GENOMIC MEDICINE

Alzheimer's disease genes and genetic testing in clinical practice

P. C. Gaskell, Jr., PA-C; Jeffery M. Vance, PhD, MD

Mr. Gaskell is a Genetic Study Coordinator at the Center for Human Genetics, Duke University Medical Center, Durham, NC. Dr. Vance is Professor of Medicine and Associate Professor of Genetics at Duke University, and Associate Director of the Center for Human Genetics. The authors have indicated no relationships to disclose relating to the content of this article.

To educate patients, PAs must understand the genetic heterogeneity of AD and be able to discuss both genetic testing and the implications of test results.

Mr. and Mrs. Smith, 61 and 57 years old, respectively, are established patients in your practice. Mr. Smith is a college graduate, currently a manager in a local business. He has been healthy, having been seen only for routine health maintenance appointments. Six months ago, he arrived for an appointment on the correct day of the week and time but a week early. Today, Mrs. Smith insisted on accompanying Mr. Smith, and he reluctantly agreed.

At her prompting, he reports some recent minor problems such as misplacing his wallet and occasionally having trouble coming up with the word he wants in conversation. He says that this is normal for his age. Mrs. Smith describes forgetfulness beginning at least 2 years ago. She indicates that her husband has forgotten appointments, often repeats both questions and comments, and has written two checks that overdrew their account. He seems unable to focus. His abilities do not fluctuate and, if anything, his difficulties are gradually becoming more noticeable. There is no history of other medical problems or any recent illnesses.

Diagnosis of Alzheimer's disease

Criteria for the diagnosis of Alzheimer's disease (AD) include onset between age 40 and 90 years, initially with progressive worsening of memory and followed by deficits in one or more other areas of cognition, no disturbance of consciousness, and absence of systemic disorders or other brain disease that could account for the dementia.¹ Dementia should be established by clinical evaluation. The diagnosis is supported by impaired functional activities and behavioral alterations and by a family history of similar disorders. Sudden onset and focal neurologic findings would make the diagnosis uncertain or unlikely.¹ AD remains the probable diagnosis if the above criteria are met, even if onset, presentation, or clinical course varies or if another systemic or brain disorder is present that could produce dementia but is not deemed to be the cause of the patient's symptoms.¹ AD is a degenerative dementia. Although it is the most common cause of dementia in the United States, other causes that should be excluded include infectious, neoplastic, psychiatric, toxic-metabolic, vascular, and other neurodegenerative diseases (see "Evaluating Mr. Smith").

 

Evaluating Mr. Smith A focused review of systems reveals no history of head injury, spells, or focal symptoms and no change in coordination or gait. Mr. Smith denies depression or a history of depression and has had no alteration in consciousness, delusions, or hallucinations. There is no history of substance abuse. He is taking no prescription or OTC medications. Mr. Smith's father died at the age of 80 years and was "forgetful" for the last few years of his life; his mother died in an automobile accident at age 50. He has five siblings, aged 65, 63, 57, 55, and 54, and all are well. He has four children, aged 26 to 33 years, and five grandchildren. Results of a general physical examination are normal. The neurologic examination is unremarkable, other than a score of 25 out of 30 points on the Mini-Mental State Examination (MMSE). In addition, Mr. Smith cannot relate any specific current events and cannot generate the names for a "hinge" on a door or "stem" on a watch when the objects are visually presented to him. He does recognize the names when they are provided, however. Finally, he cannot calculate the number of nickels in $1.35, although he says that there are two nickels in a dime and five in a quarter. A review of his record indicates that the results of laboratory studies ordered for screening 6 months ago (CBC, chemistry 20 panel, and lipid panel) were within normal limits. You tell Mr. and Mrs. Smith that the history of decline in memory and other cognitive abilities (naming and calculation) and the score on the MMSE are not normal. Mr. Smith has significant cognitive impairment and may have a dementia. They agree to a number of studies to rule out recognized and potentially treatable causes of dementia, including tests for vitamin B12 level (vitamin deficiency), thyroid function (hypothyroidism), and rapid plasma reagin (RPR) level (neurosyphilis) and a brain MRI (stroke, significant white matter disease, or other structural change that may cause or contribute to dementia). They schedule an appointment to return in 4 weeks to discuss the results.

