More Case Against Amyloid Hypothesis

[Mark Thorson]

It is a fact that beta amyloid is heavily involved
in causing Alzheimer's. This was proven beyond a
shadow of a doubt when the Nature article was
published in 2012 showing that a single mutation
which reduced beta amyloid production by
approximately 40% greatly reduced the incidence of
Alzheimer's. If beta amyloid was in fact protective,
then this mutation should have resulted in more
Alzheimer's, not less. Some beta amyloid is essential
for normal brain functioning, but too much causes
Alzheimer's.

The article is here:

http://extremelongevity.net/wp-content/uploads/app.pdf

This study concerns an allele of the gene for the
amyloid precursor protein (APP) which has a protective
effect against diagnosis with AD.

It does appear to be true that APP has an important
role in the pathology that leads to clinical diagnosis
with AD. There are APP mutations which increase the
risk of diagnosis with AD, so that was known before
this study. But that does not mean that amyloid beta
_causes_ AD.

It's like airbags. Airbags in cars reduce the risk
of dying in a collision. Does this mean that airbags
reduce the risk of having a collision? Of course not.
Airbags mitigate the consequences of a collision, but
they have absolutely nothing to do with the risk of
having a collision. Lack of airbags or defective
airbags do not cause collisions between cars.

The A673T allele which is the focus of this study
does more than reduce the risk of being diagnosed
with AD, which is a late event in the course of AD.
The disease process which leads to a diagnosis of AD
is believed to begin decades before diagnosis with AD.
As shown in Figure 1 of this paper, the A673T allele
also exerts a protective influence against the decline
in cognition which occurs naturally in people who
do not have AD.

It also has a powerful effect on non-cognitive aspects
of health. This study estimated that having the A673T
allele increases the chance of living to age 85 by
a factor of 1.47. That's a huge increase! Something
more than protecting the brain is going on here.

If amyloid beta causes AD and this allele was
protective against the initial events that cause AD,
the effect would be much more specific to preventing
diagnosis of AD. But it's not. It has protective
effects on both non-AD age-related cognitive decline
and lifespan in general.

A recent trend toward understanding the cause of AD
focusses on pathology of the small blood vessels
in the brain. If this is an important stage in the
etiology of AD, and if the A673T allele protects
against microvascular pathology, that would explain
its protective effect against AD, normal age-related
cognitive decline, and other disease processes (such
as cardiovascular disease) that have nothing to do
with the brain or cognition. Even if microvascular
pathology is not the cause of AD, the A673T allele
is doing something which has a profound effect on
lifespan without regard to its effect on the risk
of being diagnosed with AD.

Amyloid beta is certainly not a bystander to the AD
disease process. I think soluble amyloid beta may be
the cause of the progression from mild to moderate AD.
There seems to be an important stage transition here,
because the anti-AD drug memantine is effective in
moderate to severe AD, but despite efforts to show an
improvement in mild AD, it has none. This suggests
there are two disease mechanisms, one which causes
the initial development of mild AD (which is
insensitive to memantine) and another which causes
the advancement to moderate and severe AD (which are
sensitive to memantine).

But the notion that amyloid beta causes the initial
events in AD is neither proven nor suggested by this
study.

[Ed Friedman]

Mark,

You are ignoring one key conclusion of the study:
"Furthermore, the fact that the A673T substitution also protects against
cognitive decline in the elderly without Alzheimer’s disease provides
indirect support for the hypothesis that the pathogenesis of Alzheimer’s
disease and normal cognitive decline of the elderly may be shared, at
least in part."

Basically, they are saying that there is nothing unique about
Alzheimer's, but rather that is the logical end of what starts out as
cognitive decline. Furthermore, there is no evidence that APP has any
biological role other than being a precursor to the amyloids, so it is
inconceivable that the improved memory is due to anything other than
less beta amyloid.

The correlation between lack of cognitive decline and longer lifespan is
well known. E.g., check out this article titled "Familial Longevity Is
Marked by Better Cognitive Performance at Middle Age: The Leiden
Longevity Study" at:
www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057962

Ed Friedman

Post by Mark Thorson

It is a fact that beta amyloid is heavily involved
in causing Alzheimer's. This was proven beyond a
shadow of a doubt when the Nature article was
published in 2012 showing that a single mutation
which reduced beta amyloid production by
approximately 40% greatly reduced the incidence of
Alzheimer's. If beta amyloid was in fact protective,
then this mutation should have resulted in more
Alzheimer's, not less. Some beta amyloid is essential
for normal brain functioning, but too much causes
Alzheimer's.

