[Rhonda]: Maybe we can start a little bit by just talking about some of the characteristics
and pathological distinguishing features of Alzheimer's disease and maybe what your thoughts
are on what can cause Alzheimer's disease or leads to it.
[Dale]: Right, so it's a good point because cognitive decline, very common, and Alzheimer's
is the most common cause of cognitive decline, ultimately dementia.
And by definition, this means that you have amyloid plaques in the brain and phosphorylated
tau tangles.
So those are the two main pathological hallmarks of Alzheimer's.
But as you can see, that doesn't tell you why you got it, it just is something you look
at the brain, and of course, you can get something that looks virtually identical without the
amyloid and you can get amyloid without the cognitive decline.
So, it's a marker but it's an imperfect one.
[Rhonda]: Yeah, that's a really good point you brought up.
And do you have any thoughts on why there are some people that do have amyloid plaques
in their brain that aren't demented and then some others that just don't seem to handle
it?
[Dale]: Yeah, it's a great point.
So, here's the thing, the whole world is turning upside down now when it comes to our understanding
of Alzheimer's.
It's been over 100 years, of course, going back to Alois Alzheimer's publications back
in 1906 and 1907, and there hasn't been a good understanding of this disease.
And of course, amyloid has been for years vilified and there's no question, it is a
neurotoxin.
It does have toxic effects.
The surprise has been that this is also a protectant.
It's actually something that is made by your brain when you have specific insults.
And for example, Professor Rudy Tanzi and Professor Robert Moir of Harvard a few years
ago showed that it is an antimicrobial.
It also, as Professor Ashley Bush showed a number of years ago, it's actually quite a
good binder of divalent metals like copper and zinc, and things like that, iron.
And we showed a number of years ago, it is also a response to a reduction in trophic
support, so you actually get a change in signaling.
So, there are multiple different insults and metabolic changes that lead the brain to produce
this stuff.
And so I think there's been confusion because it's clear that when you produce it you're
at this increased risk for having a degenerative process, but as you indicated, there are many
people that produce it and they successfully are protecting themselves, they don't actually
have the downsizing.
What's often been stated is those who then have inflammation on top of that seem to be
the ones that do worse, and that's a very general idea, but really it is a set of things.
And we identified and published, a number of years ago, 36 different factors that all
contribute to this, but they actually break down into just a couple of categories.
So, any sort of pathogens, anything that's giving you inflammation, whether you have
it because you have a leaky gut or because you have P. gingivalis in your brain, or because
you have Borrelia of Lyme disease, or you've been exposed to specific fungi, things like
that, all of these things can engender that response.
And in fact, we think more and more of amyloid as being like napalm.
You got the bad guys coming across the border, so you're now going to put down stuff that
kills the bad guys, the napalm but in so doing you're now going to reduce your arable soil.
You're now living in a smaller country, and that's exactly what's going on in the brain,
you are downsizing the overall network.
So, that's what we call type 1 or inflammatory or hot Alzheimer's.
And I should mention, it turns out ayurvedic physicians from thousands of years ago who
recognized dementia that was related to something that was hot, that was abnormal and ultimately
inflammatory, as well as that was related to dryness, which is what we call type 2,
where you have decreased trophic support.
It can be nerve growth factor, brain-derived neurotrophic factor, estradiol, testosterone,
pregnenolone, progesterone, thyroid, vitamin D, all of these things are critical to support
of synaptogenesis.
So we think of the signaling as being a ratio of synaptoblastic activity where you're actually
sending signals to make and store synapses (just like you think of osteoblastic activity)
versus synaptoclastic activity where you're actively pulling back and you're reorganizing.
And of course, this is going on all the time.
You're actively forgetting the seventh song that played on the radio on the way to work
yesterday and you're actively forgetting a lot but you're remembering the key things,
like where your keys are and where your son is and all that sort of stuff.
And so, there is a change in that ratio in Alzheimer's disease because of type 1 with
inflammation or type 2, which we call atrophic or cold, because you don't have the support
for those synapses, so you're literally...it's a little bit like someone saying, "I've got
five children and I can only feed four.
I can either watch all five starve slowly or I can put one in a foster home and feed
four," and that's basically the downsizing that's happening when you cannot support the
neural network that you have.
And then we have a type that's actually type 1.5, which is glycotoxic.
And we named it that because it has features of both type 1, inflammatory, and type 2,
atrophic.
So what happens is you develop insulin resistance, so you now have a change in signaling that
actually occurs because of this chronic high insulin.
So you actually phosphorylate your IRS-1, as shown very nicely by Professor Ed Goetzl
over at UCSF.
So you change the ratio of the serine/threonine phosphorylation to the tyrosine phosphorylation
and you're literally changing your response to insulin, so that gives you the type 2 because
you no longer have insulin as the supportive trophic factor to the extent it was previously.
But of course, you're also glycating proteins with...and we measure this, of course, as
hemoglobin A1C.
But you're glycating many proteins, so you get now a response to that as well.
So you have an inflammation in an atrophic and so that's why it's 1.5.
And then type 3 turns out to be completely different, and that is a response to toxins.
So there is a toxic form, which we call toxic or vile Alzheimer's disease.
In addition, there are people we called type 4 who have more of a vascular component and
then type 5, which is more of a traumatic component, but they're really both related
to these other ones.
It's really about, do you have inflammation?
Are you fighting something off?
Do you have trophic support, and are you exposed to specific toxins?