Unraveling the Mysteries of Dementia

Alzheimer's disease (AD), with its characteristic neurofibrillary tangles and amyloid plaques that clutter the brain, is the most common of all neurodegenerative disorders. The number of affected Americans is currently estimated at four million and is expected to quadruple by the year 2050 unless a cure or an effective preventive is found. AD is by far the most common cause of admission to nursing homes in the U.S. with an estimated total annual cost of $100 billion. For several years, AD and other dementias have been a major focus of interest at the IU School of Medicine.

Two $2.5 million grants were awarded to IUSM, one in 1991 and one in 1996, by the National Institute on Aging, National Institutes of Health, to support the creation and continuation of the Indiana University Alzheimer Disease Center (IUADC). This has allowed researchers, clinicians and educators to gather and systematize the growing amount of data on dementias and provide resources to families they affect.

The most common of the dementias, Alzheimer's disease is an insidious assailant, slowly destroying memory, thought and personality. Because of its stealth, Mickey McNulty isn't sure exactly when AD struck her husband Leo. But it was in 1983 when the Indianapolis mother of five adult children had her first inkling that something just wasn't right with her then-56-year-old spouse. Initially, both Mickey and Leo denied the problem - a typical reaction on the part of AD victims and their loved ones, says Mary Guerriero Austrom, PhD, clinical associate professor in the Department of Psychiatry and director of the education core for the IUADC.

Over the next few years though, Leo's frequent memory lapses and "strange" behaviors became harder and harder for the couple to explain away. Mickey suspected a brain tumor, one of their sons believed work stress was to blame, and two doctors thought the problem was depression. It wasn't until 1990 that the family finally received the crushing diagnosis.

Is It Really AD?

Nearly a decade after Leo McNulty was told he had AD, there still is no definitive diagnostic test short of brain biopsy or autopsy. Fortunately, one of the major clinical advances in recent years has been the development of diagnostic criteria for possible and probable AD. In other words, says Hugh Hendrie, MBChB, professor and chairman of the Department of Psychiatry and an associate director of the IUADC, AD no longer is a diagnosis of exclusion.

"Physicians now can make a positive diagnosis of AD based upon a characteristic history obtained from a spouse or other close relative or friend, physical and neurologic examination, a few laboratory studies, and an imaging study - a head CT or MRI," explains Dr. Hendrie. And, he stresses, the earlier the diagnosis is made, the better. Early diagnosis allows patients and their families time to plan for the future, such as developing advanced directives and appointing durable power of attorney when competence is not yet an issue. Furthermore, prompt recognition of the signs and symptoms of AD allows the possibility of treatment with drugs that can slow cognitive decline.

A Treatment Breakthrough

Up until the early 1990s, absolutely nothing could be done to alter the relentless course of AD. Finally, the first treatment breakthrough occurred. Clinical trials conducted by IUSM faculty and researchers at several other medical centers in the United States and Canada showed that a cholinesterase inhibitor called tacrine (Cognex) improved symptoms in many patients with mild-to-moderate AD. Last year, donepezil (Aricept), another cholinesterase inhibitor with far fewer side effects than tacrine, became the second drug approved to reduce symtoms of AD. Once again, IUSM investigators were involved in the pivotal clinical trials that led to approval.

"Both tacrine and donepezil moderately improve memory, language, and the ability to perform simple tasks," says Martin Farlow, MD, professor of neurology and psychiatry and a principal investigator of these drug trials. "The symptomatic relief they provide can temporarily improve cognitive deficits and their global functions, postponing the need for family and professional home care services and ultimately delaying nursing home placement."

Leo McNulty was one of the 38 patients participating in the IU tacrine study, and the drug "made a world of difference" for him, Mickey recalls. At the start of the study, Leo no longer could remember how to shower or use the toilet. Within a few months, he once again could manage his personal hygiene. This improvement, which persisted for about 18 months, allowed Mickey to continue caring for her husband at home without assistance.

Developing New Drugs

By the year 2000, another half dozen cholinesterase inhibitors likely will reach the market. Clearly though, these agents are no panacea. In Leo's case, tacrine eventually stopped working, and about two years ago, Mickey had to make the painful decision to place him in a nursing home.

For future patients, there is more hope. Within the next five years, Dr. Farlow believes it will be possible not only to mildly ameliorate symptoms with drugs like tacrine and donepezil but also to add new treatments that actually slow disease progression in AD patients or delay its onset in people at high risk.

One potential treatment may involve suppressing the inflammatory response that occurs secondarily in AD through the use of commonly prescribed anti-inflammatory agents like ibuprofen, aspirin and prednisone. And because inflammation contributes to cell death in part by triggering the release of free radicals that cause oxidative cell damage, inhibiting or detoxifying free radicals via antioxidant agents may be yet another way to protect neurons and stall AD development or progression.

"The AD Cooperative Study Group, of which we (IUSM) are a member, recently showed that 2,000 IU daily of the antioxidant alpha-tocopherol (vitamin E) slows AD progression by as much as 25 percent," Dr. Farlow reports. "Consequently, we now recommend that many of our patients take high doses of vitamin E along with a cholinesterase inhibitor." Selegiline (Eldepryl), a drug used to treat Parkinson disease, also may be effective as an antioxidant in AD patients.

In postmenopausal women, estrogen replacement therapy is another possible AD intervention. A number of retrospective epidemiologic studies have found that women taking estrogen after menopause have a lower incidence of AD. A few small prospective trials have showed that estrogen replacement offers some cognitive benefits in women with AD. IUSM faculty now are participating in a multicenter study of estrogen replacement in women with AD and expect to have some preliminary data by year end.

