Learning Objectives:
- Briefly define Alzheimer’s disease (AD) and explain the major presenting symptoms
- Explain the epidemiology of Alzheimer’s disease including the lifetime prevalence, prevalence in first degree relatives of persons with Alzheimer’s disease, incidence, prevalence by gender, and age at onset
- Describe current thoughts on the etiology of Alzheimer’s disease
- Describe the role of genetic counseling with regard to Alzheimer’s disease
Pretest Questions:
1. For a person with a first-degree relative with Alzheimer’s disease the risk of developing the disease is:
A. Increased by 10% over the average risk of the general population
B. No greater than the general population
C. Four times greater than the general population
D. This person will develop Alzheimer’s disease inevitably
2. Which of the following is the strongest risk factor for developing Alzheimer’s disease?
- Age
- Sex
- Race
- Educational level attained
3. Which of the following genes plays a role in the movement and distribution of cholesterol for repairing nerve cells during development and after injury and is believed to be a major risk factor for late-onset Alzheimer's?
A. ApoA2
B. BA4
C. ApoE4
D. NF2
Case Study:
Ms. D is a 41 year-old woman who presents to her primary care doctor for a routine annual exam. Her mother was diagnosed with Alzheimer’s disease a few years ago. Ms. D. is caring for her mother which has become increasingly difficult. She is concerned about developing Alzheimer’s disease in the future.
Family History: Ms. D. is the youngest of 3 children. She works in the fashion industry and is happily married with 2 sons. Aside from having high cholesterol, she is healthy. Her parents immigrated from Russia before she was born. Her father died from a heart attack at age 68. Her mother, age 75, is currently living with Ms.D. and has Alzheimer’s disease.
Questions For Discussion:
- What is Alzheimer’s disease?
- Who gets Alzheimer’s disease? Describe the characteristics of the disease and the pathology.
- What are the risk factors for developing Alzheimer’s disease?
- What is the prevalence of Alzheimer’s disease in men verses women?
- What is the age of onset of Alzheimer’s disease in men verses women?
- What is known about the inheritance pattern of Alzheimer’s disease?
- What type of work-up would be appropriate for this woman now?
- What genetic testing could you offer this woman?
- What other type of support could you offer her as the caregiver of a person with Alzheimer’s disease?
- What is Alzheimer’s disease?
Alzheimer's disease (AD) is the most common cause of dementia. It is a slowly progressive disease that initially presents with short-term memory loss. Additional symptoms include executive dysfunction, confusion, aphasia, gait, and behavioral disturbances. The typical age of onset is older than 65 years. The average duration of illness ranges from 4 to 20 years and there is no recovery.
No single clinical test that identifies AD exists. A comprehensive patient evaluation includes a complete health history, physical examination, neurologic and mental status assessments, and other tests, including analysis of blood and urine, electrocardiogram, and an imaging examination such as computed tomography or magnetic resonance imaging. Although this type of evaluation may provide a diagnosis of possible or probable AD, confirmation requires the examination of brain tissue at autopsy. Today, new diagnostic tools and criteria make it possible for all physicians (primary care as well as specialists) to make a positive clinical diagnosis of probable AD with an accuracy of approximately 90%.
Pathologically, AD is characterized by diffuse cerebral atrophy associated with β-amyloid (Aβ) neuritic plaques, neurofibrillary tangles, and amyloid angiopathy as first described by Alois Alzheimer in 1911. Senile plaques are complex structures consisting primarily of a core of abnormal aggregates of a small protein molecule known as Aβ. Neurofibrillary tangles are dense bundles of helically wound abnormal fibers composed of a modified form of a normally occurring neuronal protein, the microtubule-associated protein tau. The presence of either senile plaques or neurofibrillary tangles is not pathognomic of AD . They are both known to occur in other neurodegenerative disorders as well as in normal aging. A higher density of these lesions in specific brain regions along with the presence of a clinical history of dementia consistent with AD confirms the diagnosis of AD.
- Who gets Alzheimer’s disease?
AD is the most common form of dementia among persons over the age of 65 years. Recent studies estimate that up to 4.5 million persons currently have the disease, and the prevalence doubles every 5 years after the age of 65. By 2050, if current population trends continue and no preventive treatments become available, approximately 13.5 million Americans will have AD. More women than men are affected even after adjustment for the greater longevity of women.
AD primarily affects the elderly. One in 10 persons who are 65 years old or older and nearly half of those who are more than 85 years old have AD. It is important to note, however, that AD is not a normal part of aging and can strike the young; cases of patients in their 30s and 40s have been reported.
3. What are the risk factors for developing Alzheimer’s disease?
The risk for AD increases with advancing age. The next most important risk factor for AD is family history. Epidemiologic studies show that individuals who have an affected first-degree relative with AD have an approximately fourfold greater risk of developing AD and a total lifetime risk of 23% to 48%, although more recent European studies do not report such high estimates. To date, reports on monozygotic and dizygotic twin pairs have suggested higher concordance rates in monozygotic twins than in dizygotic twins. Although the sample sizes are small, they suggest that genetic components play an important role. The lack of complete concordance in monozygotic twins suggests that environmental components are also important in the etiology of AD. In addition to genetics and apoE, education, diet, environment, and viruses are being studied to learn what role they might play in the development of this disease.
