"Decoding Darkness:

The Search for the Genetic Causes of Alzheimer's Disease"

President Reagan’s battle with Alzheimer’s has brought significant attention to this disease. Consequently, many people think they know a lot about Alzheimer’s. What don’t people know about it?

When Reagan first announced that he had Alzheimer’s, everyone was shocked that someone of his stature was brave enough to face the public with this very private battle. The announcement made people realize Alzheimer’s is a fairly common disease among the elderly. But I think most people still don’t realize there’s two different kinds of Alzheimer’s—late onset and early onset. Reagan has late onset. People also don’t understand the genetic component to Alzheimer’s. If you have a family member who has Alzheimer’s, it doesn’t mean you should panic. In late onset, the common form that hits the elderly, there are several genes at work which carry alterations that can make one more susceptible to the disease. But most cases of late onset Alzheimer’s involve the interplay of the gene alterations and environmental, also known as external, factors that we’re exposed to in everyday life. Only in early onset Alzheimer’s does the presence of an Alzheimer’s gene mean you’re definitely going to get the disease. Fortunately, only five percent of Alzheimer’s is early onset.

What separates Alzheimer’s from the normal decline that comes with aging?

Think of your brain as a stereo whose music is memory. Your stereo works great for a lot of years. Eventually, as it ages, it occasionally short circuits. That’s normal decline, normal wear and tear. In Alzheimer’s, there’s a toxic invader in the stereo—one that actively destroys the wires that make up the circuit. It doesn’t just temporarily disrupt the music, it silences it.

Are there any effective therapies for Alzheimer’s out there right now?

The drug Aricept is often prescribed. It preserves the neurochemicals in the brain that are needed for memory. To use our stereo metaphor again, it helps you make use of what you have left of the circuitry. But it’s not a cure by any means.

How many Alzheimer’s genes have been found and how many more do you expect to find?

Four major genes—ones with high impact for causing risk for the disease—have been found, along with several minor genes. We expect to find four or five more major ones and as many as two-dozen more minor gene alterations. Of the four major ones that we’ve found, three cause early onset, which is technically characterized as that which presents itself in people under sixty years of age, though it usually hits people in their forties and fifties. We know that the three early onset genes that we’ve found only account for half of all early onset Alzheimer’s. So we’ve still got a lot of work to do. For late onset, it’s even worse—we only have ten percent of the genetics figured out.

Is it possible to test for Alzheimer’s genes?

Yes, there’s a pretty reliable test for the major mutations associated with early onset. But since the presence of an early onset gene means you’ll definitely develop Alzheimer’s, you have to ask yourself whether or not you really want to know. After all, there’s nothing you can do to prevent early onset, though taking lots of Vitamin E can help to delay it. For late onset, there’s also a test, but it’s not as reliable and it can’t tell you for sure that you’re going to get Alzheimer’s. It just shows you have a higher risk for it.

To what extent is Alzheimer’s an inherited disease?

For early onset, there’s a strong inheritance pattern. If your parent got the disease before age fifty, there’s a fifty/fifty chance that you inherited an early onset gene. With late onset, genetics is still a strong component, but only in determining risk and susceptibility. It’s not as causative.

Much of your book focuses on the amyloid hypothesis. What is it, and why do so many scientists believe this theory might explain what causes Alzheimer’s?

One of the most consistent features of Alzheimer’s disease is accumulation of a gooey substance called beta-amyloid that clumps around nerve cells and in brain blood vessels. Amyloid is made of a small protein called A-beta, and we’ve learned that all of the known Alzheimer’s gene defects lead to excessive accumulation of amyloid in the brain.

Is amyloid in the brain like cholesterol in heart disease?

Exactly. Small amounts of it accumulate with age, but the Alzheimer’s gene defects cause a drastic increase in amyloid—more than the brain can handle. Recently, it has been shown that the more A-beta produced in the brain, the greater the degree of dementia, just like in heart disease the greater the cholesterol buildup, the greater the risk of heart attack.

As your book recounts, several first-time therapies based on the amyloid hypothesis just started patient trials this year. When we will know if they’re effective?

The most exciting new trials all hinge on the idea of curbing the accumulation of amyloid in the brain. Some of the trials are aimed at lowering the production of A-beta, the major component of amyloid, while other trials are employing drugs that prevent A-beta from turning into amyloid in the first place. Some of the trials are even aimed at clearing the amyloid after it has been laid down. We’ll probably start hearing about the efficacy of these drugs in the next two to five years.

Why have you devoted your life to researching Alzheimer’s as opposed to some other disease?

My research started as a natural extension of work I was doing in the early eighties on Down syndrome, because people with Down syndrome almost inevitably acquire the features of Alzheimer’s by middle age. I looked for a link between the two diseases, and found one. That’s how I was able to isolate what turned out to be the first Alzheimer’s gene in 1987. Once I got into Alzheimer’s research, I became obsessed with solving the puzzle. I quickly realized that the only way to get 100% certain answers was to do genetics. On a personal note, my grandmother developed Alzheimer’s shortly after I started researching it. I witnessed firsthand the insidious loss of self. But that’s just one of the things that has kept me in Alzheimer’s research. I’ve also gotten to know many of the families who’ve donated blood for our studies. That’s how I’ve come to see it as one of the worst medical tragedies one can encounter. You’re alive but you lose your identity.

Why did you write this book?

Because I really want people to understand the progress we’ve made in the last 20 years, and I want them to share in the excitement of it. We went from being totally in the dark about Alzheimer’s to having a deep understanding at the molecular level of what’s going wrong in the brain—enough so that we can now develop highly specialized drugs that go right to the root of the problem. I also wrote this book because many of the current books on Alzheimer’s scare me. They’re not just lacking in information, they’re actually full of misinformation. I think it’s because they’re not written by individuals who are actually in the field doing research—people who have been fully immersed in solving the puzzle from day one. Finally, I wrote this book because I want people to see how research in general is really done. Medical scientists aren’t white-coated nerds in stainless steel labs. This kind of research is intense and competitive, but it’s also collegial and a lot of fun. It sounds weird to talk about how much fun it is to research such a tragic disease, but it really is an amazing experience. We learn from our mistakes, we have some luck. That’s how we learn about Alzheimer’s.

In terms of treating Alzheimer’s, where will we be in five to ten years?

In five to ten years, we’ll be using genetics to predict who’ll get the disease and to custom tailor medications. This will allow us to prevent the disease from occurring before it even starts. But ask me about twenty years from now.

Okay, where will be twenty years from now?

We’ll have drugs that can cure or even reverse Alzheimer’s. And I can honestly say I’ll be thrilled to be out of a job

China Millennium Council 2005

A Chinese Proverb
I am the seasoned traveler of the Labyrinth.
I overturn barriers and boundaries, opening new paths and portals for
innovation.