Peter Attia article on statins and dementia

 

Peter Attia Unsubscribe	6:00 AM (3 hours ago)
to me

Does low cholesterol cause cognitive impairment? Part II  (click the link above to view on the website) Greetings - Last week I discussed the theoretical possibility that lipid-lowering drugs might negatively impact cognitive function, specifically, whether PCSK9 inhibitors had such an impact. The answer appears to be no, at least according to studies addressing this question. While PCSK9 inhibitors are the most potent drugs to lower apoB and LDL-C, they are not the most common—a distinction that belongs to a class of drugs you are no doubt familiar with: statins. Is it possible that statins may alter brain cholesterol synthesis in a way that is unique to their mechanism of action (and distinct from all other pharmacological mechanisms that lower cholesterol)? Based on their mechanism of action, one of the biggest concerns with potent statin use is that it may increase the risk of cognitive impairment, dementia, or hemorrhagic strokes. Fortunately, after decades of research and billions of patient-years of use data, it doesn’t appear that people taking statins are at greater risk of these conditions. In fact, population studies actually suggest that statin use is associated with a reduced incidence of dementia, but observational studies like these are incapable of determining a cause-and-effect relationship. Why would statins reduce Alzheimer’s disease (AD) risk? Perhaps because there’s a reduction in vascular risk when taking statins, and there’s likely a vascular component to AD. If you recall from last week, there’s a widely held notion that what is good for the heart is good for the brain. This may be particularly relevant in the context of vascular health. (Listen to my podcast with Francisco Gonzalez-Lima where we explore this topic in more detail.) One of the limitations to population-level observational studies is that they might not tell you the whole story about individual differences. The old adage, you can still drown in a body of water that is, on average, 3 feet deep holds—some parts are likely much deeper. Similarly, just because on average, statins seem to reduce the risk of dementia, it does not mean we should assume this is true across the board. Is it still possible that statins might over-suppress cholesterol synthesis in the brain in at least some individuals and increase the risk of cognitive impairment in this subset?    If you recall from Part I, cholesterol is critical to normal brain function, but it’s unlikely that plasma cholesterol affects cognition because there’s no relationship between plasma cholesterol and tissue pools of cholesterol. However, it’s still possible that cholesterol levels in the brain can affect cognition, and because some statins have a variable ability to cross the blood-brain barrier (BBB) and reduce cholesterol synthesis (unlike PCSK9 inhibitors or ezetimibe which have no effect on synthesis) potentially lowering brain cholesterol below the level required for normal cognitive functioning. At least that’s the question we want to explore. First, a word on cholesterol synthesis.  There are two pathways for cholesterol to be synthesized within each cell in your body. One is called the Kandutsch-Russell pathway, which is believed to be the predominant pathway, where lathosterol is the penultimate sterol (i.e., the molecule that is converted into cholesterol via the final step of this pathway). The other is called the Bloch pathway, which is thought to be by some a less prominent path, where desmosterol is the penultimate sterol. Since cholesterol is ubiquitous, and highly recycled, a clever way to measure cholesterol synthesis is to measure direct levels of lathosterol and desmosterol. There is some evidence that the Bloch pathway is the predominant pathway in the brain, especially during infancy and childhood. This raises the hypothesis that desmosterol, specifically, may serve as a biomarker of cholesterol synthesis in the brain. It turns out that the brain tissue in AD patients are depleted in desmosterol and that desmosterol levels are relatively low in the cerebrospinal fluid (CSF) compared to individuals without AD. Unfortunately, it’s not especially pleasant or convenient to get a spinal tap to assess the desmosterol levels bathing your brain.  