editorial review. the genetics of alzheimer’s disease— new opportunities and new challenges

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 11: 491-497 (1996)

EDITORIAL REVIEW

The Genetics of Alzheimer’s Disease-New Opportunities and New Challenges

The new medicine resulting from advances in molecular biology and genetics has been heralded for some time. Enthusiasts have forecast treatments for common and rare disorders alike and new therapeutic opportunities such as gene therapy have been anticipated. However, the absence of tangible benefits from the new biology, at least for psychiatric and neurological disorders, might lead to a wearied cynicism on behalf of those who mis- interpret the timescales of such forecasts. In considering Alzheimer’s disease (AD), the progress in molecular biology seems very likely to result in therapeutic treatments, but the timescale for such development will be measured in decades rather than years. The rapid progress in genetic research, on the other hand, is likely to yield the fruit of clinical application in the very near future. Whether this fruit turns out to be a poisoned apple remains to be seen, and is at least partly dependent on the response of old age psychiatry as a discipline.

It has been recognized for many years that there is a familial risk for Alzheimer’s disease although estimates of the degree of this risk have differed. One central difficulty inherent in studies of genetic risk factors is the very late onset of AD. For such a disorder, many at-risk individuals will die of other causes before the age of expression of the disease process. Multiple pedigree analysis studies will tend to underestimate the genetic risk at any given age because of attrition by other causes before that given age and because of onset of AD after it. A number of recent studies have examined an age- related risk and find that the risk in first-degree relatives of AD patients approaches 50% by the age of 90 (Breitner and Folstein, 1984; Breitner et al., 1988; Huff et al., 1988; Martin et al., 1988;

Address for correspondence: Dr Simon Lovestone, Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London SE5 BAF, UK. Tel: 0171 919 3239/3550. Fax: 0171 701 0167. e-mail: [email protected].

CCC 0885-6230/96/060491-07 C 1996 by John Wiley & Sons, Ltd.

Korten et al., 1993) although other studies report lower figures (Sadovnick et al., 1989; Farrer et al., 1989). The interpretation of such findings is not straightforward, as the prevalence and incidence of dementia in this very elderly population is itself not fully determined and the numbers of individuals surviving beyond the ninth decade are too small to draw firm conclusions regarding the slope of the cumulative incidence graph in this group (Korten et al., 1993). Breitner, however, points out that these results, together with data from twin studies, are compatible with an autosomal-dominant model of the genetics of AD (Breitner, 1994). It is already apparent that this is unlikely to be the case, as the inheritance of AD is complex, but nonetheless Breitner’s comments do serve to emphasize the importance of genetic factors in the aetiology of the condition.

A major clinical endeavour of those with responsibility for treating patients with dementia is to attend to the wider needs of relatives and carers. Significant stress in carers has been noted in many studies and it might be thought that this would be greater if carers believed themselves to be at risk. Yet it is not known whether the major influence of genetic factors in causing AD is widely recognized. However, while no research data exist, the clinical experience of many old age psychiatrists is that at least some relatives do perceive themselves to be at risk and that this does give rise to concern. In order to introduce needs-sensitive services for genetics in Alzheimer’s disease, further studies in this area are required.

Molecular genetic studies have begun to identify loci associated with AD. The first genetic risk to be identified was trisomy 21 as it was recognized that most, or even all, individuals with Down’s syndrome show the neuropathological signs of AD at a relatively early age (Mann, 1988). Subsequently, a rare form of early onset AD was shown to be associated with mutations in the amyloid precursor protein (APP) gene, carried on chromosome 21

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(Goate et al., 1991). The product of the APP gene is a ubiquitous transmembranous protein, a portion of which is deposited in the core of amyloid plaques (McLoughlin and Lovestone 1994). A variety of different APP mutations result in autosomal-dominant early onset AD and have been reported in a small number of families around the world (Murrell et al., 1991; Chartier-Harlin et al., 1991; Mullan et al., 1992). The identification of these mutations has been the single most important advance in Alzheimer’s disease research but has had little clinical importance as APP mutations are found in only a tiny proportion of early onset familial AD cases (Kamino et al., 1992).