Other therapies that work by a variety of different mechanisms are currently being evaluated in early clinical trials, however none of these mechanisms actually interrupt the underlying pathophysiologic process that causes AD. "The major problem in trying to develop such treatments, which are at least a decade away, is that many of the proteins involved in AD which are abnormally processed or deposited are necessary for the brain to function," says Dr. Farlow.

Nature Versus Nurture

What causes AD - faulty genetics or environmental factors? The answer, most likely, is a combination of both. Mutations in the beta-amyloid precursor protein gene on chromosome 19, discovered in 1991 by Professor of Medicine (now Chairman of Medical and Molecular Genetics) Merrill Benson, MD, and Jill Murrell, PhD '92, in collaboration with Distinguished Professor Bernardino Ghetti, MD, appear to be one cause of early-onset familial AD. A genetic factor on chromosome 19, specifically the apolipoprotein e4 allele (ApoE-4), is also associated with the late-onset form of the disease. "We have subsequently found that the absence of ApoE-4 is a protector against the deposits of beta amyloid in the transgenic mouse brain," says Dr. Ghetti, who published his findings last November.

"For humans, the effect appears to be dose-dependent," explains Dr. Hendrie. "Persons with a single ApoE-4 gene (meaning they received one copy from either their mother or father) are at two to four times greater risk of developing AD. Risk increases four- to eight-fold for those with two copies of the gene." Nonetheless, Dr. Hendrie emphasizes that a large percentage of individuals with AD do not possess the ApoE-4 gene, and some persons who do never develop the disease. Other genetic factors probably are involved, and environment almost certainly plays some role.

IUSM researchers believe that one way to explore the interconnection between genetics and environment in the development of AD is to study groups of people with similar genetic origins living in different locations. The National Institute on Aging has awarded more than $6 million to Dr. Hendrie's team to conduct an epidemiological study in Indianapolis and Ibadan, Nigeria. For the past several years, his research team has been collecting data on the prevalence and incidence of AD in about 2,200 blacks living in Indianapolis and nearly 2,500 blacks living in Ibadan, Nigeria, all age 65 and older.

"The differences in prevalence in the two communities are striking," reports Kathleen Hall, PhD, assistant professor of psychiatry and director of the Indianapolis Study of Health and Aging. "Just 1.4 percent of the Nigerians in our study group were diagnosed with AD compared with almost 3.7 percent of the Indianapolis group. And when nursing home residents were included in the Indianapolis sample (there are no nursing homes in Ibadan), the percentage jumped to 6.2 percent."

Drs. Hall, Hendrie and their colleagues at IUSM and the University of Ibadan College of Medicine are in the process of evaluating the relationship between the ApoE-4 gene among the Nigerian study subjects and also are looking at environmental factors that may explain the discrepancy in AD prevalence. "The biggest difference in the two populations is diet - the Nigerians in our sample are almost exclusively vegetarian," Dr. Hall notes. "Other differences include body mass index and the incidence of hypertension, which is relatively rare among Ibadan blacks but fairly common in the Indianapolis group."

Other Forms Of Dementia

Dr. Ghetti, who is director of neuropathology in the Department of Pathology and Laboratory Medicine and director of the Indiana University Alzheimer and Related Diseases Center, has devoted most of his professional life to studying the human brain, searching for biological causes of dementia. Last year, Dr. Ghetti and co-investigators at IUSM and the Medical Research Council of Great Britain identified a new inherited form of dementia that is clinically and pathologically different from AD. Symptoms of the disease, which first appear in early middle age, include short-term memory deficit, eye movement alterations, disequilibrium, rigidity and gait problems. Affected individuals live an average of 11 years after disease onset.

Dr. Ghetti and his colleagues named this new form of dementia Familial Multiple System Tauopathy with Presenile Dementia and localized it to a genetic mutation on chromosome 17 that causes abnormalities in tau, a key brain protein. "We don't yet know why tau becomes abnormal in patients with this disease, but we do know that it becomes abnormal in a different way than it does in patients with other types of dementia, including AD," says Dr. Ghetti. "We now have the challenge of finding a new gene that may have an extremely important role in maintaining the central nervous system."

Dr. Ghetti also is studying "contagious" dementias caused by prions - proteins that sit on the surface of brain cells and turn deadly only when they, literally, are bent out of shape. A new form of Cruetzfeldt-Jakob disease (CJD), which has killed at least 24 people in Britain in the past three years, is thought to be contracted by eating prion-laced beef from "mad" cows infected with bovine spongiform encephalopathy. Transmission of sporadic CJD has been documented in persons receiving corneal transplants or human growth hormone obtained from individuals who died from the disease.

Scientists do not yet know the precise mechanisms by which prion proteins from an animal or person can change the way these proteins behave in another individual. And while most people probably do not have to worry about "catching" dementia from their next meal or medical procedure, the potential implications of a contagious dementia are staggering. This is just one reason, Dr. Ghetti says, why dementia must be studied more intensely than ever before.

Where to Get More Information

Information on AD and other dementias is available from a variety of sources including: Alzheimer's Disease Education and Referral Center (ADEAR): (800) 438-4380; Alzheimer's Association Central Indiana Chapter: (317) 575-9620 or (888) 575-9624; Alzheimer's Disease and Related Disorders Association: (800) 272-3900; Indiana University Alzheimer Disease Center: (317) 278-2546.