Alzheimer’s Disease Pathophysiology

Question 1

What is a monomer ?

Answer 1

a molecule such as an amino acid, sugar, fatty acid, or nucleotide

Question 2

what is a dimer ?

Answer 2

two monomers joined together

Question 3

what is an oligomer ?

Answer 3

a combination of monomers (amino acids) into a structure consisting of a few number of monomers

Question 4

what is a polymer ?

Answer 4

a combination of monomers (amino acids) into a structure consisting of a large
number of monomers

Question 5

what is a protein ?

Answer 5

a combination of several polymers

Question 6

explain Alz pathology ?

Answer 6

Question 7

What is confirmation of a protein ?

Answer 7

shape of a protein

Question 8

explain conformational change

Answer 8

change in the shape of the protein … misfolded proteins

Question 9

Explain Protein Aggregation

Answer 9

clumping or accumulation of mis-folded proteins

Question 10

Summary

Answer 10

Question 11

Monomer Combinations 1

Answer 11

Question 12

Monomer Combinations 2

Answer 12

Question 13

Monomer Combinations 3

Answer 13

Question 14

Confirmational Change

Answer 14

Question 15

Tau propogation

Answer 15

Question 15

Alz Features

Answer 15

Question 16

What is impact of tangles and plaques …1…?

Answer 16

tangles and plaques get in the way of normal neurotransmission.

Question 17

What is impact of tangles and plaques … 2…?

Answer 17

And when they get in the way of normal neural transmission, neurons can’t activate each other.

Question 18

What is impact of tangles and plaques … 3…?

Answer 18

And when neurons can’t activate each other, neurons start to atrophy if they’re not getting stimulation. So, over a period of time, the entire brain just starts to atrophy.

Question 19

brain atrophy - note widening of the sulcus , volume shrinkage

Answer 19

Question 20

what are models of Alz disease management ?

Answer 20

univariant and mulrivariant

Question 21

explain univariant

Answer 21

So, a univariate model is, there’s one mechanism, one cause of Alzheimer’s disease. And if we can just treat that one cause then we should be able to reverse that. Medical model looking for the silver bullet

Question 22

give examples of univariant

Answer 22

In the univariate model, in the world of pharmaceutical management and drug development, has had many different hypotheses and different mechanisms that have had clinical trials conducted for them. One was the amyloid hypothesis. One was tau propagation hypothesis, one was the neuro transfer hypothesis, I’ll go over some of these with you. And they were trying to find a single drug to impact Alzheimer’s disease. And just so you know, after the billions of dollars spent, they’ve never been able to identify a single drug to reverse Alzheimer’s disease or to even slow down Alzheimer’s disease.

Question 23

and the multivariant model

Answer 23

And then you have the multivariate model, which is there’s a lot of variables involved. And there is a… these variables all have an influence on each other. And you can’t just treat it by one single mechanism, that you have to treat multiple mechanisms, really like a web. And this is where a personalized medicine approach comes in. So, let’s talk about the univariate model first.

Question 24

more on univariant model

Answer 24

example of the univariate model, like when you look at the development of Alzheimer's disease, the basic pathophysiology is there is the amyloid precursor protein, and there's a pathway that's normal. And the amyloid precursor protein gets cleaved by an enzyme called alpha-secretase and the gamma-secretase. And this then helps with normal neurological neuron functions. But in some states, the enzyme beta-secretases and the alpha-secretase comes in and this creates these protein aggregates, and amyloid plaques, and tau.

Question 25

more on univariant

Answer 25

So, here you can see in this diagram several clinical trials that were published, where they were trying to either impact the amyloid plaque development by impacting these pathways with beta-secretase, gamma-secretase, or they're trying to impact pathways that are involved with tau phosphorylation. And pretty much every single one of these clinical trials have failed, none of them worked. Despite billions of dollars being spent on these trials, when they tried to reduce the plaquing, they actually had some of these patients get dramatically worse.

Question 26

take a look

Answer 26