By David N. Leff

Unlike most medical maladies, the one sure-fire diagnosis of Alzheimer's disease (AD) is postmortem. Only autopsy of the brain can tell it apart from the 30 percent of dementias that are not AD - simple senility, depression, vascular dementia (result of multiple strokes) - for which there are specific therapies. To treat the memory and cognitive losses of advancing AD, there are only Cognex, Exelon and Arecept, which can stabilize but not cure the disease.

The neuronal hallmarks of AD revealed by brain autopsy are amyloid plaques surrounding neurons in the hippocampus and areas of the cerebral cortex, as well as fibrillary tangles cluttering up the neurons' interiors. The genetic risk factor that triggers these pathogenic peptides is APOE, a gene on human chromosome 19, which encodes a protein called apolipoprotein-E - APOE for short - that escorts cholesterol around the body. One subtype of this seemingly unrelated molecule, APOE-4, is featured in the genomes of men and women with a likelihood - but not a certainty - of inheriting familial Alzheimer's disease.

Even autopsy of the brain falls short of total accuracy in detecting AD's neuronal hallmarks. "Autopsy has its problems," observed chemist Michael Phelps, who heads the departments of nuclear medicine and medical pharmacology at the University of California, Los Angeles (UCLA). "The good part," he added, "is that you get access to the tissue, to look at it pathologically. But the bad part is you have to sample portions of the brain where you don't know well that you've hit the right areas affected by Alzheimer's disease. What you really want in drug assessment is to have biological markers. So rather than wait for a lengthy population study outcome, you'd like to be able to say, 'OK, here's a biological deficit, give the drug and does that deficit go way - a direct measure.' And that's what PET - positron emission tomography - provides."

Seeing Brain Function, Not Just Structure

"Most of our imaging techniques are oriented toward the anatomy of the body," Phelps explained. "For example, the major techniques used to make a diagnosis are CAT scan [computer-assisted tomography] and NMR [nuclear magnetic resonance]. They look at the structure of the brain and make a diagnosis based upon alterations in that structure. So there's a fundamental issue about an anatomical diagnosis vs. one based upon biology. If you ask anybody which is better for looking at disease - structure or biology - they'll all say biology.

"The way that PET works," Phelps continued, "is that the fuel your brain runs on is a simple sugar - glucose. It generates more than 95 percent of the ATP [adenosine triphosphate], the energy that allows the brain to function. What the PET scan of glucose metabolism does is look at the ability of the brain to function energetically. Or examine it when it fails. In effect, it replaces the postmortem autopsy.

"There are several key issues in drug discovery clinical testing," Phelps went on. "First of all, make sure you have a population of the disease you think you do. You need an accurate way not only to detect Alzheimer's, but also to characterize its stages. PET identifies AD at its earliest stages, separating it away from all the other organic dementias, and also from normal aging. It gives you a highly enriched population, so you know it's really AD and you know what stage it's in."

Phelps is senior author of a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated May 23, 2000, titled: "Cerebral metabolic and cognitive decline in persons at genetic risk of Alzheimer's disease." Its first author is psychiatrist Gary Small, director of the UCLA Center on Aging. Five years ago, he and his co-workers conducted a study of the APOE-4 genetic risk factor and PET-imaged cerebral glucose metabolism in AD relatives at risk for the familial form of the disease. Of 912 people who volunteered, they selected 38 participants, ages 40 to 85, from 15 families. (See BioWorld Today, March 23, 1995, p. 1.)

"What we did in the present PNAS study," Small told BioWorld Today, "was to replicate what we found in 1995. Namely, that middle-aged people with the genetic risk for AD have lower parietal [cerebral cortex gray matter] brain metabolism than those without the APOE-4 genetic risk. We extended those findings to other brain regions - the posterior cingulate and temporal region," Small went on, "but even more important is that we followed 20 subjects over a two-year period, repeating the PET scans. What was remarkable in this follow-up study was that of the 10 people with the AD genetic risk gene, all 10 showed observable decline in lateral, temporal and parietal brain metabolism."

New Treatment-Testing Strategy Takes Off

"These are the areas of the brain that are affected by AD early on in the disease course," Small pointed out. "The degree of brain function decline was such that we now have a strategy to test new treatments aimed at preventing age-related memory decline, and AD.

"What that means," Small explained, "is that we looked at the extent of decline in these people, and made a mathematically based calculation on how good we thought our drug is going to be compared to placebo, then we calculated that we would need only 40 subjects over a two-year period to see if this compound actually works.

"So it brings us to a new era of preclinical drug development," he continued." Right now a national study is under way, looking at people with mild cognitive impairment and testing whether a cholinesterase inhibitor such as Arecept or vitamin E is more effective than placebo in preventing the incidence of AD. To do those studies investigators needed hundreds of subjects, who are generally hard to find, and the studies are done in multiple centers throughout this country.

"Now we can do such a study in a single site. And actually, we've started it. We've got a new UCLA memory clinic, and the last few weeks we've begun a study looking at the new anti-inflammatory drug Celebrex to see if it prevents brain-function decline. We're using genetic risk and PET imaging as our baseline measures, and PET as the primary outcome measure."

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