the disease was observed. Hypercortisolemia in AD appears to be related to the clinical progression of the disease, but not to aging or length of survival. It was confirmed that higher levels of cortisol are not associated with cognitive decline in older persons over a period of 6 years. However, elevated basal cortisol level predicted lower hippocampal volume and cognitive decline in Alzheimer’s disease over a 2-year follow-up period. Cortisol levels in AD patients seem to be of prognostic relevance; the most severely demented patients had the highest cortisol concentrations, and increased cortisol plasma levels have been associated with more rapid disease progression in AD subjects. However, a large prospective study did not confirm the relation between serum levels of cortisol and the risk of developing dementia or AD, which suggests that morning serum cortisol is not a causal factor in the development of dementia. It was concluded that dysregulation of the HPA axis in AD seems to be a consequence rather than a cause of AD; this was supported by observation that improvement of cognitive function was associated with decreased saliva cortisol. Nevertheless, significantly increased cortisol was included in a biomarker panel for diagnosis of AD.” (11)
Nevertheless, chronically elevated cortisol levels can have profound negative effects on the body making an investigation prudent to check levels.
The primary recommendation here would be to consult with a capable endocrinologist.
There are a number of dietary and lifestyle factors that can affect the thyroid, iodine and selenium, for example, but making guesses about what you should or shouldn’t eat are pointless without knowing if you have any thyroid issues.
With that in mind having a doctor run a full thyroid function panel will help to reveal any issues you may have, the doctor can then suggest treatment as appropriate.
Estradiol and progesterone
In regards to hormone replacement therapy for women, many women and doctors were put off by the results of the WHIMS study, as detailed above, but more recent studies have helped to allay some of that fear. The decision to begin hormone replacement therapy involves a number of factors, a more detailed explanation is really beyond the scope of this piece but a review published in December 2014 in the journal The Obstetrician & Gynaecologist details the latest evidence on using hormone replacement therapy following menopause. The review can be read here (12)
Again, consulting a doctor would be a prudent course of action to check your testosterone levels.
Improving diet and getting exercise can aid here as testosterone decline so often linked to ‘aging’ is most likely the result of factors and has been linked to obesity, metabolic syndrome, insulin resistance, type 2 diabetes etc (8, 13, 9)
Getting enough sleep, exercise, reducing stress and eating a nutritious diet can all help control cortisol levels.
11. Optimize Gut Health
Repair any damage if necessary with prebiotics and probiotics
Perhaps only in the last few years have scientists come to realise the importance the gut plays in overall health and the direct effect it has on the functioning and well being of the brain. This combined with improved technology has led to a boom in research looking at the human microbiome and the role it plays in health and disease.
There are multiple benefits of having a healthy gut with a healthy and diverse microbiome. They digest substances we can’t and excrete nutrients that are beneficial to our health, some can also produce B and K vitamins, they compete and hopefully outcompete pathogenic bacteria that find their way into the gut, they can metabolize and destroy potential carcinogens and even play a role in shaping our immune system and immune responses.
Particularly of interest here is the fact that some bacteria can produce molecules that either directly benefit the brain whilst other species may produce neurotoxic compounds. Taking prebiotics – substances that feed beneficial bacteria, or probiotics – beneficial bacteria themselves are thought to help improve the gut, health overall and the brain.
Other aspects of gut health and the microbiome are also relevant, too in terms of controlling and preventing excessive or chronic inflammation and autoimmunity issues which can arise from poor gut health.
Recommendations here are pretty difficult as we are really still unsure of just what exactly makes up a healthy microbiome and so taking prebiotics and probiotics is a subject fraught with many unknowns and large assumptions.
Having said that, eating a wide variety of plant foods including a range of fermented foods is generally thought to be a sound idea for improving general gut health.
One particularly interesting substance is resistant starch that can be sourced from a number of foods particularly potatoes.
For more information on this topic you can read a paper entitled The Gastrointestinal Tract Microbiome and Potential Link to Alzheimer’s Disease here which also links to many other review papers looking at various related aspects.
12. Reduce Beta-amyloid
Take curcumin and ashwagandha
Curcumin, isolated from the plant curcumina longa, which goes by the more commonly known name of turmeric, is thought to be neuroprotective as it activates a number of special proteins within cells known as heat shock proteins.
Heat shock proteins (HSP) perform a number of essential functions within cells primarily helping proteins to fold correctly, refold slightly misfolded proteins, prevent proteins from accumulating and clustering and help to transport severely damaged proteins to be degraded(14).