Rather more early onset autosomal-dominant families appear to be linked to markers on chromosome 14 (Schellenberg et al., 1992). A desperate search for the gene responsible for this linkage appears to have ended with the report that missense mutations in a novel gene, designated S182, are associated with a particularly virulent autosomal-dominant early onset form of the disorder (Sherrington et al., 1995). The gene identified by this impressive and important study appears to encode for a membrane-bound protein which might be predicted to be a receptor, an ion channel or a structural membrane protein. Some homology is found to a protein, SPE4, previously of little interest to neurobiologists, that is intimately involved in spermatogenesis in the round worm, C . elegans. This protein seems to have a role in the interaction between membrane proteins and fibril- lary proteins and, by analogy, it might be that in AD S182 it exerts its effects by altering APP processing or affecting the interactions between APP and the cytoskeletal protein tau. AD biolo- gists will now set upon S182 in order to further elucidate the molecular pathogenesis of the condition. In marked contrast to the situation following the APP mutation discovery, this new gene will have practical and clinical consequences as it will now be possible to provide predictive and diagnostic testing to most early onset autosomal- dominant AD families. The role of S182 mutations in early onset AD with indeterminate or unknown pedigrees will become clear over the next few years.

The third gene linked with AD is the apolipoprotein E (apoE) gene, carried on chromosome 19 (see Utermann, 1994, for review). There are three isoforms of apoE common in the population, designated as E2, E3 and E4. These isoforms are produced from allelic variation at a single locus. Therefore the majority of individuals in the

population will be one of six genotypes (homozygous for ~ 2 , ~3 and ~ 4 , or heterozygous ~213, ~314, €214). An initial report that the ~4 allele was associated with AD has been confirmed in many studies for both sporadic and familial late onset AD (Saunders et al., 1993; Poirier et al., 1993; Corder et al., 1993; Anwar et al., 1993; Liddell et al., 1994). This finding has initiated a vast research effort which is attempting to quantify the risk attributed by ~ 4 , to determine whether this risk is different in different ethnic groups and to determine whether the risk is for AD specifically or for neurodegenerative conditions in general.

It is clear already, however, that carrying the €4 allele is neither a necessary nor a sufficient condition to acquire AD pathology. Individuals without the ~4 allele have been found to have plaques and tangles at postmortem and homozygous ~4 individuals can remain free from symptoms and from neuropathology to a relatively late age. Neither is it certain that the association with apoE is specific to AD, as some studies suggest an association with Creuzfeldt-Jacob disease, vascular dementia and Lewy body dementia (Frisoni et al., 1994; Amouyel et al., 1994; St Clair et al., 1994; Lippa et al., 1995). These findings are currently under some scrutiny, however, as the studies are bedevilled by problems of diagnostic accuracy and much further work needs to be done. It is possible that another allele at this locus, apoE ~ 2 , offers some protection against AD and that this accounts for some or all of the association data (Corder et a[., 1994). Again, a considerable amount of research is required to test this hypothesis and, in particular, the role of apolipoprotein E in the molecular pathogenesis needs to be determined. Nonetheless, it is clear that possession of the apoE ~4 allele confers a substantially increased risk of suffering from AD.

The identification of genetic risk factors for AD raises the possibility of clinical genetic testing. Three types of genetic test can be envisaged-a diagnostic test in a patient with symptoms to determine a definitive diagnosis, a predictive test in a relative to determine whether they carry the disease gene and hence will acquire symptoms, and finally the use of a genetic test to contribute to risk assessment. Diagnostic and predictive testing based upon molecular genetic markers is now routine in departments of medical genetics for a variety of conditions. Molecular genetic diagnostic testing can make significant contributions to the assessment of individuals with familial dementia and motor disorders as a number of genetic

EDITORIAL REVIEW 493

changes causing these conditions have been identified. If a diagnostic test for Huntington’s disease (HD), for instance, is positive, then predictive testing can be offered to unaffected relatives. Those found to carry the gene will express the disorder at some point; those without the gene mutation can be reassured that neither they nor any of their children will have Huntington’s disease. Such use of genetic information requires that clinicians exercise considerable control over the testing process from the initial contact with the patient through to giving the result, and indeed after, in order to minimize possible adverse consequences and to ensure that this quintessentially personal information remains confidential. For HD, extensive discussions have resulted in a counselling procedure that is internationally observed (Simpson and Harding, 1993).

