Model shows how mutation tips biochemistry to cause Alzheimer's

Your fate can be determined by tiny events. Imagine you live in the city and you walk everywhere to get exercise – you are healthy and not afraid of getting mugged. You almost never eat breakfast so you don’t stop at the donut shop on the way to work, until one day the manager replaces the girl at the counter with her pretty red-haired younger sister. This seemingly unimportant change in your world is just enough to overcome your ability to resist high-fat temptation. A million donuts later, your cholesterol level surges and then your heart gives out. Curse you, little red-haired girl!

Like staff change at the donut shop, subtle, seemingly inconsequential differences in human genetic design can lead to some unexpected tipping points in cellular chemistry that can lead to disaster. Cellular processes, like all the routines of life, are unfathomably complex, constantly evolving, and are sometimes dramatically sensitive to the smallest of changes. Consider the case of Alzheimer’s disease…

Alzheimer’s is a terrifying brain-destroying disease whose causes have proven very difficult to pin down. In recent years, science has been closing in on solving the puzzle, particularly regarding some of the hereditary, “early onset” forms of the illness. Unusual by-products of cell metabolism, clumps of protein aggregates, have been shown to have a toxic effect on brain cells and certain gene mutations have been shown to be associated with increasing production of these by-products, though the evidence for an exact mechanism has remained hidden.

Now, using sophisticated computer simulations, a team of physical chemists have shown precisely how a minor, seemingly inconsequential mutation results in unexpected changes in a very delicate chemical balance, creating build-up of the toxic by-products.

The mutation, the substitution of a single base among the 3 billion found in human DNA, seems to have the greatest effect on a fragment of a specific protein that is abundantly present in living cells. The difference causes a subtle change in the shape of the fragment at a critical point, which can slightly shift the odds towards an inappropriate biochemical reaction that sidetracks the metabolic path. The increase in the reaction simply tips the balance of chemical processes, causing the build-up of a substance that kills brain cells, leading to the early deterioration of mental capacity and, eventually, death.