Alzheimer's Disease

[Guest guest]

Hi folks,

For my upcoming website on cholesterol (I'll release the URL to the

group in a week or two), I'm doing research for an article on

alzheimer's disease, because AD is being used all over the web to

advocate a " brain-healthy " low-fat low-cholesterol diet based on the

fact that cholesterol is involved in the production of beta-amyloid

peptide, which, in AD, forms plaques that deposit all over the brain.

I happen to have access to the full-text articles in a neuroscience

journal that is proving extremely helpful.

So far, even though most of the AD thought seems to focus on

beta-amyloid plaques being causal in AD, it appears that they might

just be coincidental. This seems counterintuitive, because these

plaques are deposited all over the place coincident with massive

neurodegeneration. However, these plaque deposits can be induced

selectively in mice, and by and large, mice that exhibit these plaque

deposits do NOT have neurodegeneration NOR do they exhibit behavioral

cognitive decline.

What DOES seem causal, from what I've read so far (and I'll discover

more as I go along...) is DHA depletion, which is reversable by adding

DHA to the diet, and which is related to a high rate of DHA oxidation

in familial AD-mutant genes. (Adding DHA reverses the cognitive

decline and neurodegeneration while the high rate of oxidation

persists, so the DHA depletion seems causal.) This has a relation to

insulin resistance in the brain. Also, it appears that the APP

protein itself (the protein that generates beta-amyloid when cleaved),

especially the mutant form found in familial AD, inhibits heme

oxygenase which generates bilirubin, and antioxidant, which is one of

the factors in the high rate of oxidation. So interestingly, it

appears that the intact APP, and not the beta-amyloid being cleaved

from it, is the culprit.

The drugs being tested all target beta-amyloid. One class is

gamma-secretase (which cleaves APP to form beta-amyloid) inhibitors,

but get this-- the gamma-secretase enzyme is necessary for all sorts

of important functions, so the gamma-secretase inhibitors CAUSE

massive neurodegeneration!

Anyway, the main point I wanted to get to relates to 's earlier

statements about needing to read full-text articles and not just

abstracts.

One study tested immunizations against beta-amyloid. In the abstract,

they claim that the beta-amyloid antibodies themselves are shown to

reduce cognitive decline. Yet the study groups people into those who

had low-levels and did not change, and those who had big increases,

and never compares data of the total levels. So the only point where

a dose-response is shown is when they divide into three groups by

*increase*, not by total level, and do a bar graph. Obviously to show

causality of the antibodies, we would need to see an individually

plotted line where absolute levels of antibodies were graphed against

cognitive decline. Also, on one of the tests, the " control " group

that was immunized but didn't have significant antibody increase did

almost as much WORSE than average as the " experimental " group did

BETTER than average. So hmm, is it really working?

Some other funny things about the study: the " control " group was the

group that was immunized but didn't respond with a large antibody

increase. They didn't have a group that wasn't immunized!

Before the study really went on, the dosing of the immunizations had

to be stopped because 6% of them developed immunization-related

aseptic meningoencephalitis. Of the thirty who continued, two for

some reason dropped out (6.7%), and three (10%) developed aseptic

meningoencephalitis!

So there is no data on the actual absolute level of antibody with

performance on cognitive testing, 1/3 of the subjects who didn't

repsond with antibody increases did worse than normal on the tests,

and 2/3 who did respond did somewhat better on the tests, and 10%

developed aseptic meningoencephalitis.

It seems to me that if it was the *increase* that was correlated

rather than the absolute level of antibody, couldn't this just be a

guage of immune system health and maybe therefore of general health?

Anyway, I'm looking forward to writing the article but I have more

work to do. It might turn into a book!

Chris