Neurons and Exercise

Neurons and Exercise

Wednesday, October 17, 2018

APOE-e4 Gene - Nigeria

Excerpt from my book Silica Water the Secret of Healthy Blue Zone Longevity in the Aluminum Age

in this write up

OSA is Orthosilicic Acid which is the  bioavailable form of silica

AD is Alzheimer's 

Blue Zones are Demographic regions of the world where people commonly live active lives past the age of 100 years. The areas of which are Okinawa Japan, Sardinia Italy, Nicoya pennisula Costa Rica, Ikaria Greece and the Seventh-Day Adventist in California



Aluminum and the Risk of AD in People with the APOE-e4 Gene

The APOE-e4 gene increases the concentration of beta-amyloid peptide in the brain and has been linked to a higher risk of AD.  The e4 allele of the APOE gene was introduced into the human population at least 1.5 million years ago280. The reproductive advantage of carrying the e4 allele was to promote human fertility in highly infectious environments in spite of its adverse effects on late onset diseases (i.e. an example of antagonistic pleiotropy)281. Because of this reproductive advantage the e4 allele frequency slowly increased during the last 1.5 million years with currently approximately 14% of the worldwide population carrying the e4 allele280.
Because of improved hygiene and vaccines there is no longer a reproductive advantage to those that carry the e4 allele. In the absence of a reproductive advantage, the e4 allele frequency in the worldwide human population is not predicted to change (e.g. the Hardy-Weinberg principle).
Therefore the recent exponential growth of AD is not due to an exponential increase in e4 allele frequency. Instead the exponential growth of AD is due to a newly introduced environmental chemical that potentiates APOE-e4 making one of its protein products or their derivatives, such as oligomeric beta-amyloid peptide, more neurotoxic. This was proven to be the case by Denise Drago in 2008 when she tested a variety of metal ions (e.g. aluminum, iron, zinc, and copper) and found that only aluminum when bound to the oligomeric beta-amyloid peptide resulted in significantly increased neurotoxicity282.
Aluminum is a causal factor of AD in people with and without the e4 allele of the APOE gene, but in those with this allele there is more oligomeric beta-amyloid for aluminum to toxify. For this reason usually those with the APOE-e4 gene have a higher risk of AD than those without the e4 allele. But what if there is an exception? What if there is an undiscovered Blue Zone on earth where people with the APOE--e4 gene had the same risk of AD as those without the APOE--e4 gene? What if people in this undiscovered Blue Zone drank OSA rich water and ate an OSA rich diet that lowered their aluminum body-burden to the point where they were protected from the APOE-e4 gene?
The Exception – Ibadan, Nigeria an Undiscovered Blue Zone
The exception to APOE-e4 being a casual factor of AD is the Yoruba people of Ibadan, Nigeria who coincidentally have the same e4 allele frequency as people in the U.S.A. From 1992 to 2006 the APOE gene was genotyped in 2,245 elderly Nigerians living in the city of Ibadan who were also clinically diagnosed. Surprisingly, in contrast with other populations, the e4 allele in the Yoruba people was not significantly associated with AD or dementia283.
The Yoruba people living in Ibadan are in general in better health than people living in the U.S.A. Age-matched annual incidence rates of both dementia and AD were found to be 2.4 and 2.2 times lower respectively, in a longitudinal study of a cohort of 2,459 elderly Yoruba people living in Ibadan versus a cohort of 2,147 elderly African-Americans living in Indianapolis, Indiana284.  In addition, these elderly Yoruba people have lower incidence of vascular disease and vascular risk factors including hypertension than does the age matched cohort of elderly in the U.S.A.283.   
OSA in Ibadan’s Drinking Water
Ibadan, Nigeria has a community water system that distributes water from the Eleyele reservoir. Tap water sampled at 11 sites across the distribution system indicated the water contained OSA at 22.4 to 25.6ppm285. This level of OSA in drinking water is approximately the same as average drinking water on mainland Japan (e.g. 26ppm) and more than twice the level of U.S.A. drinking water (e.g. 11ppm).  This more than 2-fold increase of OSA in drinking water is associated with a more than a 10-fold lower rate of death due to AD in Japan versus the U.S.A. (see Table 9).
It is not surprising that both the Yoruba people of Ibadan and Japanese living on mainland Japan both have lower incidence rates of AD than people in the U.S.A., since OSA in drinking water lowers the body-burden of aluminum, a causative factor of AD. It is also not surprising that among the Yoruba people of Ibadan the e4 allele was not significantly associated with AD or dementia, since without a body-burden of aluminum there is no increase in neurotoxicity of oligomeric beta-amyloid. This is the peptide that occurs in higher than normal levels in those people with the APOE-e4 gene.   
OSA in Ibadan’s Food
Nigeria is the leading worldwide producer of cassava with annual production of 45 million metric tons286. Cassava, the most important dietary staple in Nigeria, is a tuber whose skin is very rich in OSA286,287. This makes cassava one of the richest vegetable dietary sources of silicon as OSA (e.g. approximately 270mg of silicon per 100 grams of cassava with skin that is equivalent to 920mg of OSA per 100 grams – see Table 23)286,287.
The cassava root is toxic if not treated properly. Although cassava can be peeled with some difficulty, the tuber is usually cut into pieces with the skin on, dried, and fermented, in order to eliminate toxicity, and finally converted into three main foods by the Yoruba people288.
Gari – granular cassava flour with a ferment flavor and a slightly sour taste is eaten in stews and soups and served with fried fish. Gari is also used as a snack when mixed with milk and sugar.
Fufu – cassava flour mixed into a paste with hot or cold water is ranked next to gari as an indigenous food of the Yoruba people. 
Lafun – fibrous powdery form of cassava that is made into dough with boiling water.
The Yoruba people of Ibadan are a living example of how increased dietary OSA in their drinking water and food can lower the aluminum toxification of the oligomeric beta-amyloid peptide. This is the peptide that occurs in higher than normal levels in those people with the APOE-e4 gene. By following the example of the Yoruba people of Ibadan and increasing dietary OSA by consuming OSA rich drinking water and OSA rich food, the risk of AD is significantly decreased in everyone either with or without the APOE-e4 gene. 

