Neurons and Exercise

Neurons and Exercise

Monday, September 5, 2016

Chapter 1 Part 2 Is there a genetic defect that could be responsible for AD ?

Is there a genetic defect that could be responsible for AD?  Yes Watson, there are two types of AD: familial and sporadic. Familial AD is believed to have a genetic link but accounts for only 1-2% of AD cases9.  Sporadic AD accounts for the remaining 98-99% of AD cases and after extensive searching only the apoE4 gene has been found to increase the risk for sporadic AD9.  Carriers of the apoE4 gene, about 20% of the population, have a 60% chance over age 80 of having AD versus a 10% overall risk of AD over age 80 in the general population.  Therefore the difference in risk for AD between carriers and non-carriers of this gene is 50%. In 2002 there were 9 million people in the U.S. who were 80 years of age or older10.  A 50% chance of AD in the 20% of those over 80 with the apoE4 gene corresponds to 10% of 9 million people or 0.9 million cases of AD.  There were 2.7 million AD cases in the U.S. in 200211.  This means approximately 1/3 (33%) of the sporadic AD cases in the U.S. could be due to genetics involving the apoE4 gene. 
Carriers of the apoE4 gene are more vulnerable to AD because they have higher than normal levels of Aβ peptides that can result in higher levels of oligomers and plaques. ApoE proteins are chaperones that complex with Aβ peptides and facilitate there transfer across the blood-brain-barrier and out the brain.  Carriers of the apoE4 gene may be more vulnerable to AD because they produce an Aβ peptide chaperone molecule apolipoprotein E4 (apoE4).  This chaperone works with a slow receptor that slows peptide clearance from the brain12.  Also carriers of the apoE4 gene produce have less apoE protein in their serum and this also slows Aβ peptide clearance from the brain9. Therefore carriers of the apoE4 gene have higher than normal levels of Aβ peptides in their brains that can result in higher levels of oligomers and plaques in their brains.
Is there any other indication that AD is caused by a genetic defect? In 1987 L.E. Nee, et al. reported a clinical and family study of 22 twin pairs in which one or both twins had AD.    In approximately 40% of the cases, AD affects both twins showing that about 40% of cases in the U.S. could be due to genetics (i.e. the apoE4 gene) 13.  Within experimental errors this 40% agrees with the 33% derived from the math based upon the frequency of the apoE4 gene in the U.S. population. 
So as you can see Watson with the data agreeing from a risk analysis and a study of twin pairs we can conclude that greater than 50% of AD is not related to genetics and more than likely caused by environmental factors.  But before turning our back on genetics, could it be possible there is a gene other than the apoe4 gene responsible for AD? 
Could any dominant gene or genes spread through the population and cause a modern disease? If a dominant gene is inherited from either parent it is always expressed in that parent’s children. For a recessive gene to be passed on, both parents must have it, so dominant genes spread more quickly through a population than recessive genes.    
As we now know Watson, Alzheimer’s disease is a modern disease first observed 110 years ago in a person 56 years old at the time of death. Since Alzheimer’s is a modern disease, a mutation, such as the apoE4 gene, that could cause Alzheimer’s would have had to occur approximately 180 years ago. A human generation lasted, on average, 30 years during the last 200 years14.  A period of 180 years corresponds to 6 generations.  But how many generations did this gene have to spread through the population by the time people were born who are currently over 80 years old? The 9 million people in the U.S. over 80 were born after approximately 3 of those 6 generations.  Therefore the gene carrying the mutation would have had only 3 generations to spread through the population before those people currently over 80 were born.
Watson asked: “How many people can potentially carry a dominant gene three generations after the single mutation that created the gene?” Holmes answered: “If there was a single mutant and every one of the three succeeding generations had both a dominant gene and eight children, there would be only 512 carriers of the gene worldwide after three generations.  As already mentioned there are 9 million people over age 80 in the U.S. and 20% (1.8 million) of them are carriers of the apo4 gene. The calculated 512 carriers are not even close to the estimated 1.8 million carriers of this gene in the U.S. population over age 80.  So a mutation 180 years ago of the apo4 gene, or for that matter any gene, could not be the cause of AD”. 
At this point Holmes turned and noticed that Watson was madly calculating 8 x 8 x 8 = 512 on a sheet of scratch paper and looking confused.  Watson looked up and asked: “So can a modern disease as common as AD be due to a recent mutation?”  Holmes replied: “No, it takes thousands of years to spread even a dominant mutation to a significant percentage of the population”.
Since AD is a modern disease and not an ancient disease we now know three important facts from which we can draw a conclusion:
·         Because of its prevalence the apoE4 gene as it exists today is an ancient gene not a modern gene
·         Twenty percent of humans who have the apoE4gene have been living with higher than normal levels of Aβ peptides in their brains for thousands of years and did not get AD.
·         Only one third of those with AD in the U.S. have the apoE4 gene.
This is the first crux of the case Watson! Because the apoE4 gene is ancient it alone can’t be the cause of a modern disease like AD. Since the apoE4 gene causes higher than normal levels of peptides, a good percentage of people have lived with these high levels of peptides for thousands of years and not gotten AD. Therefore excessive levels of these peptides can’t cause a modern disease like AD.  

Watson looked startled and said: “Amazing Holmes this proves that AD is not caused by the ancient apoE4 gene or a recent genetic mutation or even higher than normal levels of peptides in the brain. So if not genetics and Aβ peptides, then what is the cause of AD?”  

 Is AD caused by high levels of plaque?
Watson noted: “Aβ plaque is a hallmark of AD and it is found in higher than normal levels in the brain of the case of strange death.  This puts Aβ plaque on the list of suspects. But is there any evidence that Aβ plaque is harmful to the brain?” Holmes replied: “No, AD-related neuron loss and dementia are mediated by Aβ oligomers, not Aβ plaque536.  This is because Aβ oligomers inhibit neuronal viability ten times more that Aβ plaque and forty times more than Aβ peptides15.  Soluble oligomers (e.g. clusters of soluble peptides) are converted in the brain to insoluble plaque16.  Metals, such as aluminum, facilitate the conversion of peptides to oligomers and then to plaque16,17.   Aβ oligomers have been isolated from the cerebral cortex and cerebrospinal fluid in concentrations six times higher than normal in the brains of AD patients18”. 
Watson then suggested: “Since these findings suggest that Aβ oligomers rather than Aβ plaque might be a cause of AD, we should add Aβ oligomers to our list of suspects. After all it would appear that Aβ oligomers had to be present in order to make Aβ plaque observed in the brain of the case of strange death.” 
Holmes replied: “Excellent deduction Watson, our new list of suspects now includes:
·         NFTs
·         Aβ oligomers
·         Aluminum”