Lan Xiong, MD, PhD, CHUM Research Centre, Notre-Dame Hospital, Montréal Hospital, Montréal, QC.
Claudia Gaspar, PhD, CHUM Research Centre, Notre-Dame Hospital, Montréal Hospital, Montréal, QC.
Guy A. Rouleau, MD, PhD, FRCPC, CHUM Research Centre, Notre-Dame Hospital, Montréal Hospital, Montréal, QC.

Both Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are genetically complex and heterogeneous disorders. Although fully penetrant (causal) mutations leading to predominantly familial early onset AD have been identified in three genes (APP, PSEN1, and PSEN2), they only account for a small fraction of AD patients. PSEN1 is considered the most frequently mutated gene in early onset AD. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases of FTD. One partially penetrant genetic risk factor (APOE4) has been established for the more common late-onset form of AD. Despite advances in elucidating the genetic epidemiology of AD and FTD, the etiology for most patients with dementia remains unclear.

Key words: Alzheimer’s disease, frontotemporal dementia, genetics, linkage, mutation.

Oral cancer is the most common neoplasm of the head and neck and the ninth most common cancer worldwide. A simple, novel genetic test may now help with early diagnosis of this disease. The most common premalignant lesion of the oral cavity is oral leukoplakia, the presence of white patches in the mouth. Leukoplakia is recognized as an increased risk for cancer but there are no reliable clinical or histologic features that can be used to predict whether it will progress to cancer.

Researchers measured the DNA content (ploidy) of 150 patients with oral leukplakia, classified as epithelial dysplasia. What they found was that ploidy could be used to predict outcome. Patients with leukoplakia containing the normal 46 chromosomes were unlikely to progress to cancer. However, a startling 84% of patients with aneuploid lesions developed squamous cell carcinoma. The test was 97% accurate in its ability to predict that a patient would not develop cancer, and 84% accurate in its ability to predict that one would.

Unfortunately, a single molecular marker or class of markers cannot be used to predict the outcome of every case of oral leukoplakia because oral cancers develop along complex molecular pathways. Further studies are needed to support these data.

Sources

1. Sudbo J, Kildal W, Risberg B, Koppang H, Danielsen HE, Reith A. New England Journal of Medicine. 2001;344:1270-8.

Nariman Malik, BSc
Contributing Author,
Geriatrics & Aging.

Lou Gehrig: A Brief History
Lou Gehrig was born June 19, 1903 in New York City. He played for the New York Yankees from 1923 to 1939 and was one of the most famous first basemen in the history of major league baseball.¹ The man known as the 'iron horse of baseball' and 'Columbia Lou' was originally recruited for only two games in 1923.² However, this durable athlete went on to play in 2,130 consecutive games.³ In fact, he never missed a game until he voluntarily benched himself on May 2, 1939.

Gehrig had an impressive career. He had a lifetime batting average of .340, hit 493 home runs and was a four-time winner of the Most Valuable Player award.³ He was also inducted into the Baseball Hall of Fame. The 1938 season had proven to be a bad one for Gehrig as he was not playing up to his usual standard. During spring training for the 1939 season, he began having trouble getting power behind the ball and had difficulty with his movements.² Unhappy with his performance, Gehrig voluntarily benched himself.

Six weeks later, Gehrig was referred to the renowned Mayo Clinic where he was diagnosed with amyotrophic lateral sclerosis (ALS). Gehrig was never told his true diagnosis and was unaware that the outcome was fatal. Only his wife and a few of her confidantes knew the true nature of Gehrig's illness.

Lilia Malkin, BSc

Throughout the centuries, people have turned to medicinal substances to improve their health and quality of life. Today, medi-cations continue to be invaluable partners in humanity's war against disease. However, each person has a unique response to his or her medication(s). The differences among patients' reactions to pharmaceutical therapy can be at least partially explained by the inter-individual variation in drug metabolism. As biotechnology continues to make progress, the genetic foundation for illness and the consequent response to treatment is becoming increasingly apparent.^1,2 The basis for patient-to-patient variability in the effects of pharmaceutical agents has thus far been attributed predominantly to the drug-metabolizing capacity of the liver.¹ Accordingly, this article will focus on the hepatic biotransformation enzymes and the contribution of genetic polymorphism to individuals' thera-peutic responses and to treatment-related complications. It should be noted that tissue receptors and transporter proteins are also often subject to polymorphic variations, contributing to the variable response to medications and toxins; a discussion of this topic is, however, beyond the scope of this paper.