http://extremelongevity.net/wp-content/uploads/app.pdf
This study concerns an allele of the gene for the
amyloid precursor protein (APP) which has a protective
effect against diagnosis with AD.
It does appear to be true that APP has an important
role in the pathology that leads to clinical diagnosis
with AD. There are APP mutations which increase the
risk of diagnosis with AD, so that was known before
this study. But that does not mean that amyloid beta
_causes_ AD.
It's like airbags. Airbags in cars reduce the risk
of dying in a collision. Does this mean that airbags
reduce the risk of having a collision? Of course not.
Airbags mitigate the consequences of a collision, but
they have absolutely nothing to do with the risk of
having a collision. Lack of airbags or defective
airbags do not cause collisions between cars.
The A673T allele which is the focus of this study
does more than reduce the risk of being diagnosed
with AD, which is a late event in the course of AD.
The disease process which leads to a diagnosis of AD
is believed to begin decades before diagnosis with AD.
As shown in Figure 1 of this paper, the A673T allele
also exerts a protective influence against the decline
in cognition which occurs naturally in people who
do not have AD.
It also has a powerful effect on non-cognitive aspects
of health. This study estimated that having the A673T
allele increases the chance of living to age 85 by
a factor of 1.47. That's a huge increase! Something
more than protecting the brain is going on here.
If amyloid beta causes AD and this allele was
protective against the initial events that cause AD,
the effect would be much more specific to preventing
diagnosis of AD. But it's not. It has protective
effects on both non-AD age-related cognitive decline
and lifespan in general.
A recent trend toward understanding the cause of AD
focusses on pathology of the small blood vessels
in the brain. If this is an important stage in the
etiology of AD, and if the A673T allele protects
against microvascular pathology, that would explain
its protective effect against AD, normal age-related
cognitive decline, and other disease processes (such
as cardiovascular disease) that have nothing to do
with the brain or cognition. Even if microvascular
pathology is not the cause of AD, the A673T allele
is doing something which has a profound effect on
lifespan without regard to its effect on the risk
of being diagnosed with AD.
Amyloid beta is certainly not a bystander to the AD
disease process. I think soluble amyloid beta may be
the cause of the progression from mild to moderate AD.
There seems to be an important stage transition here,
because the anti-AD drug memantine is effective in
moderate to severe AD, but despite efforts to show an
improvement in mild AD, it has none. This suggests
there are two disease mechanisms, one which causes
the initial development of mild AD (which is
insensitive to memantine) and another which causes
the advancement to moderate and severe AD (which are
sensitive to memantine).
But the notion that amyloid beta causes the initial
events in AD is neither proven nor suggested by this
study.

[Mark Thorson]

Post by Ed Friedman
"Furthermore, the fact that the A673T substitution also protects against
cognitive decline in the elderly without Alzheimer’s disease provides
indirect support for the hypothesis that the pathogenesis of Alzheimer’s
disease and normal cognitive decline of the elderly may be shared, at
least in part."

That's a pretty weak speculation without saying
how much or how significant. I don't think it's
in doubt that AD is a disease process distinct from
normal aging, though as they say there may be some
shared mechanisms. However, this does not speak
toward causation. Once AD takes off, it ravages
the brain. You don't see that in normal aging.

Post by Ed Friedman
Basically, they are saying that there is nothing unique about
Alzheimer's, but rather that is the logical end of what starts out as
cognitive decline. Furthermore, there is no evidence that APP has any
biological role other than being a precursor to the amyloids, so it is
inconceivable that the improved memory is due to anything other than
less beta amyloid.

Amyloid beta is less than 50 bases long, but
the parent APP molecule is hundreds of bases
long. APP obviously has other functions,
even if we don't know what they are.

Also, there are non-demented people who die
with amyloid deposits comparable to people
with AD. If it was a simple a relation as
amyloid beta = poor memory, this would never
happen. Also, the correlation between amyloid
deposits and clinical symptoms is poor, as
compared to the correlation between
neurofibrillary tangles and symptoms which
is a good correlation.

Post by Ed Friedman
The correlation between lack of cognitive decline and longer lifespan is
well known. E.g., check out this article titled "Familial Longevity Is
Marked by Better Cognitive Performance at Middle Age: The Leiden
www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057962

This study does not show a correlation between
lack of cognitive decline and longer lifespan.
It shows a correlation between having parents
that had a long lifespan and higher cognitive
performance. We don't know anything about
how long the subjects of this study will live.

Also, the subjects of this study had an average
age of about 66. The subjects of the A673T
study were much older, with an age range of
80 to 100. At 66, the effects of lifestyle
choices such as smoking will be much stronger,
because many of those people will not survive
to 80. The correlation may be due to these
lifestyle choices, which may indeed be
influenced by parents.

It would be surprising indeed if they have the
profound benefit in lifespan provided by the
A673T allele. That allele has a strong benefit
in preventing AD, preventing non-AD cognitive
decline, and prolonging lifespan. It is doing
something that is beneficial to health in
general and not necessarily specific to AD.

Interesting that they report a difference in
vascular pathology. That may explain their
other findings -- better vascular health may
contribute to both better cognitive preformance
and longer lifespan. It could be that these
children of long-lived parents come from
families that are more athletic. If true,
that's a lifestyle choice which has nothing
to do with amyloid beta and points toward
other causes for cognitive decline.