So, instead we can look at plasma levels of desmosterol which are, fortunately, highly correlated with CSF levels. A 2012 study was the first to report decreased plasma desmosterol levels in patients with AD and mild cognitive impairment (MCI). MCI is the stage between the expected cognitive decline associated with aging and the more severe decline of dementia. The investigators in this study measured cholesterol and desmosterol in both the plasma and CSF in Caucasian patients and looked at the relationship between the two locations. Their analysis revealed that the desmosterol-to-cholesterol ratio in the CSF correlated well with its plasma ratio, suggesting that plasma levels of desmosterol reflect brain sterol synthesis and metabolism. In the same paper, the investigators found a significant change in desmosterol and the desmosterol-to-cholesterol ratio in the plasma of both MCI and AD patients compared with healthy elderly controls, as shown in the Figure below. They also found a significant correlation with worsening Mini-Mental State Examination (MMSE) scores, which is a widely-used test of cognitive function among the elderly.  Figure (from Sato et al., 2012). Plasma desmosterol levels and plasma desmosterol-to-cholesterol ratios in controls, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) patients. In 2015, the same group from this 2012 paper measured plasma desmosterol and cholesterol samples from about 400 Japanese participants — approximately half of which had AD with the other half serving as healthy controls — and followed a subset of them over a range of two to three years to see if there was an association between the desmosterol-to-cholesterol ratio and cognitive decline in patients with AD over time. The investigators found that the plasma desmosterol-to-cholesterol ratio was reduced in Japanese AD patients. They also found that after two to three years of follow-up, the ratio was relatively stable in normal controls whereas it significantly decreased in AD patients. In those with MCI or AD with a more rapid disease progression, there was a more rapid decline in the plasma desmosterol-to-cholesterol ratio compared with those with slower progression. The change in the plasma desmosterol-to-cholesterol ratio also tracked with the change in the MMSE score over time. The more pronounced the decrease in the plasma desmosterol-to-cholesterol ratio, the lower the MMSE score, the greater the cognitive impairment.   One of the most common causes of reduced desmosterol is statin therapy. Statins can cross the BBB — and while the data is conflicting — a recent study confirmed the hypothesis that lipophilic versions including simvastatin (Zocor) and atorvastatin (Lipitor) may more easily cross the BBB than hydrophilic ones including rosuvastatin (Crestor) and pravastatin (Pravachol), and therefore may inhibit cholesterol synthesis in the brain. Is low desmosterol a cause of cognitive impairment and dementia or the result of it? The short answer is we don’t know. What we do know is that cholesterol is critical to brain function and there are observational studies like the ones above (and more recent ones) suggesting low plasma desmosterol is a biomarker for MCI and AD. Unfortunately, the 2012 and 2015 papers discussed above don’t include patients on statins, which would be helpful for us to elucidate any links between statin use, desmosterol levels, and cognitive decline. It may sound cliché to hear this, but more, and better, research is needed to understand whether statins have an effect on cognition or neurological disorders like AD, in at least a subset of users.   From a clinical perspective, low desmosterol levels in patients with cognitive symptoms may serve as an indication that cholesterol synthesis is over-suppressed and the statin dose should be decreased (or stopped altogether in favor of a different drug class). We don’t like to see absolute concentrations of desmosterol below 0.8 mg/L in our patients. We also treat patients with one or two copies of the APOE e4 alleles or a family history of dementia with kid gloves and make sure they have a desmosterol level greater than 1.0 mg/L. While we don’t know for sure whether low desmosterol from statin use increases the risk of dementia, a personalized approach may be necessary. Population data are helpful and RCTs are important, but as any doctor will tell you, the only patient that matters is the one in front of you. - Peter

