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December 2000
Vol. 9, No. 12, pp. 37–38 40.
Health Perspectives
Leela Holliman
sketch of brainAn Alzheimer’s Epidemic?

As the boomers age, the number of cases is expected to triple.

As the national population ages and baby boomers face the fact that the surviving Beatles can soon claim retirement benefits, diseases associated with aging are receiving much attention. The most prevalent one, Alzheimer’s Disease (AD), is expected to become a major health problem in the 21st century. It has been estimated that, over the next 50 years, the number of cases of AD worldwide will more than triple to 45 million.

AD was first characterized in 1906 by German neurologist Alois Alzheimer, after he discovered atypical structures in a demented woman’s brain. Although it had been known that people lose some of their mental abilities as they age, Alzheimer speculated that these structures caused the decline in cognitive skills. Since then, the perception of AD has changed from a natural process of aging to a manageable, treatable disease. Today, thousands of researchers, physicians, and care providers worldwide are working to understand AD, develop treatments, and ultimately prevent the disease.

What Is AD?
Alzheimer’s Disease in the United States:
  • AD is the third leading cause of death. By 2050, it is expected to surpass cancer for second place.
  • Four million people have AD now. By 2050, that number will rise to 14 million.
  • Nineteen million people are affected as caregivers for AD sufferers.
  • AD costs the U.S. economy more than $100 billion a year. Neither Medicare nor most private health insurance covers the long-term care most patients need.
  • AD costs American business more than $33 billion a year—$26 billion to lost productivity due to employee caregiving, the rest for business’s share of health and long-term care costs.
  • More than 7 out of 10 people with AD live at home, and almost 75% of home care is provided by family and friends. The remainder consists of paid care, which costs an average of $12,500 per year, and is paid for almost entirely by families.
  • Half of all nursing home residents suffer from AD or a related disorder. The average cost for nursing home care is $42,000 per year.
  • The average lifetime cost of care per Alzheimer patient is $174,000.
AD is a progressive, degenerative brain disease that destroys the ability of those affected to function in their daily lives. Although the cause(s) of the disease is under investigation, AD is apparently linked to two types of deposits in the brain. These deposits, called amyloid plaques and neurofibrillary tangles, are essential features of AD and are thought to interfere with the brain’s ability to transmit messages. It is still unclear whether these deposits are the cause or effect of AD, but studies have linked both the number of tangles and the amount of free plaque-forming protein in the brain to the degree of dementia in the patient.

Proteins. Plaques are primarily composed of a fragment of the amyloid precursor protein (APP). This protein is a necessary component of the brain and is normally cut by an enzyme to form the final amyloid protein. A secondary pathway for amyloid protein formation exists, however, in which APP is clipped by two enzymes, resulting in the formation of the -amyloid peptide. It is this fragment that clumps together to form plaques in the brain. Tangles, by comparison, are largely composed of a phosphorylated form of the tau protein. Unphosphorylated tau is nonpathogenic and is involved in cell structure. Upon phosphorylation, however, it is thought to wrap around neurons and interfere with their structure. Many researchers believe that these plaques and tangles lead to deterioration of memory and thought (1).

Genes. Several factors have been associated with increased incidence of the disease, including age, genetics, and gender. One in 10 people over 65 and half of those over 85 are afflicted with AD. A specific form of the apolipoprotein E (APOE) gene—the epsilon4 allele—is a well-established risk factor, and individuals carrying this mutation significantly raise their AD risk by eating a diet extremely high in fat (i.e., a diet in which more than 40% of total calories are derived from fat). However, the association between the APOE gene and AD is variable and dependent upon ethnicity. In both African and African-American populations, the epsilon4 allele of the APOE gene is weakly correlated, at best, with developing AD.

Brains. Studies indicate that more women than men are diagnosed with AD, but whether this is simply the result of a difference in life span between the genders is unknown. Other studies have found a higher incidence of dementia in those with no education versus those with at least a high school diploma and that an increase in intellectual activity from early to mid-adulthood was associated with a significant reduction in the likelihood of AD onset. Researchers in Sweden have also found that in individuals engaged in productive leisure activities and with a rich social network, dementia incidence was reduced by 40 and 31%, respectively (reviewed in 2).

Early Warning Symptoms of
Alzheimer’s Disease
The Alzheimer’s Association (www.alz.org) has developed a list of warning signs that include common symptoms of Alzheimer’s disease. Individuals who exhibit several of these symptoms should see a physician for a complete examination.
  • memory loss that affects job skills,
  • difficulty performing familiar tasks,
  • problems with language,
  • disorientation with reference to time and place,
  • poor or decreased judgment,
  • problems with abstract thinking,
  • misplacing things,
  • changes in mood or behavior,
  • changes in personality,
  • loss of initiative.
Detection and Diagnosis

Scanning.
Much effort is going into developing new methods to diagnose AD, because the only current physiological method of diagnosis is postmortem examination of brain tissue. Using positron emission tomography, researchers have determined that in specific regions of the resting brain, an AD sufferer reveals a pattern of metabolic deficits such as decreased glucose metabolism and blood flow, but when the brain is stimulated, it compensates for these deficits. In contrast, this compensatory effect is not observed in those suffering with later stages of AD. It is not yet known whether this effect is present in preclinical stages of the disease; however, it is thought to exist before cognitive symptoms appear (3).