Risk assessment might be thought of as a variant of predictive testing, where having the pathological genetic variant does not confer near certainty of acquiring the disease. For common diseases, including AD, genetic factors are unlikely to demonstrate Mendelian inheritance patterns and are more likely to confer a relative increase or decrease in risk. While protocols for genetic counselling for predictive and diagnostic testing are well-tried, genetic testing for risk assessment is a new endeavour.

Diagnostic and predictive testing is already available for early onset familial AD. For families with an APP mutation, and for those previously shown to be linked to chromosome 14, diagnostic testing can be offered for all new incipient cases and predictive testing for unaffected relatives by a direct screen for the mutation(s). The result that is given is absolute-the individual either does or does not have the mutation. Moreover, it appears that these mutations have complete penetrance, with all those possessing the mutation acquiring the disorder, although this will have to be substantiated for S182 mutations in other families.

For late onset AD, apoE genotyping is unlikely to be of substantial value as a predictive or diagnostic test (Roses et al., 1994), although it remains possible that ongoing large-scale studies will result in a greater specificity or sensitivity. However, it is already clear that variation at the apoE locus confers substantial risk and when this risk is quantified for different ethnic populations, then apoE genotypes data may contribute to an assessment of future risk of AD (Nalbantoglu et al., 1994). Whether anyone would want this

relatively ‘soft’ form of genetic testing is as yet unknown.

Why do individuals seek genetic information? Historically, most patients of medical genetics services have been seeking advice relating to family planning. Decisions as to whether to have children or to continue with an at-risk pregnancy are aided by genetic testing for a number of conditions and diagnosis of foetal and infant conditions can be made by cytogenetic and molecular genetic tech- niques. However, it seems unlikely that these procedures will be relevant in AD. Prenatal testing of foetus may be requested by some individuals carrying the early onset Alzheimer’s disease genes, as it is by a very few individuals carrying the HD genes (Adam et al., 1993). In the majority of cases, however, it seems improbable that couples would want to make family planning decisions based on a foetus having a disease 50-70 years hence.

Increasingly, however, individuals seek genetic information for reasons unconnected with having children. These reasons might be grouped together as rational medical, rational but non-medical and non-rational. Rational medical refers to genetic testing to aid treatment or prevention. For instance, if a knowledge of a genetic risk for cardiac disease in an individual resulted in a cardioprotective lifestyle or early treatment, then genetic testing would be widely welcomed, and indeed recommended. For AD, no risk reduction strategies are available but it is possible that this will change. Clinical trials of putative Alzheimer’s disease agents are underway and the first drug has been approved in the USA and much of continental Europe. If a compound is found that confers some protection, then those with a genetic risk might usefully be advised to take such an agent at an early stage.

While medical rational reasons for wanting genetic information would be generally applauded, there is considerable unease at the prospect of non-medical yet rational decisions. Life-planning decisions and decisions regarding insurance and employment might all be thought of as rational non-medical reasons for wanting to seek genetic information. The ethical and moral implications of some such uses of genetics, however, are very considerable and the implications for health service delivery substantial.

The actual reasons why individuals seek genetic information are largely unknown, and likely to be different for different conditions. Clinical experience, and studies of attitudes among those at risk


of HD (Decruyenaere et al., 1993), however, suggest that at least one major motivating factor is non-rational. If a test is available, then many individuals at risk appear to want to avail themselves of the opportunity without being able to identify a reason for doing so. It seems that the wish to end uncertainty is itself a motivating factor.

What is the outcome of genetic testing for late onset conditions? For HD, early experience of linkage analysis suggested that the outcome was relatively favourable, with both those having a ‘bad news’ result and those having a ‘good news’ result showing improvement at follow-up (Wiggins et al., 1992; Bloch et al., 1992). For AD, predictive genetic testing has only been reported in the literature for one family (Lannfeldt et al., 1995). In this case, various family members were tested for the APP mutation known to exist in an affected relative. The one presymptomatic individual found to carry a mutation had a traumatic time after testing, with an extended period of depressive symptomatology and suicidal ideation. This experience emphasizes the caution that needs to be exercised in testing, even for late onset conditions.

