Why is Diabetes a Risk Factor for Alzheimer's Disease?

We know that controlling risk factors for type 2 diabetes reduces the risk for Alzheimer's disease, but why?  Some interesting research from South Korea may provide new insight.  The research was described in a recent article in the ALZForum, "Stress-Associated Protein Modulates γ-Secretase to Make More Aβ."  What's that about?

In order to advance from the 10th to the 11th grade in Washington State public schools, you're required to know that the endoplasmic reticulum (ER) is a component part of most cells in the body, and it synthesizes lipids and cholesterol.  The ER is an organelle (sort of like an organ of the cell) and is a structure made up of various proteins.  This is one piece of the puzzle.

In diabetes there is excess glucose running around in the blood stream.  The excess glucose is destructive and causes a form of stress for the cells.  Another piece of the puzzle.

Beta amyloid is a malformed protein that is characteristic of Alzheimer's disease.  It is formed when the "amyloid precursor protein" (APP) is cut by, among other things, the γ-secretase protein.  (No one knows what the purpose of APP is, but it sure plays a big role when things go bad in the brain.)  Apparently, changes in γ-secretase activity can vary the production of beta amyloid by doing more APP cutting.  This implies that varying the amount of γ-secretase can affect the advance of Alzheimer's disease.  Still another piece of the puzzle.

There is a protein called "the stress-associated ER protein 1" (SERP1) located on the surface of the ER.  It promotes γ-secretase activity which results in more APP cutting and, therefore, more beta amyloid generation.  Another puzzle piece.

SERP1 responds to stress from excess glucose -- a condition occurring in diabetes -- and prompts the generation of more γ-secretase and therefore more APP cutting and the generation of more beta amyloid.  And so the excess blood glucose in diabetes can promote Alzheimer's disease.  (This may be a serious over-simplification, but I think it's a reasonable overview.)

Well, anyway, that's the hypothesis.  So how can this hypothesis be tested -- as we must inevitably do?  For this, the researchers did a number of things, but one was to review the autopsy findings of normal brains and people who died with Alzheimer's disease.  One finding was that the hippocampi in diseased brains contained ten times the SERP1 as in the normal brains.  This was one of several confirmatory research findings.

The completed puzzle:  Excess glucose in diabetes causes cellular stress.  The stress stimulates the SERP1 protein, which encourages γ-secretase activity.  γ-secretase activity results in more APP cutting and the generation of more beta amyloid.  More beta amyloid means that Alzheimer's disease progresses.

The bottom line?  Control your risk factors for type 2 diabetes!  Eat right and get plenty of exercise!  (Of course, you must always manage any type of diabetes in accordance with your physician's direction.)