Labeling. Work is also underway to radiolabel plaques for in vivo detection. Mice with AD have been injected with a labeled -amyloid peptide that has been modified to more easily cross the blood–brain barrier. In these studies, the protein bound to plaques that were then detected by autoradiography (4).

Diagnostics. Researchers have found higher concentrations of -amyloid in the cerebrospinal fluid and blood of AD sufferers; this suggests the possibility of using -amyloid measurements as a diagnostic tool. Brain atrophy is also being studied because loss of brain matter and overall brain volume in people with AD has been reported (reviewed in 5).

Treatments
Current.
Today’s treatments are predominantly palliative and include such activities as caregiving and psychosocial interventions, as well as antidepressant, antipsychotic, and anxiolytic medications. AD symptoms are treated with drugs such as Cognex (tacrine), Aricept (donepezil hydrochloride), and Exelon (rivastigmine tartrate) to prevent the breakdown of acetylcholine, a neurotransmitter that serves as a connector between neurons. A number of cholinesterase inhibitors and drugs that boost the production of acetylcholine are in various stages of approval and clinical trials. Unfortunately, these drugs function only to suppress the mental decline of AD and do not appear to reverse the process.

Researchers have also been working on ways to delay the onset of AD. Studies performed in the mid-1990s have shown that nonsteroidal anti-inflammatory medication and the antioxidant vitamin E have protective effects against disease development. Also, estrogen replacement therapy for women has been effective in diminishing the incidence of AD and in improving the cognitive abilities of sufferers.

Future. Ampakines, a group of drugs based on dl-amino-3-hydroxy-5-methyl-4-isoxazone-propionate (AMPA), have been shown to improve memory. These drugs act by increasing the sensitivity of AMPA receptors in the brain to the neurotransmitter glutamate. Thus, ampakines facilitate the long-term potentiation of neurons, leaving them in the “on” state for longer periods. In early Phase I clinical trials on volunteers aged 65–76, one particular ampakine was well tolerated and resulted in good responses in short-term memory tests.

Because one of the last events before the death of a neuron is an influx of calcium into the cell, researchers hope that stopping this influx with calcium channel blockers—drugs already used for hypertension—will prevent the death of neurons and, therefore, slow down the disease’s progression. Also, as amyloid plaques are thought to play a crucial role in AD, scientists are trying to find ways to inhibit either of the two enzymes that form the -amyloid peptide, thereby slowing its ability to form plaques (6).

A few years ago, the idea of a vaccine for AD would have been considered a pipe dream, but researchers at Elan Pharmaceuticals (Dublin) recently reported promising clinical trial results. Their vaccine is a synthetic form of the -amyloid peptide that, upon injection, appears to cause the body to produce antibodies against -amyloid. The resulting immune response clears the peptide from the body. The vaccine has been well-tolerated in a Phase I clinical trial and, in experiments with mice, vaccination not only seemed to prevent the disease, but also to prompt the breakdown of plaques in the brain (7). Although much research must yet be done to determine the risks, identifying the potential vaccination may be the first step in curing this debilitating disease. Furthermore, researchers in Boston recently reported success in testing an inhaled form of an Alzheimer’s vaccine. Nasal administration produced a smaller immune response than injection but corroborated the results of the injection vaccination study (8). Clinical trials of the nasal vaccine are pending.

References

  1. Guela, C. Pathogenesis of Alzheimers Disease. www.medscape.com (accessed October 2000).
  2. Hake, A. M; Scherer, P. On the Brink of the Pandemic: Epidemiology and Risk Factors for Alzheimer’s. www.medscape.com (accessed October 2000).
  3. Rapoport, S. I. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5696–5698.
  4. Wengenack, T. M.; Curran, G. L.; Podusio, J. F. Nat. Biotechnol. 2000, 18, 868–872.
  5. Galasko, D. R. Early Detection and Differentiation of Alzheimer’s Disease. www.medscape.com (accessed October 2000).
  6. Thorsett, E. D.; Latimer, L. H. Curr. Opin. Chem. Biol. 2000, 4, 377–382.
  7. Bard, F.; Cannon, C.; Barbour, R.; Burke, R. L.; Games, D.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; et al. Nat. Med. (N.Y.) 2000, 6, 916–919.
  8. Weiner, H. L. Ann. Neurol. 2000, 48, 567–579.

 


Leela Holliman is a freelance science writer living in Alexandria, VA. Comments and questions for the author can be addressed to the Editorial Office by e-mail at tcaw@acs.org, by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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