"Keys! Where are my keys? Now where'd I put them?"

It's a question you've asked yourself hundreds of times in your life, but now - maybe because you're older or because you seem to be forgetting things more frequently - you begin to wonder...could it be? Is this how it starts?

It's also the kind of question that Mayo Clinic neurologists hear every day.

"Some people are so concerned that they interpret every little forgetfulness as Alzheimer's Disease (AD). That's why in our investigations into aging and dementia we are studying the total spectrum of cognitive changes—memory, forgetting, language problems—that develop in normal aging," explains Ronald Petersen, M.D., Ph.D., director of the Alzheimer's Disease Research Center at Mayo Clinic in Rochester, Minn. "Where do we draw the line between pathology and normal aging? We all become forgetful as we age. Providing patients with perspective is one of the most important thing our research does."

Preparing medical providers to treat—and hopefully prevent—Alzheimer's is another important aspect of the Mayo Clinic work. Nationwide, the number of Alzheimer's cases is expected to quickly rise as the first wave of the post-WWII generation reaches 60.

Says Dr. Petersen: "When the baby boomers reach the age where they are at risk for Alzheimer's, which is not too far down the road, it's going to become a huge public heath concern. And it's not something we can wait to study when it happens. We have to anticipate it and try to prevent it. Otherwise, with millions more people who have cognitive impairment and dementia, it's going to be an enormous health care problem."

The Mayo neurology team, which spans all three Mayo Clinic locations—Rochester, Minn.; Jacksonville, Fla.; and Scottsdale, Ariz., are recognized leaders in AD and related neurodegenerative disease research. In creative, interdisciplinary collaboration, researchers conduct investigations that range from the molecular workings of memory to clinical trials that test new drugs for treating neurodegenerative conditions. In all, the needs of the patients come first.

Says Dr. Petersen: "When we conduct patient-oriented research, we work on the very earliest signs of abnormal memory function—forgetfulness—and try to detect it."

Mayo Clinic neurologists do this by examining patients, taking careful family histories, administering memory tests, and using imaging such as MRI to look at various regions of the brain. At key sites, they evaluate the structural integrity and test functioning. Dr. Petersen collaborates closely with MRI investigator Clifford Jack, M.D.

"Our purpose in this is to see if we can pick up the very earliest signs of what might become Alzheimer's disease in the future,'' says Dr. Petersen. "The goal of early detection is key to achieving the most effective treatment."

Predicting AD with a Clinical Model

Dr. Petersen's group is working on an important clinical tool, called a multivariate predictive model, to facilitate early diagnosis. Ultimately, the goal is to use the tool to identify people at risk and treat them with novel therapies thereby forestalling the whole situation before it evolves. An apt analogy of a clinically useful predictive model already exists in cardiovascular medicine.

"When you're 45 years of age, our colleagues in cardiovascular medicine try to predict your risk of developing heart disease when you're 65 with tests such as measuring the cholesterol in your blood and doing a stress test. If they find a problem, they can recommend a lifestyle modification or a cholesterol-lowering drug to correct it. The idea is to try to prevent heart disease before it develops," explains Dr. Petersen. "We're not there in Alzheimer's yet, but this is where we're headed."

Cutting Edge Research in Jacksonville

The 12 Neuroscience Research laboratories at Mayo Clinic in Jacksonville, Fla., have gained international recognition for their contributions to the field.

Steven Younkin, M.D., Ph.D., is a pharmacologist in Mayo's Department of Molecular Pharmacology and Experimental Therapeutics and a faculty member of the Molecular Neuroscience Program. Dr. Younkin is excited to be partnering with the pharmaceutical industry to develop the group's basic science discoveries into treatments that will help patients with AD. The discovery centers around a substance produced in all human cells: amaloid beta-protein 42 (Aß42).

"Aß42 is a peptide that is deposited in the brains of patients with AD in large numbers," explains Dr. Younkin. "They produce microscopic lesions called senile plaques. Our results indicate that reducing the number of senile plaques in the brain will likely be an excellent way to treat AD."

Todd Golde, M.D., Director of Neuroscience Research at Mayo Clinic Jacksonville, and pharmacologist Christopher Eckman, Ph.D., are also searching for drugs that lower Aß42. They are focusing on repurposing existing drugs by examining their potential for reducing Aß42.

"Remarkably, both laboratories have been successful in finding therapies that are effective in early preclinical trials," says Dr. Younkin. "This is particularly exciting because we already know how to give the existing drugs safely. They have yet to pass the rigorous clinical trials that are necessary before we can declare them effective for human therapy but their early success makes us optimistic that more effective treatment for AD will be available in the not too distant future."

Dr. Younkin is confident that Mayo Clinic's deep and broad collaborations will continue to facilitate Mayo's leadership in neurodegenerative research.

"We are one of the few centers in this country who have both an NIH-sponsored AD Disease Research Center and an NIH-sponsored Udall Parkinson's Disease Research Center," says Dr. Younkin. "Perhaps the best way to convey the quality of our work is to point out that three of our scientists have received the MetLife Award, and two have received Potamkins. In addition, our scientists have received both the Beeson and Ellison awards."

The MetLife Award, and the Potamkin Prize given by the American Association of Neurology, are the most prestigious awards made to senior scientists working in the neuroscience research field. The Beeson and Ellison Awards are the equivalent for junior scientists."

Aß42: The Alzheimer's Disease "Cholesterol?"