Hepatic Drug Metabolism Enzymes: An Overview
The metabolism and elimination of pharmaceutical agents may occur at several sites in the human body, including the liver, kidneys, gastrointestinal (GI) tract, lungs, and skin.

Down's Syndrome, a potential model for the pathogenesis of Alzheimer's disease

Nariman Malik, BSc

Alzheimer's disease (AD) is the most common cause of dementia in the elderly.¹ It affects more than 5% of all people age 65 and over and about 25% of those aged 85 and over.^2,3 This devastating disease is characterized by a progressive loss of cognitive abilities, usually beginning with short-term memory difficulties and progressing to include language, visuospatial and executive dysfunction.¹ Mean survival time following a diagnosis of Alzheimer's disease is about 8 years and death usually occurs as a result of intercurrent disease.⁴ In 1991, the Canadian Study of Health and Aging estimated that over 160,000 Canadians met the criteria for Alzheimer's disease.⁵ If the current trends continue, by the year 2031 the number of cases are predicted to triple while the population will have only increased by a factor of 1.4.⁵

The main risk factors for developing AD are advancing age and family history. The disorder can be classified as familial or sporadic. Familial cases are usually early-onset (onset before age 65), while sporadic cases are usually late-onset (onset after 65). The majority of cases of AD are sporadic. Individuals with a first degree relative with sporadic AD, are at twice higher risk of developing the condition.

Philip Dopp, BSc

The disturbing statistics with regard to the prevalence of osteoporosis among older women are well known. By 65 years of age, one in four women have experienced an osteoporotic fracture, and the rate of incidence rises to one in two by the age of 75. The incidence of hip fractures among women in the United States is 2 per 1000 patient years by the age of 65 and 30 per 1000 patient years by the age of 85.1 More importantly, hip fractures in the elderly are associated with a high mortality rate. Both men and women are between two and five times more likely to die during the first 12 months following a hip fracture when compared to age and sex matched controls without hip fractures. Given this and other serious consequences, there is much interest in discovering factors that can prevent or slow the rate of development of this disease.¹

Pathophysiology of Osteoporosis
Osteoporosis is the generalized, progressive diminution in bone tissue mass per unit volume which causes skeletal weakness, even though the remaining bone is normal morphologically. It is well known that factors that decrease bone mineral density (BMD) and increase the risk of osteoporotic fractures include family history, white race, female gender, estrogen deficiency, low dietary levels of calcium and vitamin D, limited physical activity or immobility and medications such as corticosteroids.^1,2 Currently, there has been an increased interest in determining the role that genetic factors play in the pathogenesis of osteoporosis.

Human Genome Project Nears Completion--Vast Implications for Medical and Biological Sciences

J. Sedmihradsky BSc, MA

Genetic technology has been in the news regularly in recent years, thanks to the enormous advances that have been made in the technological world. The genes linked to diseases such as Alzheimer's disease, Parkinson's disease, asthma and various cancers have been identified and in some cases, patented. By identifying the genes associated with different diseases, researchers may be able to learn more about disease mechanisms and discover new therapies or possible cures.

The Human Genome Project
The Human Genome Project (HGP) is an international research project aimed at establishing an accurate map of all the genes in human DNA. Anticipated outcomes of the project include better understanding, treatment, cure and possible prevention of over four thousand genetic diseases. Advances in forestry, biotechnology and agriculture are also expected,¹ as researchers have studied the genetic makeup of several non-human organisms for purposes of furthering the mapping of human DNA. Project planning began in the mid-1980s but most of the research has taken place since the implementation of the HGP in 1990. The project was initially estimated to span a period of 15 years, from 1990 to 2005,² but the expected completion date was recently moved forward to 2003.

A Promise of Breakthroughs in Geriatric Medicine with the Imminent Completion of the Human Genome Project

Barry Goldlist, MD, FRCPC, FACP
Editor in Chief,
Geriatrics & Aging

When I started practicing geriatric medicine in 1979, I felt that I had left genetic diseases behind. Little did I know how much medicine would change with the advent of molecular genetics. One of the crucial changes in geriatrics is, of course, the elucidation of the genetic nature of Alzheimer's disease. Although currently only symptomatic treatments for the disease are available, an understanding of the genetics of the disease is helping us understand where we should target therapeutic strategies. There is great hope that modulating the metabo- lism of the amyloid precursor protein will allow us to influence the course of Alzheimer's disease. Understanding molecular genetics has been crucial in the development of a mouse model for Alzheimer's disease, which will likely speed the pace of discoveries in the future. Families of patients with Alzheimer's disease are aware of these genetic links, and they require an explanation of the risks that they personally face.