Silica Water Protects Amyloid Beta Regulation

Why are annual incidence rates of both dementia and AD 2.4 and 2.2 times lower respectively in Ibadan, Nigeria than in the U.S.A.? The answer is OSA in the drinking water and food of Ibadan’s inhabitants protects amyloid beta (b-amyloid) regulation in their brains. Amyloid beta is a 36-43 amino acid peptide that is neurotoxic causing inflammation of neurons that can result in cellular death. Excess amyloid beta can also result in plaques in the brain that are a hallmark of Alzheimer’s disease (AD). Due its neurotoxicity amyloid beta is normally regulated in the brain. Amyloid beta regulation involves not producing too much amyloid beta and quickly degrading the amyloid beta that is produced to non-toxic fragments.  Aluminum interferes with both of these processes. Drinking OSA rich water and eating OSA rich vegetables facilitates aluminum excretion, thereby protecting amyloid beta regulation.
Amyloid beta is made enzymatically in the brain by a series of enzymes that cleave off chunks of amyloid precursor protein (APP).  b-secretase 1 (BACE-1) is one of the enzymes involved in making amyloid beta.  Aluminum epigenetically increases expression of b-secretase favoring the production of more amyloid beta289,290.
Oligomers of amyloid beta (dimers, trimers, tetramers, etc.) are neurotoxic. Aluminum complexes of these amyloid beta oligomers are spherical droplets that are even more neurotoxic than amyloid beta oligomers282. Aluminum “freezes” the amyloid beta oligomer by inhibiting its further degradation to smaller fragments291.  The rate-limiting step in the degradation of amyloid beta is catalyzed by the enzyme neprilysin.  Aluminum epigenetically decreases expression of neprilysin that favors more amyloid beta in the brain289,290.
Drinking OSA rich water and eating OSA rich vegetables decreases aluminum in the brain and restores amyloid beta regulation. In addition OSA prevents amyloid beta oligomers from becoming more neurotoxic. Treatment for high levels of amyloid beta in the brain can also be done with aerobic exercise, and sleep.  Aerobic exercise for 30 minutes increases the level of somatostatin in the brain that in turn decreases amyloid beta by increasing the activity of neprilysin1.  Aerobic exercise also increases hippocampal volume292.  In addition, sleep increases somatostatin expression and facilitates the purging of amyloid beta from the brain1,293

281.      Van Exel, E., et al.; Effect of APOE 4 allele on survival and fertility in an adverse environment; PLoS ONE; 12(7):e0179497 (2017)
282.      Drago, D., et al.; Potential pathogenic role of b-amyloid1-42-aluminum complex in Alzheimer’s disease; Int. J. Biochem. Cell Biol.; 40:731-46 (2008)
283.      Gureje, O., et al.; APOE e4 is not associated with Alzheimer’s disease in elderly Nigerians; Ann. Neurol.; Jan.; 59(1):182-185 (2006)
284.      Hendrie, H.C., et al.; Incidence of dementia and Alzheimer’s disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana; JAMA; Feb.; 285(6):739-47 (2001)
285.      Awopetu, M.S., et al.; Water quality in a pipe distribution network: a case study of a communal water distribution network in Ibadan, Nigeria; WTI Transactions on Ecology and the Environment; 171:175-86 (2013)
286.      Adepoju, A.D., et al.; Preparation of silica from cassava periderm; J. Solid Waste Tech. Manag.; 42:216-21 (2016) Cassava peel was hand-sorted for pieces with brown periderm (approximately 5% of the cassava), was ashed at 600oC, and contained 61.5% silicate.
287.      Adebisi, J.A., et al.; Extraction of silica from cassava periderm using modified sol-gel method; Nigerian J. Tech. Dev.; June;15(2):57-65 (2018) TGA of periderm at 600oC results in 30% ash.
288.      Evans, E., et al.; Nigerian indigenous fermented foods: processes and prospects; Mycotoxin and food safety in developing countries; Chapter 7:153-80 (2013)
289.  Luo, Y., et al.; Altered expression of Abeta metabolism-associated molecules from D-galactose/AlCl(3) induced mouse brain; Mech. Ageing Dev. Apr.; 130(4):248-52 (2008)
290.  Sun, Z.Z., et al.; Alteration of Aβ metabolism-related molecules in predementia induced by AlCl3 and D-galactose; Age; 31:277-284 (2009)
291.  Drago, D.; Aluminum modulates effects of beta-amyloid1-42 on neuronal calcium homeostasis and mitochondrial functioning and is altered in a triple transgenic mouse model of Alzheimer’s disease; Rejuvenation Reas.; 11(5):861-871 (2008)
292.  Erickson, K. I., Exercise training increases size of hippocampus and improves memory; PNAS; 108(7):3017-22 (2011)