Rhonda: I think I also read one in your papers where you did this metabolic profiling there was a very prominent zinc deficiency in that.

Dale: Yes, so for reasons that we don't entirely understand yet, many of the people with the type 3, the toxic sub-type have low serum zinc, high copper-zinc ratios, and low triglycerides. The low triglycerides may turn out to be related to malabsorption, we don't know for sure yet, but we don't really understand why the people often have these low copper-zinc ratios.

Rhonda: What does that mean, the copper-zinc ratio, what is that?

Dale: The high copper-zinc ratio, low zinc.

Rhonda: Low zinc, yeah.

Dale: Yeah, so as, you know, copper and zinc actually are competitive, for example, in their absorption. And so, too much of one actually is often associated with too little of another. And then typically in our society, as you know, most of us are deficient in zinc. There are actually about a billion people on Earth is the estimate for zinc deficiency. It's a very common problem because if you have poor gastric acidity, which is common as we age, if you're taking PPIs for GERD, if you're taking something for reflux, you won't absorb the zinc very well, if you have copper piping which most of us do, the copper will often compete with the zinc. And so many people have a little too much copper and a little bit too little zinc. And in fact, it was noted over 30 years ago that people with high copper-zinc ratios tended to have dementia more than those with normal copper-zinc ratios.

Rhonda: Wow. So does this have something to do with it? I know there's like over 300 to 500 different enzymes in the body that require zinc. So does copper then bind to those enzymes and then sort of mess up the function or is that like the theory?

Dale: So, no. The theory is that, as you know, copper is a generator of free radicals. You know, copper can act like iron in that sense. It has a free electron in the D orbital which does not occur with zinc. So in general, as you indicated, in these various enzymes, and it's hundreds, just as you said, it is an important structural component and it has a very specific architecture with the enzymes that it serves, so it is a structural thing in general. And copper, to my knowledge, doesn't actually replace that. But for example, zinc is important in many things that are related to cognitive decline, it's important in diabetes, it's important in functioning of insulin, it's important, of course, in the trophic activity of insulin and, you know, on and on. It's important in immune responses. So, it actually has many effects that are related to cognition.

Rhonda: So it may even just be a biomarker for something underlying going on right in the toxic insult type of Alzheimer's disease you're talking about.

Dale: It something to keep in mind when you see that, and especially if the person presents, and these people tend to be very distinctive, the people who have type 3. So, they tend to be young, and we see them in their late 40s, mid 50s very commonly. We've seen them as late as starting their first symptoms in the mid-60s, but typically, their first symptoms are currying in the 40s and 50s. They are often women, they are often ApoE4 negative although not always. There are certainly people who are ApoE4 positive to have this. As you mentioned, they often have the low zinc, and then they typically present in a non-amnestic way. Interestingly, unless they are homozygous for E4, in which case they do present typically with an amnestic presentation, but the ones who are E4 negative typically present with problems, as I mentioned earlier, executive dysfunction problems.

And so I always ask people, are you having trouble organizing things? We had one person, for example, who was known for her tremendous organizing capability and as she started to get the problem she just lost it. She could not organize things that she could do before, it's a very common complaint. Or as I said, people will say, "Oh, I can't calculate a tip anymore, or I can't pay the bills anymore," anything that is math-related or visual perception or word finding, things like that.