In fact, chronic diseases that have strong genetic contributions dominate geriatric medicine. Examples include diabetes mellitus and coronary artery disease. The genetics are often not simple, and currently modification of risk factors is the only therapeutic strategy that is commonly used. However, it is not inconceivable that this will change in the future and we will be better able to predict who is at risk, and perhaps even use specific therapies that directly modulate the genetic risk. Our experience with most modern medical therapies indicates that the elderly benefit at least as much as younger people. It will be interesting to see if this holds true for more specific interventions directed at the proteins for which specific genes code.

One of the greatest issues in geriatric medicine is that of 'polypharmacy'. Clearly the elderly have more diseases, and are more likely to require medications than younger patients. However, they are more prone to side effects as well. Our ability to tailor medications is very limited because we are often unable to accurately predict the likelihood of side effects. It is possible that a greater understanding of the genetic variability of drug metabolism will allow us to predict more accurately who will benefit from certain drugs and who will not.

These breakthroughs will all be brought about through the growth in knowledge of the human genome. Clearly the field of molecular genetics will dominate medical progress for years to come. This journal has an article on the human genome project. One of the major controversial issues currently is who 'owns' the rights to the human genome. I am one of those who firmly believes it should be in the public domain. I think there is an analogy here from the era of colonial exploitation. When European explorers 'discovered' new areas (ones that were already inhabited!) their actions resulted in untold human misery. Millions perished, some after enduring unimaginable agony. In fact, the explorers had not really discovered anything. North America and Africa had always been there, and had been inhabited by sophisticated societies. Similarly, the human genetic code has 'always' been there. If private concerns 'own' rights to the genome I feel we open up the process to great abuse, and might actually increase human misery.

I don't have the same concerns when it comes to new drugs or therapies, based on an understanding of genetics, being developed. Profit from such endeavors is a spur to innovation and improvements in health care and patent protection is clearly appropriate. However, no one created the human genetic code, and I feel no one should have exclusive rights to any part of it.

Enough moralizing! We have some very interesting interviews for you this month. To complement our article on the Human Genome Project, we have questioned Dr. Jamie Cuticchia, Head of the Bioinformatics Group at the Hospital for Sick Children, on the Genome Project and how having the entire human sequence may one day alter the field of medicine. We also have a fascinating interview with Dr. Tomas Prolla, an Assistant Professor in the Department of Genetics and Medical Genetics at the University of Wisconsin, who discusses recent evidence that the biology of aging is actually controlled by a very small set of genes. Finally, an interview with Dr. John Phillips from the University of Guelph, a specialist in 'oxygen toxicity', reveals that data from his research into fruit fly genetics led to important discoveries about how antioxidants may prevent some of the ravages of old age.

I hope you enjoy this issue, and its emphasis on genetics. I also hope you appreciate the irony for those specializing in geriatrics once again being overwhelmed by trying to understand genetics.

David M. Kaplan, MScHA
Joint Center for Bioethics
Faculty of Medicine, University of Toronto

Alzheimer's disease (AD), a disorder characterized by a progressive loss of cognitive function, affects approximately five and a half million North Americans.¹ Advances in the Human Genome project and genetic testing over the last decade have allowed clinicians and researchers to assess an individual's genetic risk of developing AD.² This paper examines the practical and ethical implications of using genetic testing in order to screen for an individual's risk of developing AD. A useful screening test should be able to exclude unaffected individuals--that is, it should have a high sensitivity and be able to identify affected individuals. It should also have a high specificity. Traditionally screening tests have only been applied for diseases for which preventive measures were available.

Alexandra Nevin, BSc

Type II diabetes is a complicated, multifactorial disease process characterized by a relative insulin insensitivity leading to prolonged hyperglycemia. In comparison with type I diabetes, which is primarily due to the auto-immune-mediated destruction of the insulin producing beta cells of the pancreas, type II diabetes is the more predominant, generally adult- onset form, which predisposes individuals to pathological complications, and is more amenable to lifestyle modifications.

Senior citizens are the population most susceptible to type II diabetes. The Canadian Heart Health Survey reported that 13.2% of men and 12.0% of women between the ages of 65 and 74 have diabetes. In light of the aging population in Canada, researchers continue to investigate the intertwined role of genetics and the environment in the pathogenesis of type II diabetes in an effort to better understand and, ideally, to devise true preventative therapy measures to combat the disease.

Pathogenesis
Two fundamental defects underlie the pathogenesis of type II diabetes. The primary problem is the development of insulin resistance. In an attempt to compensate for the increased blood glucose load, a period of relative maladaptive hyperinsulinemia occurs.