Ashwaghanda, has been used in ayurvedic practices for the treatment of a range of conditions, but has recently garnered the interest of a number of research groups due to some very interesting properties.
With regards to Alzheimer’s and dementia it seems to upregulate a protein called low-density lipoprotein receptor-related protein which helps to remove beta-amyloid from the brains of Alzheimer’s model mice (15, 16).
Curcumin seems to be stable within the brain but is rapidly metabolised and excreted in the blood. It is also poorly absorbed, though relatively large amounts of up 12g a day seem to be well tolerated, but substances like piperine, found in black pepper can help increase bioavailability as too can the presence of fat during ingestion. (14)
Ashwaghanda has traditionally been used for the treatment of many ailments and along with possible benefits for Alzheimer’s it also seems to have a positive impact on cortisol, anxiety, stress. The root extract appears to be non-toxic and is well tolerated.
13. Cognitive Enhancement
Take bacopa monniera, magnesium threonate
One of the sources cited in the original paper has since been retracted, citing the following reason
“This article described the effects of elevating brain magnesium on preventing and reversing cognitive deficits in an Alzheimer’s disease mouse model. During recent efforts to extend this work, we discovered errors in the quantification of the expression and/or phosphorylation of a subset of signaling pathways, particularly related to Figures 4 and 5D. Despite these errors, the major conclusions of the paper remain substantiated. As any correction will require substantial rewriting of the manuscript, we ask to withdraw the article. A corrected treatment will be published in the future. We apologize for any confusion caused by this error.” (15)
Despite this there is still is still a wealth of data to suggest that magnesium is beneficial not only for the brain but for several other health markers. Specifically, magnesium threonate seems to be particularly beneficial when it comes to cognitive function and possible neuroprotection.
Looking at just the benefits in terms of the brain, magnesium helps to prevent over excitation of neurons by temporarily and reversibly blocking a key receptor in the brain known as the NMDA receptor (16). Low levels of magnesium have been linked to over excitation and more frequent random firing of neurons. Increased levels of magnesium in the brain also boost long term potentiation (see video below)(17)
Magnesium threonate was used in the study as it has a very high bioavailability, meaning that it is readily absorbed though it should be possible to achieve the same effect using other forms of magnesium such as magnesium citrate or magnesium gluconate (17)
The source referenced in the paper looked at a commercial supplement that comprised a mix of different ingredients and so while the study found the supplement to have positive effects in terms of memory it isn’t possible to, from the source alone, to ascribe benefits from bacopa monnieri alone.
However, Bacopa monnieri, like ashwaghanda, has been used in ayurvedic practices and has also received a lot of attention in terms of research. There have been many studies looking at the effects of bacopa monnieri, mainly in animal models, but the results are still intriguing as are the results from the limited number of human clinical trials.
Bacopa may also be neuroprotective in that it seems to ameliorate or lessen the effects of known neurotoxins in animal models and whilst the mechanism has yet to worked out it seems to involve the boosting cellular protective mechanisms, upregulating endogenous antioxidants like superoxide dismutase and glutathione.
Bacopa seems to boost memory by increasing levels of tryptophan hydroxylase and the expression of the serotonin receptor and by increasing levels of a vital molecule for memory formation; acetylcholine, by affecting the enzymes responsible for its synthesis and degradation.
In the limited number of human clinical trials it produced positive results in terms of enhancing memory.
There are numerous studies looking at Bacopa monnieri, many of which are covered in a fairly readable open access review entitled Neuropharmacological Review of the Nootropic Herb Bacopa monnieri
Magnesium threonate was used due to its high bioavailability i.e. it was readily absorbed. Other forms of magnesium should be just as effective, though, if taken regularly. A common form used in supplements is magnesium oxide, but this tends to have low bioavailability and can cause diarrhea in some. Magnesium citrate, magnesium glycinate and magnesium aspartate have better absorption rates with magnesium gluconate (hard to find in supplement form) perhaps being comparable to magnesium threonate.
Of course you can always obtain magnesium from dietary sources. Dark leafy greens like spinach contain magnesium, as do nuts and many other foods. For a list click here, though it may be difficult for some to eat enough foods to get adequate amounts and so supplementing may help.
The typical dose used of bacopa monnieri is 300mg per day, it can cause upset stomach in some and is best taken with other food, though some studies have seen benefits with doses as low as 125mg (18). It also seems to take time to work with better results reported after 12 weeks compared to 4 weeks.