In 1992, Dr. Younkin's lab discovered that Aß is a secreted protein, normally present in blood and cerebrospinal fluid. It was an unexpected discovery with enormous implications for the potential of developing a blood test to predict AD in the same way that blood levels of cholesterol are used to predict heart disease.

The lab has since developed a test that does that very thing—measures the level of Aß42 in the blood. Dr. Younkin is now using it in collaboration with Dr. Petersen in Rochester, and Neill Graff-Radford, M.D., a neurologist at Mayo Clinic in Jacksonville, to test its validity in correlating a high level of Aß42 with increased risk for AD.

"We have a large longitudinal study underway to consolidate early evidence that the test may be a simple first screen that could be analyzed to identify a high risk group," says Dr. Younkin. "More sophisticated tests and close follow up would then be performed on the high risk group with elevated Aß42. Then, once safe and effective drugs are developed to lower Aß42, we can initiate therapy to prevent AD in the high risk group."

Genetic Predisposition

Another area of inquiry at Mayo Clinic in Jacksonville is analysis of genetic characteristics in patients with AD. About one percent of AD cases are caused by genetic mutations that run in families. More than 100 disease-producing mutations have been identified by analyzing families in which this rare, early onset familial form of AD occurs.

Both Dr. Younkin and neurobiologist, Michael Hutton, Ph.D., are searching for the genetic determinants that increase risk for typical late onset AD.

"My lab carefully studied the mutations that cause early onset familial AD," says Dr. Younkin. "We showed that they all increase production of Aß42. This indicates that reduction of Aß42 is likely to be an excellent approach to therapy. Virtually all major pharmaceutical companies now have substantial programs to develop drugs for AD that target Aß42."

Pioneering Transgenic Mice

One of the Jacksonville group's most important contributions to AD research worldwide is making their mouse model of AD Disease—the world's first—widely available. Genetically engineered, or transgenic, animals are a staple of biomedical research worldwide.

"By expressing one of the mutated human genes that cause AD in transgenic mice, we were able to produce a line of mice that develop plaques in their brain which are just like those that occur in people with AD," explains Dr. Younkin. "To do this, we collaborated with Dr. Karen Hsiao-Ashe's group at the University of Minnesota. Mayo then licensed the model to many major pharmaceutical companies enabling them to test therapies aimed at stopping plaque formation, and we also made this model freely available to academicians."

More recently, Dr. Hutton received the Potamkin Prize and he and Dennis Dickson, M.D., were jointly awarded the MetLife prize for their pioneering work in creating a second successful mouse model—one that consistently produces the other AD hallmark, neurofibrillary tangles.

In addition to senile plaques formed by the protein Aß42, patients with AD Disease have other microscopic lesions called neurofibrillary tangles in their brains. The molecule that forms tangles is a protein called tau.

Dr. Hutton focused on identifying the genetic mutations that cause a rare neurodegenerative disease called frontotemporal dementia with Parkinsonism—also called FTDP-17 because the gene that causes it is on chromosome 17. Patients with FTDP-17 develop tangles in their brains, but no plaques.

"In beautiful work published in the prestigious journal Nature, Dr. Hutton showed that the mutations that cause FTDP-17 are in the tau gene—the gene that makes the major protein that forms tangles," lauds Dr. Younkin.

Dr. Hutton then collaborated closely with Jada Lewis, Ph.D., to develop transgenic mice expressing human mutations that cause FTDP-17. Simultaneously, he collaborated with pathologist Dennis Dickson, M.D, who analyzed the progression of disease in the brains of mouse models. Working together, this group succeeded in developing the first animal model that develops authentic neurofibrillary tangles.

To link plaque formation to tangle formation, the group then crossed the mice that develop plaques with the mice that develop tangles.

Memory Loss Study

Mayo Clinic has provided comprehensive, consistent care of patients under uniform reporting conditions for more than 100 years—and carefully recorded, organized and archived this information in custom-designed patient record-keeping systems. As a result, Mayo Clinic has what is believed to be the largest, most comprehensive patient data base in the world.

Combined with Mayo Clinic scientists' exceptional analytical abilities, this resource gives Mayo Clinic a leadership advantage for discerning disease trends in a population.

The Alzheimer's Disease Research Center in Rochester is taking advantage of this resource in a collaborative longitudinal study with the Olmsted County Medical Center on the memory habits of Rochester citizens. A "longitudinal" study monitors changes over time for many years. Study participants have had their memory strength analyzed and documented for the past 18 years, and will continue to do so for many more. The study will help Dr. Petersen's group to define a normal amount of memory loss due to aging.

Successful Aging Study

Widespread longevity is a 20th century phenomenon. As a result, there isn't a great deal of data that characterizes normal, healthy aging. To fill in the gaps in understanding, Dr. Petersen's group is studying successful aging in the context of community.

"We're investigating why one person is successful at aging actively and another is not," says Dr. Petersen. "We gather data about genetic make-up, medical history and lifestyle habits and integrate the knowledge with images from brain scans that show structure and function.

4.5 million Americans now have Alzheimer's disease and U.S. society spends $100 billion a year to care for them. By the year 2050, the figure is expected to quadruple as more people live into their 80s and 90s. By learning how to predict dementia, collaborating with industry to develop new treatments, and conducting basic research with a goal to discovering preventative therapies, Mayo scientists are working hard to stop this serious threat to the health of our elderly.