[Michael]

Post by Mark Thorson

It is a fact that beta amyloid is heavily involved
in causing Alzheimer's. This was proven beyond a
shadow of a doubt when the Nature article was
published in 2012 showing that a single mutation
which reduced beta amyloid production by
approximately 40% greatly reduced the incidence of
I caution you against the 'reduced', I would suggest 'contrasted'. Reducing is comparable to curing and co-existing factors though often telling in medical discoveries, should not be looked upon as definitive causes.
Alzheimer's. If beta amyloid was in fact protective,
then this mutation should have resulted in more
Alzheimer's, not less. YET IT DID NOT. Some beta amyloid is essential
for normal brain functioning, but too much IS THOUGHT A 1 OF POSSIBLE MANY cause(s)
Alzheimer's.

http://extremelongevity.net/wp-content/uploads/app.pdf
This study concerns an allele of the gene for the
amyloid precursor protein (APP) which has a protective
effect against diagnosis with AD.

Again you have only identified a correlation but not a protection. >

Post by Mark Thorson
It does appear to be true that APP has an important
role in the pathology that leads to clinical diagnosis
with AD. There are APP mutations which increase the
risk of diagnosis with AD, so that was known before

In all fairness the diagnosis is not he risk the condition is, and unless hte condition is better understood and less conflated with diagnosis of broad sets of symptoms overlapping incidence of fundamental variation of brain/age markers such as protein hypothesis until the mechanism of what is causing the memory loss is better understood research is better served researching the underlying brain tissue of aging individuals then trying to pick off simple cause/correlation 'obvious' factors >

Post by Mark Thorson
this study. But that does not mean that amyloid beta
_causes_ AD.

A lie at this point, this is like saying a tumor is the cause of the cancer, yes they correlate but there is more going on here >

Post by Mark Thorson
It's like airbags. Airbags in cars reduce the risk
of dying in a collision. Does this mean that airbags
reduce the risk of having a collision? Of course not.

Just because a whole of people who have one trait suffer from one thing way less than people who do not have the trait, does not mean the trait is the cause of the condition of the suffering. PLEASE CORRELATING less-likely conditions based on total populations puts us back with the dinosaurs when we should be pushing medical research into the future with good solid logic. Now if you can establish a pre-cursor effect with the hypothesis and plot cognitive/soft data such as symptoms severity onset with waning levels of protein markers in the brain you might have something, but you have not done this yet.

Post by Mark Thorson
Airbags mitigate the consequences of a collision, but
they have absolutely nothing to do with the risk of
having a collision. Lack of airbags or defective
airbags do not cause collisions between cars.

Good point. >

Post by Mark Thorson
The A673T allele which is the focus of this study
does more than reduce the risk of being diagnosed
with AD, which is a late event in the course of AD.
The disease process which leads to a diagnosis of AD
is believed to begin decades before diagnosis with AD.
As shown in Figure 1 of this paper, the A673T allele
also exerts a protective influence against the decline
in cognition which occurs naturally in people who
do not have AD.

So look at all cognitive decline is unnatural and you have a firm start. >

Post by Mark Thorson
It also has a powerful effect on non-cognitive aspects
of health. This study estimated that having the A673T
allele increases the chance of living to age 85 by
a factor of 1.47. That's a huge increase! Something
more than protecting the brain is going on here.

I hope so. >

Post by Mark Thorson
If amyloid beta causes AD and this allele was
protective against the initial events that cause AD,
the effect would be much more specific to preventing
diagnosis of AD.

Protect from the deterioration not the diagnosis or you will risk harming life with well-meaning doctors putting ammunition in between the bureaucrats and the less attentive. But it's not. It has protective

Post by Mark Thorson
effects on both non-AD age-related cognitive decline
and lifespan in general.
A recent trend toward understanding the cause of AD
focusses on pathology of the small blood vessels
in the brain. Before focusing on size determine whether or not blood vessel size change is a cause. If not don't bother, and focus elsewhere instead of wasting on investigation of just one size (small). If this is an important stage in the
etiology of AD, and if the A673T allele protects
against microvascular pathology, that would explain
its protective effect against AD, normal

(as long as you are calling this normal you should not be a researcher in my opinion, unless you are explaining this to a journal or other people who are less intelligent who make you feel smart by assuming normal bad things are okay and have nothing to do with the really sever bad things that are not okay! Please use your brain on this! age-related

Post by Mark Thorson
cognitive decline, and other disease processes (such
as cardiovascular disease) that have nothing to do
with the brain or cognition.

Even if microvascular

Post by Mark Thorson
pathology is not the cause of AD, the A673T allele
is doing something which has a profound effect on
lifespan without regard to its effect on the risk
of being diagnosed with AD.
Amyloid beta is certainly not a bystander to the AD
disease process. I think soluble amyloid beta may be
the cause of the progression from mild to moderate AD.
There seems to be an important stage transition here,
because the anti-AD drug memantine is effective in
moderate to severe AD, but despite efforts to show an
improvement in mild AD, it has none. This suggests
there are two disease mechanisms, one which causes
the initial development of mild AD (which is
insensitive to memantine) and another which causes
the advancement to moderate and severe AD (which are
sensitive to memantine).
But the notion that amyloid beta causes the initial
events in AD is neither proven nor suggested by this
study.