Genetics: Simple and complex

Clinicians are generally familiar with single-gene defect disorders that are inherited in Mendelian patterns: autosomal dominant (ADm), autosomal recessive (AR), X-linked dominant (XD), and X-linked recessive (XR).² Common examples are Huntington's disease (ADm), cystic fibrosis (AR), and Duchenne's muscular dystrophy (XR). Each is an example of a simple genetic disease for which the cause is a mutation in a single gene (ADm or XR) or in each copy of a pair of genes (AR). Genes involved in single-gene disorders can be called causative. The disorders that arise from them are "Mendelian"—that is, they follow Mendel's rules. Mutations in these single genes result in the disease phenotype; no other mutations are needed to cause the disease. No major environmental interaction is needed for such diseases. The clinical disease results only if an abnormality in a single gene is present.

Genetic disorders can also result from multifactorial inheritance—combinations of genetic variation and/or environmental factors.^2,3 Genes in which variations occur that appear to contribute to disease but do not cause it are called susceptibility genes. Disorders of multifactorial inheritance include diseases such as asthma, diabetes, and coronary artery disease that affect large numbers of people.

Though AD is treated as one disorder, genetically it is heterogeneous. Researchers have identified three causative genes involved in Mendelian forms of AD and one susceptibility gene for AD. Evidence indicates that other genes not yet identified are associated with the disease. Still unknown are the roles that modifier genes or environmental factors may play in phenotypic expression in either Mendelian traits or in multifactorial disorders. Though AD may be a uniform clinical diagnostic category, its etiology is complex.

The genetics of Alzheimer's disease(s)

Mendelian Genetic mutations that cause AD were identified through the study of large kindreds with apparent ADm inheritance of disease. Onset of symptoms is usually before age 60 years, and the disease is thus described as early onset. Sequence alterations in the chromosome 14 gene coding for presenilin 1 (PSEN1) are the most common causative mutations.⁴ Next most common are mutations in the chromosome 21 gene coding for the amyloid precursor protein (APP).⁵ Least common are mutations in the chromosome 1 gene coding for presenilin 2 (PSEN2).⁶ Usually, the disease caused by these mutations is fully penetrant, meaning that anyone whose genome has the mutation will develop AD eventually. Age of onset tends to be more similar within families than between them. The mutation causes the disease in an invariable and deterministic fashion.

These mutations are rare, however, and account for only 1% to 2% of all cases of AD. Given the extremely low percentage, AD in the majority of patients, even those whose disease appeared before age 60, will not be caused by mutations in any of these genes.

Multifactorial Because the mutations described in the preceding paragraph are so rare, AD in the vast majority of patients must have a different causal basis. Currently, one gene, APOE, has been shown to be important in increasing the risk for AD. It was identified when researchers looked for portions of the human genome that were inherited more often by patients with AD than by their unaffected family members.⁷ Portions of the genome located in a region of chromosome 19 fit this pattern. Previous studies had determined that APOE was located in this region of chromosome 19.

APOE codes for a protein, apolipoprotein E, involved in cholesterol transport and known to affect risk of cardiovascular disease. The protein has a role in nervous system growth and repair processes. The APOE gene exists in three forms or alleles, APOEe2, APOEe3, and APOEe4, each of which codes for its own corresponding protein. Each person will have two copies of the gene, one from the mother and one from the father. Thus, there are six possible genotypes.

When researchers evaluated patients with AD, they found that the e4 allele was strikingly overrepresented in those with familial AD (52%) compared to age-matched controls (16%).⁸ Further research revealed that the number of e4 alleles correlated both with risk of disease and with earlier age of onset.⁹ This overrepresentation has been corroborated in more than 200 subsequent studies using patients with both familial and sporadic disease.

APOE is a susceptibility gene. Its presence in the genome is neither necessary nor sufficient for the development of AD, but its presence does increase risk. Some people have an APOE genotype of 4/4 but live into their 80s without developing dementia. A significant number of patients with AD have no e4 allele.

APOE is reported to account for less than 50% of the genetic effect in AD. The search continues for additional susceptibility genes or risk factors. Genetic locations of interest have been reported on chromosomes 9, 10, and 12, although no additional genes have been identified that researchers agree are susceptibility genes (see Table 1).^10-12 For the person with one or even two copies of APOEe4, if and when disease begins, how it manifests, and its rate of progression must depend on the additional contribution of other genetic and environmental factors. Thus, etiologically, AD is a complex disorder because multiple genes cause or contribute to the disease (making it heterogeneous) and both genes and environmental factors appear to modify the genetic effect (making it multifactorial) (see "Mr. Smith's return appointment").