I found many lines in this song spoke to me

To understand you know too soon
There is no sense in trying

That he not busy being born is busy dying

You follow, find yourself at war
Watch waterfalls of pity roar
You feel to moan but unlike before
You discover that you’d just be one more
Person crying

Advertising signs they con
You into thinking you’re the one
That can do what’s never been done
That can win what’s never been won
Meantime life outside goes on
All around you

You lose yourself, you reappear
You suddenly find you got nothing to fear
Alone you stand with nobody near

Yet you know there is no answer fit
To satisfy, insure you not to quit
To keep it in your mind and not forget
That it is not he or she or them or it
That you belong to

 Inspiration from Bob Dylan for my Alzheimer's

It’s Alright, Ma (I’m Only Bleeding)

WRITTEN BY: BOB DYLAN 

Darkness at the break of noon
Shadows even the silver spoon
The handmade blade, the child’s balloon
Eclipses both the sun and moon
To understand you know too soon
There is no sense in trying

Pointed threats, they bluff with scorn
Suicide remarks are torn
From the fool’s gold mouthpiece the hollow horn
Plays wasted words, proves to warn
That he not busy being born is busy dying

Temptation’s page flies out the door
You follow, find yourself at war
Watch waterfalls of pity roar
You feel to moan but unlike before
You discover that you’d just be one more
Person crying

So don’t fear if you hear
A foreign sound to your ear
It’s alright, Ma, I’m only sighing

As some warn victory, some downfall
Private reasons great or small
Can be seen in the eyes of those that call
To make all that should be killed to crawl
While others say don’t hate nothing at all
Except hatred

Disillusioned words like bullets bark
As human gods aim for their mark
Make everything from toy guns that spark
To flesh-colored Christs that glow in the dark
It’s easy to see without looking too far
That not much is really sacred

While preachers preach of evil fates
Teachers teach that knowledge waits
Can lead to hundred-dollar plates
Goodness hides behind its gates
But even the president of the United States
Sometimes must have to stand naked

An’ though the rules of the road have been lodged
It’s only people’s games that you got to dodge
And it’s alright, Ma, I can make it

Advertising signs they con
You into thinking you’re the one
That can do what’s never been done
That can win what’s never been won
Meantime life outside goes on
All around you

You lose yourself, you reappear
You suddenly find you got nothing to fear
Alone you stand with nobody near
When a trembling distant voice, unclear
Startles your sleeping ears to hear
That somebody thinks they really found you

A question in your nerves is lit
Yet you know there is no answer fit
To satisfy, insure you not to quit
To keep it in your mind and not forget
That it is not he or she or them or it
That you belong to

Although the masters make the rules
For the wise men and the fools
I got nothing, Ma, to live up to

For them that must obey authority
That they do not respect in any degree
Who despise their jobs, their destinies
Speak jealously of them that are free
Cultivate their flowers to be
Nothing more than something they invest in

While some on principles baptized
To strict party platform ties
Social clubs in drag disguise
Outsiders they can freely criticize
Tell nothing except who to idolize
And then say God bless him

While one who sings with his tongue on fire
Gargles in the rat race choir
Bent out of shape from society’s pliers
Cares not to come up any higher
But rather get you down in the hole
That he’s in

But I mean no harm nor put fault
On anyone that lives in a vault
But it’s alright, Ma, if I can’t please him

Old lady judges watch people in pairs
Limited in sex, they dare
To push fake morals, insult and stare
While money doesn’t talk, it swears
Obscenity, who really cares
Propaganda, all is phony

While them that defend what they cannot see
With a killer’s pride, security
It blows the minds most bitterly
For them that think death’s honesty
Won’t fall upon them naturally
Life sometimes must get lonely

My eyes collide head-on with stuffed
Graveyards, false gods, I scuff
At pettiness which plays so rough
Walk upside-down inside handcuffs
Kick my legs to crash it off
Say okay, I have had enough
what else can you show me?

And if my thought-dreams could be seen
They’d probably put my head in a guillotine
But it’s alright, Ma, it’s life, and life only

Copyright

© 1965 by Warner Bros. Inc.; renewed 1993 by Special Rider Music

You will not get this advice from any other Alzheimer's book.

 Being overweight and having diabetes mellitus are risk factors for Alzheimers. 

Best approach is to make diagnosis of pre-diabetes early and then start an Atkins type diet to prevent becoming diabetic. 

I have had DM type 4 since around 1990. 

Worse thing I did was go on insulin.  I gained more weight. 

I have insulin resistance and I had to keep increasing my insulin dosage to get my sugar down

Finally an endocrine MD got me off insulin with invokana.  

I did this with one of my obesity patients here link

I have progressed from Victoza to Ozempic and there has been a significant differenc. 

