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 Aβ oligomers and Aβ 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 Aβ 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 Aβ 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 Aβ peptides, a good percentage of people have lived
with these high levels of Aβ peptides for thousands
of years and not gotten AD. Therefore excessive levels of these Aβ 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 Aβ 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 Aβ plaque?
Is AD caused by high levels of Aβ 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 Aβ oligomers (e.g. clusters
of soluble Aβ peptides) are converted
in the brain to insoluble Aβ plaque16. Metals, such as aluminum, facilitate the
conversion of Aβ peptides to Aβ oligomers and then to Aβ 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”