 

TABLE 1 Genes of the Alzheimer’s disease(s)
Gene (gene product)	Genetic mechanism	Onset	Population affected	Chromosome	Locus/Type
PSEN1 (presenilin 1)	Causative	Early	<2%	14	AD3
APP (amyloid precursor protein)	Causative	Early	~ 20 families	21	AD1
PSEN2 (presenilin 2)	Causative	Early	~ 2 families	1	AD4
Unknown (unknown)	Causative	Early	Unknown	Unknown	Unknown
APOE (apolipoprotein E)	Susceptibility	Late	~ 40%	19	AD2
Unknown (unknown)	Susceptibility	Late	Unknown	12p11-q13	AD5
Unknown (unknown)	Susceptibility	Late	Unknown	9	AD7
Unknown (unknown)	Susceptibility	Late	Unknown	10q24	AD6
Unknown (unknown)	Susceptibility	Late	Unknown	Unknown	Unknown

 

Mr. Smith's return appointment Mr. and Mrs. Smith return a month later. They relate that Mr. Smith's supervisor has expressed concern about his job performance and suggested a leave. Mrs. Smith has noted little change in her husband at home. The results of the laboratory studies are normal. The MRI report describes a normal scan. Given the evidence supporting dementia of insidious onset and gradual progression and the lack of evidence for another cause of dementia, AD is the most likely diagnosis. You tell Mr. and Mrs. Smith of your working diagnosis and discuss the following: • Prescribing an acetylcholinesterase inhibitor to improve attention/memory and delay progression • Taking vitamin E, 400 to 1,000 IU/d, as a neuroprotective agent • Continued attention to diet and a routine exercise program • Participation in a local support group • Completion of power of attorney and health care power of attorney • Careful monitoring of Mr. Smith's abilities to maintain his safety and that of others (such as while driving) • Scheduling a return visit in 3 months for reassessment. At the end of the appointment, Mrs. Smith comments that she has heard that AD is "genetic." She asks whether any genetic tests are available that might support or weaken a diagnosis of AD in her husband. She also asks about the possible risk to her children. After reviewing the family history taken at the last appointment, you tell them that additional information about Mr. Smith's extended family is critical if a discussion of the genetics of AD disease is to be useful.

DNA testing

DNA testing can be used for diagnosis when a patient is symptomatic or to predict disease development in an asymptomatic person. In AD, DNA diagnostic testing is done to determine the cause of clinical dementia. Predictive DNA testing is done to predict future development of dementia in a person without cognitive problems or with cognitive impairment of equivocal significance. Since AD is genetically heterogeneous, use and interpretation of DNA test results depend on the clinical setting, on having a family history that goes back at least three generations, and on whether the test is for a mutation or for presence of a susceptibility gene.

Commercial testing is available for mutations in PSEN1 and PSEN2 but is not available for mutations in APP.¹³ Commercial testing can also determine APOE genotype—whether zero, one, or two copies of the AD susceptibility gene APOEe4 are present in the genome.¹³ The presence of a mutation, however, has very different implications than does the presence of one or two copies of APOEe4.

In diagnostic testing, if a causative mutation is present in a patient who is clinically demented, then the cause of dementia is AD. In predictive testing, if the same mutation is present both in an asymptomatic person and in family members with early-onset dementia, then AD will develop in the asymptomatic person but the timing cannot be predicted. Symptoms of dementia generally appear at around the same age in members of families of this type.

In diagnostic testing, if one or two copies of APOEe4 are present in the genome of a patient who has dementia that is clinically consistent with AD, then the probability is high that AD is the cause of dementia. In predictive testing, if one or two copies of APOEe4 are present in the genome of a person without cognitive symptoms, then AD may or may not develop. Although the risk is increased in that person compared to people who do not carry the e4 allele, the final risk will depend on the person's age and on the presence of or interaction with other not yet identified genetic and/or environmental factors. Any discussion of the risk of AD associated with APOEe4 must include a discussion of the empiric risk of AD.^14,15

Two of five consensus papers on genetic testing in AD recommend offering DNA diagnostic testing or predictive testing for causative mutations found in families with early-onset disease inherited as an ADm trait.^16,17 Individuals or their surrogates (if the patient is sufficiently impaired) can then accept or decline such testing.¹⁶ The most appropriate setting for such mutation testing is a specialty clinic where the paradigm of pretest counseling, test, and posttest counseling can be implemented.¹⁸ Mutation testing is not discussed in the other three papers.^19-21