The risk for AD is even higher if there are individuals in more than one generation with the disease, especially when the disease is of early onset (age <65 years). In some of these rare families, AD occurs as a single-gene autosomal dominant trait. Further proof for a genetic basis in AD is that all persons with trisomy 21 (Down syndrome) who survive beyond the age of 40 years invariably demonstrate the neuropathologic features of AD . These observations led to the finding of mutations in the amyloid precursor protein (APP) gene on chromosome 21, the first documented genetic cause of AD . Although there are fewer than 20 families worldwide with APP mutations, the discovery of these mutations confirmed that genetic factors are important in AD.
4. What is known about the inheritance pattern of Alzheimer’s disease?
The first-degree relatives of affected individuals have an increased risk of Alzheimer's disease. Three genes are directly linked with Alzheimer's disease ; Chromosome 21 carries the gene for amyloid precursor protein, the precursor of β-amyloid; this finding is consistent with the Alzheimer-like pathology on autopsy in a high proportion of adults with Down syndrome (trisomy 21). Another gene associated with early-onset Alzheimer's disease, presenilin 1 (PS1), is on chromosome 14. Autosomal dominant early-onset Alzheimer's disease is also linked to presenilin 2 (PS2) on chromosome 1. Patients with PS1 mutations have a characteristic early age of onset, between 35 and 60 years old of age, whereas PS2 mutations are found almost exclusively in families of Volga-German heritage. Together, these three mutations account for fewer than 2% of cases of Alzheimer's disease.
Although they are not directly linked to the disorder, several other genes increase the susceptibility to Alzheimer's disease. The most important is the gene for ApoE, a plasma protein involved in cholesterol and triglyceride transport and, probably, in repair of nervous tissue after injury. The ApoE gene is located on chromosome 19, and there are three common alleles, E2, E3, and E4. The E4 allele increases the risk for Alzheimer's disease, with the attributable risk estimated to be 45 to 60%. E4 homozygotes are at greater risk than E4 heterozygotes. ApoE4 is present in plaques and may facilitate the accumulation of amyloid in the brain. In addition, chromosomes 10 and 12 may harbor other polymorphisms that increase susceptibility to late-onset Alzheimer's disease.
Findings also suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.
5. What type of work-up would be appropriate for this woman now?
Cognitive function should be assessed not only in those concerned about memory loss but also in patients who may not exhibit obvious symptoms but have risk factors for the disease, such as age and family history.
Recognizing symptoms early and accurately diagnosing a patient with AD is important. Although the onset of AD cannot be stopped or reversed, an early diagnosis gives patients a greater chance of benefitting from existing treatments and allows them and their families more time to plan for the future.
6. What role does genetic counseling play for this woman?
Several genes associated with Alzheimer disease have been localized and cloned; two genetic tests are already commercially available, and new tests are being developed. Genetic testing for AD--either for disease prediction or for diagnosis--raises critical ethical concerns. The multidisciplinary Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics, and Society (PGES) presents comprehensive recommendations on genetic testing for AD. The Group concludes that under current conditions, genetic testing for AD prediction or diagnosis is only rarely appropriate.
The American Academy of Neurology’s 2002 guidelines state that routine use of APOE genotyping in patients with suspected AD is not recommended at this time and that there are no other genetic markers recommended for routine use in the diagnosis of AD.
7. What web based resources and support groups are available for this woman and her family?
(800) 438-4380 The center offers information on Alzheimer's disease and institutions that offer clinical trials.
- Alzheimer's Association www.alz.org (800) 272-3900 This organization provides names of local chapters, fact sheets, and advice. It also provides information for Safe Return, a program for wandering Alzheimer's victims.
- National Institute of Neurological Disorders and Stroke www.ninds.nih.gov
(800) 352-9424. The institute provides information on clinical trials.
- The government provides an excellent site for comparing nursing homes: www.medicare.gov/NHCompare/Home.asp
Hyperlinks:
Reference articles:
Alzheimer’s Disease: Clinical Topic Tour. MDConsult. Retrieved on April 24, 2005 from http://home.mdconsult.com/das/stat/view/46668269-2/ctt?nid=69391&sid=360598168
Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company. Retrieved on April 23, 2005 from http://home.mdconsult.com/das/book/46654082-3/view/1231?sid=360595640
Knopman DS. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.
- Neurology - 8-MAY-2001; 56(9): 1143-53. Retrieved on April 24, 2005 from http://home.mdconsult.com/das/guideline/view/46668269-
Tsuang DW. Genetics of dementia. Med Clin North Am - 01-MAY-2002; 86(3): 591-614
Retrieved on April 24, 2005 from http://home.mdconsult.com/das/journal/view/46668269-2/N/12488093?sid=360740612&source=MI2/N/11834057?ja=222181&PAGE=1.html&sid=360741804&source=MI
|