 History of my diet medicatons link.

I missed my Ozempic 1.0 mg a week by four days. 

I went right back on my high dose.  My appetite did not increase after four days.  The second night back on Ozempic I threw up after dinner.  I had had two glasses of wine as well.  No hint of nausea just boom and I threw up with ease 3 times. 

wegovy (semaglutide)

Wegovy works by mimicking a hormone called glucagon-like peptide-1 (GLP-1) that targets areas of the brain that regulate appetite and food intake.

 The medication dose must be increased gradually over 16 to 20 weeks to 2.4 mg once weekly to reduce gastrointestinal side effects.

I take Ozempic 1.0 mga week. 

As time goes by and the 1.0 not effective I can see myself slowly increasing my semaglutide up to 2.4 mg. 

Wegovy works by mimicking a hormone called glucagon-like peptide-1 (GLP-1) that targets areas of the brain that regulate appetite and food intake. 

The medication dose must be increased gradually over 16 to 20 weeks to 2.4 mg once weekly to reduce gastrointestinal side effects.

This has happened years before on lower doses of Victoza. 

Obviously I should have slowly increased my dose of Ozempic. 

wegovy (semaglutide)

Wegovy works by mimicking a hormone called glucagon-like peptide-1 (GLP-1) that targets areas of the brain that regulate appetite and food intake.

 The medication dose must be increased gradually over 16 to 20 weeks to 2.4 mg once weekly to reduce gastrointestinal side effects.

I take Ozempic 1.0 mg week. 

As time goes by and the 1.0 not effective I can see myself slowly increasing my semaglutide up to 2.4 mg. 

Wegovy works by mimicking a hormone called glucagon-like peptide-1 (GLP-1) that targets areas of the brain that regulate appetite and food intake. 

The medication dose must be increased gradually over 16 to 20 weeks to 2.4 mg once weekly to reduce gastrointestinal side effects.

My data with Ozempic and breaking through the plateau. 

Plateau and Set Point link

Recently with Ozempic I broke through my 210 lb plateau.  

After my France 2 week cruise I actually lost a lb to 209.

Now back on my moring fasting routine I have gone down to 205 lbs. 

September 16, 2021

Glucose 104 (usually I run fasting 150)

Blood ketone 5.2 (very good for AZ patient) 

Weight 194. 5 lbs

Fat %. 23.4

H2o % 57.4

After vomiting my dinner on Sept 10

Sept 19 2021

Weight 193.7  (new adult low)

Glucose 91 (amazing rarely get this low)

Ketone

Say this word to your Doctor and it will change your life.

 Ashwagandha has been around for 4,000 years. 

Ashwagandha link

I believe it has helped me with my Alzheimers. 

Two pills a day has helped me with my anxiety and my sleep at night when I take it with Magnesium threonate 4,000 mg and Melatonin 5 mg.  

My sleep is beautiful as I often get 7-9 hours a night. 

Such rest gives me a great attitude when I wake up. 

Most Doctors have no idea what Ashwagandha is,  even my smartest neurologist. 

Explanation of title: Alzheimers is inexorable.

Bruce MacCullough	Wed, Sep 15, 3:08 PM (19 hours ago)
to me

Brian,    I continue to applaud your work of documenting your life with AZ.

 I continue to think that this latest title should be changed, 

as aging, decline, and death are inexorable for everyone.

Bruce, thanks for your input.

My response:

Let me finish my damn sentence

 Something I have not seen written anywhere is that people don't allow me to finish my sentence. 

They anticipate what I am going to say,

They are usually wrong. 

I have learned not to to get angry and start yelling. 

I am surprised that the other person wants to continue his side of the discussion.

I try to point out calmly that because he has not allowed me to finish my side of the discussion he doesn't even know the point I am trying to make. 

I have learned not to get crazy about it.

amazon review of On Pluto by O'Brien

 

My Amazon review of First Surivors of AZ by Dr Dale Bredendsen

 Initial blog review link

Amazon review below: