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Clinical Update

Genetic testing for Alzheimer's disease

Peter K Panegyres, Jack Goldblatt, Ian Walpole, Carmela Connor, Toni Liebeck and Karen Harrop

MJA 2000; 172: 339-343

Abstract - Recommendations for gene testing in Alzheimer's disease - Conclusions - Acknowledgements - References - Authors' details
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Abstract Genetic factors are important in the development of Alzheimer's disease (AD). Familial AD can result from rare mutations in some genes. Other genes, such as the apolipoprotein E gene (APOE), operate as risk factors for late-onset sporadic AD. On a background of advances in the genetics of AD we suggest a way in which genetic information may be used in the diagnosis of AD.

  • If there is a positive family history of early-onset dementia and the clinical features suggest AD, patients may be tested for presenilin and amyloid precursor protein gene mutations with appropriate pretest and post-test counselling. Predictive testing should be performed under guidelines developed by the World Federation of Neurology and the Human Genetics Society of Australasia.

  • The usefulness of APOE genotyping as an adjunct to conventional diagnostic tests is unknown; data suggest it has low sensitivity and specificity and may have little predictive value in an individual patient.

  • APOE genotyping should not be performed in asymptomatic individuals, except as part of an ethically approved research project; this recommendation is supported by a number of international consensus statements.

  • APOE testing should not be used as a diagnostic test without adequate pretest and post-test counselling, education and support.

  • APOE testing should not be used as a sole diagnostic test in the work-up of patients with AD.

  • Genetic risk factors other than APOE require validation and should not be used routinely, except as part of an ethically approved research protocol.

Alzheimer's disease (AD) is one of the major healthcare problems facing First World countries. In 1995, 130 000 Australians aged over 65 years had moderate to severe dementia, and by 2041 the number of people with dementia in Australia is expected to increase by 254%.1 In recent years there have been major advances in the elucidation of genetic factors in both familial and sporadic AD. Unfortunately, the accumulation of this genetic information has outpaced understanding among the medical and genetic communities of the most appropriate way it can be used clinically. This has led to diagnostic kits for DNA markers having to be withdrawn because of misuse in counselling individuals about future risks.2 Consumer-led demand for diagnostic tests and pressure from companies that make them raise major ethical considerations about the role of genetic testing in managing families at possible risk. These developments have encouraged us to develop evidence-based recommendations on the use of molecular genetic testing in Alzheimer's disease. Background information on the genetics of Alzheimer's disease is provided in Box 1.


Recommendations for gene testing in Alzheimer's disease
Diagnosis of dementia
The diagnosis of AD requires assessment by a clinician skilled in diagnosing dementia, using the criteria established by the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA),4 shown in Box 2. The diagnosis can sometimes be difficult, and expertise is required to distinguish AD clinically from other disorders such as frontotemporal atrophy and prion diseases, especially in younger patients. The diagnostic work-up of the patients is best performed in a facility with counselling and support staff to help patient and carer cope with the diagnosis of dementia. Collaboration with a neuropathology laboratory can enhance such a service by providing postmortem confirmation of the diagnosis.

Education, counselling, support
A multidisciplinary team, including a neurologist or specialist physician, neuropsychologists, social workers, allied health workers (occupational therapists, speech therapists), all working together with the patient's general practitioner, helps patients and their carers understand the diagnosis of AD and its implications. Contact with a caring, multidisciplinary team can support the patient, carer, and family in crises such as the development of intercurrent medical problems requiring hospitalisation and respite for patient or carer. Such a team can advise the patient, carer and family on the suitability and appropriateness of genetic testing.

Genetic testing If genetic testing is considered then the staff of the multidisciplinary team must know the implications, risks and limitations of the proposed tests and counsel patients, carers and families accordingly. They must have the expertise to counsel patients, carers and families about psychosocial implications, confidentiality, and issues related to employment and insurability, of the genetic tests requested.

Accredited laboratory and DNA result disclosure
The laboratory that tests the DNA specimen must be accredited by the National Association of Testing Authorities, Australia, which advises on specimen handling, the maintenance of strict confidentiality, and good laboratory practice (Box 3). The DNA result should be given to the clinician who requested the test, who will disclose the result to the patients and carer in strictest confidence with the help of counsellors. As has been shown with Huntington's disease,34 follow-up by counsellors will help to decrease adverse reactions such as suicide, attempted suicide and psychiatric hospitalisation.

Familial early-onset AD
If there is a positive family history of early-onset dementia, and pedigree analysis suggests autosomal dominant AD, the patient and family should be referred to a clinician with an interest in familial dementia for confirmation of the diagnosis. The patient and family should then be managed by a multidisciplinary team of experts in genetic neurodegenerative disorders (such as Huntington's disease) and predictive gene testing. Genetic testing should only be offered in a comprehensive, structured, clinico-laboratory program where mutations in PS1, PS2 and APP would be sought in affected individuals. Gene testing is not recommended for sporadic cases of early-onset AD without a definite family history.

Predictive testing in unaffected and asymptomatic individuals from families in which causative mutations have been discovered must follow guidelines as developed for Huntington's disease.5-8 Only about 6% of patients at risk of Huntington's disease request the gene test, probably because many at-risk people decide against the test once they receive full information of its implications.35 The likelihood of suicide, attempted suicide or psychiatric hospitalisation after predictive testing is no greater than in the general population with symptomatic Huntington's disease, and this is probably the result of good counselling and support.34

Similar considerations may apply to AD. Like Huntington's disease, AD is an incurable condition with devastating consequences, and there are ethical issues (such as patients not wanting to know, and implications for employment and insurability) relating to predictive gene testing in such situations. These ethical issues probably contribute to the low uptake of testing for Huntington's disease and will probably be relevant to AD also.

Other dilemmas in predictive testing for AD relate to performing tests in individuals with 25% risk when an unaffected or undiagnosed parent does not request a gene test; a positive result in such individuals would result in an unwanted gene result for the parent. This represents a difficult situation for predictive gene testing programs. Similar problems arise in twins if only one wants to be tested. For ethical reasons, as in Hungtington's disease, children should not be tested for AD.

DNA banking should be considered for individuals with a family history of AD who may not want a test at present, or who may not have any of the recognised mutations -- future testing could be carried out if other mutations are recognised.

Sporadic AD In patients with the clinical diagnosis of sporadic AD, gene testing for APOE Epsilon4 status or other genetic factors is not recommended. The clinical usefulness of these tests has not been established, and there is no evidence that they improve the sensitivity and specificity of the clinical diagnosis of AD sufficiently to alter the standard diagnostic work-up of these patients. The APOE Epsilon4 genotype should never be used as a sole diagnostic test for the diagnosis of AD.

Conclusions Our recommendations are summarised in Box 4.


Acknowledgements
A National Health and Medical Research Council fellowship awarded to Dr Panegyres supported this work.

References
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  2. Lehrman S. Genetic testing for Alzheimer's disease "not appropriate". Nature 1997; 389: 898.
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  18. McConnell LM, Sanders GD, Owens DK. Evaluation of genetic tests: APOE genotyping for the diagnosis of Alzheimer's disease. Genet Test 1999; 3: 47-53.
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(Received 2 Aug 1999, accepted 14 Feb 2000)


Authors' details
Neurosciences Unit, Health Department of Western Australia, Perth, WA.
Peter K Panegyres, PhD, FRACP, Neurologist, and NHMRC Fellow, Department of Neuropathology, Royal Perth Hospital.
Carmela Connor, MPsychol, Senior Clinical Psychologist.
Toni Liebeck, BSW, Senior Social Worker.

Genetic Services of WA, King Edward Memorial Hospital for Women, Perth, WA.
Jack Goldblatt, MD, FRACP, Director.
Ian Walpole, MB BS, FRACP, Consultant Geneticist.
Karen Harrop, BSc, Genetic Counsellor.

Reprints: Dr P K Panegyres, Department of Neuropathology, Royal Perth Hospital, Wellington Street, Perth, WA 6000.
peter.panegyresATrph.health.wa.gov.au

©MJA 2000
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1: The genetics of Alzheimer's disease

Familial early-onset Alzheimer's disease
Studies of families in which Alzheimer's disease (AD) was inherited in an autosomal dominant pattern led to the discovery of three pathogenic loci that account for about 50% of all cases of early-onset AD 3 (Table). As the condition is heterogeneous, every family with early-onset AD should be offered investigation as part of a coordinated DNA testing program for neurological disease.

Mutations in the amyloid precursor protein gene (APP) were the first mutations related to early-onset AD, 9 and account for 10%-20% of familial AD. 10 Two presenilin genes, PS1 and PS2, are also associated with early-onset familial AD -- almost 50% of cases result from mutations in PS1, 10 while mutations in PS2 are rare. 11 As reproducibility in PS1 mutation testing has not been established in some laboratories, caution is warranted.

Implications for genetic testing: Gene testing for early-onset AD is probably best performed in the context of well-designed, ethically approved research projects involving large families with clear documentation in multiple-affected members who inherited the condition in an autosomal dominant fashion.

In some Australian centres, patients with early-onset AD are routinely tested outside of research protocols. As mutations in the presenilin and amyloid precursor protein genes do not account for all cases of early-onset AD, negative screening results for these mutations in an affected individual would not exclude a genetic cause of the disease.

Sporadic late-onset Alzheimer's disease
APOE: Over 90% of patients with AD have no family history of the condition. One of the more important discoveries in the understanding of these sporadic late-onset cases was that a polymorphism of the apolipoprotein E gene (APOE) was a risk factor (Table). 12,13 APOE has three alleles, designated epsilon2, epsilon3 and epsilon4. The epsilon4 allele is associated with AD in 20%-30% of the general population and in 45%-60% of patients with AD. 14 The homozygous genotype, APOE epsilon4/epsilon4, is found in 12%-15% of patients with AD, but in only 2%-3% of the general population. 14 While not everyone homozygous for APOE epsilon4 develops dementia, having this genotype might increase the chance of AD developing at an earlier age. 15 Approximately 30% of people homozygous for APOE epsilon4 develop AD. 16

The odds ratio for this, based on analysis of 1899 patients aged over 65 years, is 1.37 (versus 0.53 for the APOE epsilon2 allele). 16 In this same study, the age-adjusted odds ratio for incident dementia in individuals homozygous for the epsilon4 allele was 1.89, and 25% of cognitively normal subjects had at least one epsilon4 allele. Further, absence of an epsilon4 allele does not prevent the development of dementia and AD, and 85% of elderly people with the APOE epsilon4/epsilon4 genotype did not have evidence of cognitive decline. 16 In a pathologically proven series, a single APOE epsilon4 allele had a sensitivity of 65% and a specificity of 68% for the diagnosis of AD. 17 When used with conventional clinical criteria, APOE epsilon4 testing might increase the diagnostic sensitivity and specificity by 5%-10%; therefore, its role requires further validation. 15,17

Implications for genetic testing: APOE epsilon4 genotyping should not be used in the routine assessment of patients with suspected dementia, as it does not add significant information to other diagnostic investigations such as computed tomography (CT) and neuropsychological assessment. 18

If the DNA test is performed it should not be done without adequate pretest counselling as to its limitations and implications, or without adequate post-test psychosocial support. The results need to be stored confidentially in view of the implications for other, unrelated conditions (eg, APOE allele status was used to predict risk in cardiovascular disease long before its significance in AD was known), insurability, employment and psychosocial coping for affected individuals and at-risk families. Thus, APOE genotyping should only be performed as part of a well-structured, ethically approved research study investigating issues about the role of APOE in the pathogenesis of AD.

The evidence does not support using APOE e4 genotyping as a predictive test for the development of AD, as the exact significance of an APOE epsilon4 allele in asymptomatic individuals has not been confirmed. 19-23

APOE epsilon4 genotyping should not be used as a sole diagnostic test for AD. Diagnosis requires specialist referral for investigations, such as a CT scan (which has a 94% positive predictive value 24) and neuropsychological tests (85%-90% positive predictive value for the diagnosis of dementia, with less than 5% overlap of neuropsychology scores between patients and controls 25,26). A positive APOE epsilon4 test is not diagnostic of Alzheimer's disease, as a single APOE epsilon4 allele has a positive predictive value of 65% and a negative predictive value of 68%. The presence of the APOE epsilon4 allele does not exclude other causes of dementia. For example, a 1998 study showed that about 5% of patients with clinical criteria for the diagnosis of AD were homozygous for APOE Epsilon4, but did not have pathological features of AD. 17 APOE epsilon4 diagnostic kits should not be used in the clinical assessment of dementia. (Although such kits were previously available in the United States, they had to be withdrawn because of misuse. 2)
Other genetic factors: A number of genetic factors in addition to APOE epsilon4 have been associated with sporadic AD (Table). These include APOE A/T polymorphism in the promoter region, 27 alpha2 macroglobulin 5' splice site deletion on exon 18,28 low-density lipoprotein-receptor-related protein, 29 the G/G homozygous state of the bleomycin hydrolase gene, 30 butyrylcholinesterase K variant, 31,32 and the major histocompatibility A2 antigen. 33 The contribution of these factors to the diagnosis of AD requires more research, as they have not been sufficiently validated to be used routinely.
Implications for genetic testing: These genetic factors need confirmation and further analysis as to their role in the diagnosis of AD and should not be used as diagnostic or predictive tests outside of research programs.
Clinical application of genetic factors in Alzheimer's disease
ChromosomeDiagnostic testing*Predictive testing†
Pathogenic loci
  Presenilin 1 (PS1)14++
  Presenilin 2 (PS2)1++
  Amyloid precursor protein (APP)21+ +
 
Risk loci
  Apolipoprotein E (APOE epsilon4)19± -
  Apolipoprotein E -491AA19- -
  2 Macroglobulin12--
  Low-density receptor-related
   protein		12- -
  Bleomycin hydrolase17--
  Butyrylcholinesterase K variant3--
*In symptomatic individuals with clinical evidence of autosomal dominant familial or sporadic Alzheimer's disease, using NINCDS-ADRDA criteria for the diagnosis of Alzheimer's disease. 4
†In asymptomatic individuals using guidelines as developed for Huntington's disease. 5-8
-491AA=A/A polymorphism at position -491 in the transcription regulation region of APOE.
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2: National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for the clinical diagnosis of Alzheimer's disease 4

I. The criteria for the clinical diagnosis of probable Alzheimer's disease include:
  • Dementia established by clinical examination and documented by the Mini-Mental Test, Blessed Dementia Scale, or some similar examination, and confirmed by neuropsychological tests;
  • Deficits in two or more areas of cognition;
  • Progressive worsening of memory and other cognitive functions;
  • No disturbance of consciousness;
  • Onset between ages 40 and 90, most often after age 65; and
  • Absence of systemic disorders or other brain diseases that could account for the progressive deficits in memory and cognition.
II. The diagnosis of probable Alzheimer's disease is supported by:

  • Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia);
  • Impaired activities of daily living and altered patterns of behaviour;
  • Family history of similar disorders, particularly if confirmed neuropathologically, and laboratory results showing:
    • normal lumbar puncture as evaluated by standard techniques,
    • normal pattern or non-specific changes in an electroencephalogram, such as increased slow-wave activity, and
    • evidence of cerebral atrophy on computed tomography, with progression documented by serial observation.
III. Criteria for diagnosis of definite Alzheimer's disease are:

  • The clinical criteria for probable Alzheimer's disease, and
  • Histopathological evidence from a biopsy or autopsy.
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3: Australasian centres where genetic testing for presenilin, APP mutations and APOE genotyping and counselling is available

  • Applied Molecular Biology Unit
    Biochemistry State Health Laboratory
    Brisbane, QLD
  • Department of Pathology
    Royal Brisbane Hospital, Brisbane, QLD
  • Molecular Pathology Laboratory
    Sullivan Nicolaides Pathology
    Taringa, QLD
  • Laboratory and Community Genetics
    Kolling Institute of Medical Research
    Royal North Shore Hospital
    St Leonards, NSW
  • Institute of Medical and Veterinary Science [IMVS]
    Adelaide, SA
  • The Neurosciences Unit,
    Health Department of Western Australia, and
    Department of Neuropathology, Royal Perth Hospital, Perth, WA
  • Hollywood Private Hospital
    Perth, WA
  • Molecular Pathology Laboratory
    Canterbury Health Laboratories
    Christchurch, New Zealand
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4: Recommendations for genetic testing in Alzheimer's disease

  • Mutation testing for abnormalities in PS1, PS2 and APP should only be considered where the family history is appropriate and by referral to appropriate comprehensive, predictive testing programs. The absence of known mutations does not protect against the development of other types of dementia.
  • The use of APOE epsilon4 genotyping as an adjunct to conventional diagnostic measures is unknown and the data suggest that it has low sensitivity and specificity and is of little diagnostic value in an individual patient. It has low predictive value in asymptomatic individuals and its use in this situation should be discouraged, except in well-defined research protocols with appropriate institutional ethics approval.
  • APOE epsilon4 genotyping should not be used as the sole diagnostic test in patients in whom AD is suspected on clinical grounds.
  • APOE epsilon4 genotype testing should not be offered without adequate pre-test and post-test counselling, education and support in patients in whom AD is suspected on clinical grounds. Genetic testing should follow carer or patient consent.
  • APOE epsilon4 genotype analysis should not be performed in asymptomatic individuals. This position is supported by a number of overseas consensus statements. 19-23
  • Other DNA-based genetic risk factors should not be used in the routine assessment of patients, except as part of an ethically approved research protocol.
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