Alzheimer's is a slow, insidious disease that ravages nerve cells in the brain. It robs victims of their memory, the ability to perform simple tasks and eventually their lives. Frustrating to patients and doctors is the lack of surefire tests that warn of the disease or how far it has advanced.

High cholesterol levels can signal heart disease, measuring glucose levels can track diabetes and various tests identify cancer. But for Alzheimer's, there is no blood test or easy way to peek into the brain to detect the complex disease. In fact, a 100 percent diagnosis of Alzheimer's is possible only at autopsy when pathologists can see the plaques and tangled fibers in brain tissue that clog the brain and damage the nerve cells.

University of California researchers, however, are heavily involved in a large nationwide project to discover indicators - or biomarkers - that can not only track progression of the disease, but perhaps diagnose Alzheimer's early on.

Looking inside the brain

The Alzheimer's Disease Neuroimaging Initiative (ADNI), a $60 million nationwide study the National Institutes of Health launched five years ago, follows 800 older people - 200 with severe dementia and likely Alzheimer's, 400 with mild cognitive impairment and 200 who are healthy. Each undergoes periodic tests, including brain imaging, to learn how their brain function and structure change over time.

For some, mild cognitive impairment is the intermediate phase between normal brain function and Alzheimer's, perhaps even an early stage of the disease. In this phase, patients have difficulty with memory, such as recalling names of people they just met, trouble remembering the flow of a conversation and an increased tendency to misplace things.

"The beauty of the ADNI project is that it's a large sample and everybody's getting lots of different measurements," said principal investigator Michael Weiner, a UCSF professor and director of the Center for Imaging and Neurodegenerative Diseases at the San Francisco Veteran's Affairs Medical Center. "You're able to look at this population, and you look at their MRIs and their PET (Positron Emission Tomography) scans, their cerebrospinal fluid and their cognition data, and you can see how it all fits together."

The original goal of ADNI was to help speed up and streamline drug and clinical trials by developing biomarkers that track Alzheimer's more reliably than current clinical and neuropsychological measures. Weiner said that the study may indeed yield methods for diagnosing or even predicting Alzheimer's in patients suffering from only mild memory loss.

Researchers, for example, have developed MRI and PET brain imaging techniques to better spot and measure beta-amyloid, the main element of the plaque that plays a central role in Alzheimer's. ADNI researchers at UC San Diego have just reported a fast and accurate MRI method for quantifying subtle sub-regional brain volume loss in patients with mild cognitive impairment.

A study last year by William Jagust, a UC Berkeley neuroscientist who directs ADNI's PET studies, found that a cluster of events - beta-amyloid disposition, atrophy of the hippocampus (part of the brain critical for storing and sorting memories) and episodic memory loss - could signal early stages of the disease. Not everyone who has deposits of plaque in their brain develops Alzheimer's, and the same goes for spotty memory and brain atrophy, but a confluence these three factors is difficult to ignore, Jagust said.

"With PET, we're able to study the biochemistry of the brain, and with MRI we can study both the anatomy and structure of the brain," he said. "We can also study some of the function of the brain to see what parts of the brain are active during different cognitive tests.

"So, when you put all this information together, you can get a very detailed picture of how the brain is functioning and how function and structure might change with age."

Fine-tuning diagnosis

Susan Landau, a postdoctoral fellow in Jagust's lab, reported a study of 85 older people this summer that found that those with mild cognitive impairment, low scores on a memory recall test and low glucose metabolism in some brain regions had a 15-times greater risk of developing Alzheimer's disease within two years, compared with others in the study.

"It looks like, as different parts of the brain show deterioration, as neural degeneration develops, glucose metabolism - or how well the brain is working - that declines," Landau said. "Where we'd like to go is to start moving earlier and earlier in the disease spectrum and hopefully target people who haven't experienced any decline and target them for potential participation in clinical trials and more research."

Indeed, ADNI's greatest value, for now, is collecting data from the 58 ADNI centers in the United States and Canada, including all five UC medical centers, to identify biomarkers or signals for Alzheimer's. The promise of developing reliable biomarkers drew pharmaceutical companies into the unique ADNI project. It is supported by more than a dozen other federal agencies and private-sector companies and organizations, making it the largest public-private partnership on brain research at the NIH.

Pharmaceutical companies have already spent untold millions in the race to come up with treatments for Alzheimer's. Currently, there are only five approved drugs for the disease. But those drugs only offer some symptomatic relief and don't stifle or halt the disease, said Paul Aisen, a UC San Diego neuroscientist who directs the Alzheimer's Disease Cooperative Study, a National Institute on Aging program that coordinates dozens of clinical trials on Alzheimer's.

Proven biomarkers can help drug developers target treatments for specific stages of the disease and give researchers clear ideas during clinical trials if and how the drug is working. Every company working in Alzheimer's drug development is likely using ADNI data to design its clinical trials, said Aisen, who is a principal investigator for ADNI.

New treatments show promise

Aisen is confident that effective treatments will be available in the foreseeable future - perhaps even within the next 10 years. "The science has advanced to where we have some promising targets for drug development, and there are some good candidates in clinical trials now," he said.

The next generation of Alzheimer's drugs, Aisen said, "will target not the symptoms but rather the underlying pathology."

"Ultimately, what we want to do is prevent Alzheimer's disease," said Weiner of the future of Alzheimer's drug development. "That would mean identifying normal healthy people as early as possible and putting them on a very safe treatment that doesn't have any side effects.'

But that's a "high bar," he said. "First of all, you need good predictors."

Projects like ADNI will find those predictors, Weiner said. This fall, the project wrapped up an initial five-year phase, and funding for ADNI part two is pending. Researchers have received a $24 million grant from the American Recovery and Reinvestment Act to follow current subjects for a couple more years. The next ADNI hopes to enroll 200 new subjects with early mild cognitive impairment to help define a possible phase between healthy and early memory loss.

In addition to Weiner, Jagust and Aisen, UC researchers are prominent in ADNI. Laurel Beckett at UC Davis is the biostatistics leader and Art Toga at UCLA oversees the large databases that are accessed by thousands of Alzheimer's and brain disease researchers from all over the world.

"All the clinical data from patients - the images, the MRIs, the PET scans, the blood tests, the neuropsychological tests, the genetic tests - all of that goes into a database," Weiner said. "And what we've decided to do is release that data without embargo. Most scientists keep their data in their own computers, locked up in their laboratories and it never sees the light of day. And I think that's bad.

"We need to get this raw data available to everybody, so it can be searched and mined and used," he said. "There are many advantages to having release of raw scientific data and almost no disadvantages."

In the end, researchers and companies would benefit in their quest to develop drugs for Alzheimer's, and patients will be that closer to a treatment - or cure - for the dreaded disease.

Andy Evangelista is coordinator of research communications in the UC Office of the President's Integrated Communications group.