Only one of the five consensus papers recommends APOE diagnostic DNA testing for possible use as an adjunct along with other diagnostic tests for AD.²¹ The authors offer the qualification that "possession of APOEe4 by a patient with dementia does not guarantee the diagnosis of AD; nor does the absence of an APOEe4 allele rule it out."²¹ One paper recommends that further research be completed.¹⁷ No paper recommends APOE genotyping for predictive testing in asymptomatic people.^16,17,19-21 The authors of one paper comment that asymptomatic patients requesting APOE genotyping have "the misperception that it provides an objective and personalized means of predicting whether they will develop AD"¹⁸ (see "Follow-up appointment").

 

Follow-up appointment Family history scenario 1 Mr. and Mrs. Smith return. They tell you they have been able to obtain more information about the family history. Mr. Smith's mother had four siblings. A brother and a sister were institutionalized in their late 50s, the former for "psychiatric illness" and the latter for dementia. The parents of these five siblings died in their mid 50s of unknown cause. Mr. Smith has a 56-year-old maternal cousin, the son of the above-mentioned uncle, who is said to have significant memory problems. Since the family history suggests early-onset dementia in multiple family members, you discuss the existence of causative genes in AD with Mr. and Mrs. Smith and the potential to perform diagnostic DNA testing for Mr. Smith. You also tell them that, depending on the result, predictive DNA testing might be available to others in the family, especially their children. You ask that they discuss this further with their children and tell them that an appropriate referral can be made to a specialty clinic with a genetic counselor at a medical center nearby. Family history scenario 2 Mr. and Mrs. Smith return. They tell you that they have been able to obtain additional family history. Mr. Smith's mother had no siblings; her parents died in their late 70s. Mr. Smith's father's parents died in their late 60s with no memory problems. However, there is a paternal aunt who developed dementia of slow onset and progression beginning at age 68 and who was said to have "hardening of the arteries." Since the family history is consistent with familial AD of late onset, even though onset in Mr. Smith was age 59 or 60, you discuss APOEe4 as a susceptibility gene. You point out that whether Mr. Smith has one or two copies will not change the current clinical diagnosis or his care plan. Neither will the knowledge necessarily predict the course of his illness. You also point out that should he have one or two copies of the gene, counseling any of their children on individual risk for AD would be probabilistic at best. Finally, you tell Mr. and Mrs. Smith that since his age of onset is early, the possibility that he has a mutation in an early-onset gene, though highly unlikely, cannot be totally disregarded. Mr. and Mrs. Smith appreciate the information and indicate that they do not wish to pursue testing of Mr. Smith's APOE genotype at this time. Neither do they elect to pursue mutation testing.

The generation and use of genetic data

AD is genetically heterogeneous and complex. As such, it provides an excellent example on which to base a broader discussion of the generation and clinical use of genetic data. Before ordering a genetic test, the clinician should talk with the patient. Each should understand what information will realistically be gained from testing. Both should agree on who may want or need access to the test result. Such a person could be a relative or another health care provider. The patient must be aware of the potential for misuse of genetic data that can have an impact on insurability and/or employability²² and can also affect the patient's children.

The dialogue should be the basis of the educational process that is informed consent. The process should be documented, preferably by a formal consent for genetic testing document signed by the patient. If the patient cannot comprehend the consent process, the process should be completed and the consent signed by a legal representative.

Once a test result is available, the clinician must be able to educate the patient in a comprehensive and comprehensible manner. The clinician must ensure the total confidentiality of the test result. Clinicians who have any doubt about their ability in these areas should be prepared to refer patients to a multidisciplinary group that includes a knowledgeable genetic counselor.²³

 

KEY POINTS in this article Alzheimer's disease (AD) is the most common cause of adult-onset dementia in the United States, currently affecting more than 4 million people. Researchers have identified three causative genes and one susceptibility gene for AD and believe that other genes not yet identified are associated with the disease. APOE—a susceptibility gene—increases the risk for AD but does not predict whether it will develop. The use and interpretation of genetic tests for AD depend on the clinical setting, on having a family history that goes back at least three generations, and on whether the test is for a mutation or the presence of a susceptibility gene.

 

Acknowledgement The authors would like to thank Marylou Bembe, PA-C, Jeffrey Stajich, PA-C, and Chantelle Wolpert, PA-C, colleagues at the Center for Human Genetics, Duke University Medical Center, for reviewing the article and for many helpful suggestions.

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