For AD, then, predictive and diagnostic testing is already technically possible for early onset FAD and risk assessment may become available for late onset AD. We have little idea as to how many individuals would wish to have a genetic test, but it is suggested that if a test is available then motivating factors might be non-rational or rational but non-medical. Developments in therapy for AD might introduce a rational medical motivation which would be likely to be a powerful force to drive the widespread use of testing.

Who is to do the testing and the associated counselling? At present, most genetic counselling occurs in departments of medical genetics by qualified nurse counsellors or clinical geneticists. The process of counselling involves pedigree analysis, clinical assessment, pretest counselling and follow-up. While medical genetic services might provide such counselling to families with early onset FAD, they are unlikely to be able to do so for all families with late onset Alzheimer’s disease. The Department of Health estimates that, on average, a health district with a population of 250000 will have 18 patients with HD and 162 individuals at risk and therefore eligible for genetic counselling. Performing similar calculations for AD easily demonstrates that the total at risk for AD exceeds, possibly by many times, the total throughput of a genetic service for all conditions. If

testing is ever to be performed in AD, it seems unlikely that it will be performed exclusively by clinical geneticists, but perhaps by general practi- tioners or old age psychiatrists in collaboration with a local genetic service. The nature of the counselling accompanying testing will have to be determined.

For the time being, a number of recommendations can be made. Any family with early onset AD, inherited in an autosomal-dominant pattern, should be referred to a department of genetics for further assessment. For some, APP mutation testing will be considered, for others S182 gene mutations on chromosome 14 will be appropriate. It is possible that phenotypic differences between the autosomal-dominant early onset Alzheimer disease will guide the appropriate test (Mullan et al., 1993a; Haltia et al., 1994; Lampe et al., 1994). It is likely that such molecular genetics work would be performed in a laboratory with a preexisting research interest in the area. If neither procedure is indicated, then consideration should be given to DNA banking of affected individuals and unaffected aged relatives. Families should be advised of the value of postmortem diagnosis if they feel that they may want genetic testing in the future. For late onset familial and sporadic Alzheimer’s disease, no test is currently available. The data on apoE are not sufficiently robust to inform predictive, diagnostic or risk assessment testing. For the time being, however, the potential for anxiety among family members of individuals with late onset AD should be recognized and family members offered time to explore their own concerns and preferably to discuss the risk of inheriting the condition with a knowledgeable professional. Whether such a professional resides in a department of old age psychiatry or genetics is arbitrary, but it may be useful to establish specialist genetics clinics. Consideration should be given to DNA banking by a department of medical genetics, especially for aged affected relatives (see Fig. 1).

If testing is ever indicated for late onset AD, then the appropriate form and delivery of counselling will need to be considered (Lennox et al., 1994). A variety of groups have been established to consider this question. The Department of Health has recognized the importance of these developments and the Secretary of State has announced the establishment of a committee to consider the service implications. A Consensus Conference was held at the 1994 Alzheimer Disease International Meeting and a group of old age psychiatrists,


BE AWARE OF POSSIBLE

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Figure 1. Algorithm for management of genetic counselling in Alzheimer’s disease

geneticists, representatives from patient groups and others meet annually as part of the United King- dom Alzheimer’s Disease Genetics Consortium (Lovestone and Harper, 1994).

Over the past 5 years, it has become increasingly apparent that Alzheimer’s disease is, in great part, a genetic condition. The results of this research may one day yield useful therapeutic opportunities for Alzheimer’s disease. However, this time has not yet arrived. Instead, we are faced with research that has every possibility of increasing anxiety and distress among family members. As a discipline, old age psychiatry would do well to recognize this and to consider offering appropriate support to worried relatives. In the course of offering such

support, appropriate measures should be taken (such as DNA banking and advice on postmortem) to enable genetic testing to be performed in the future should this ever be required and available. As with all scientific developments, genetic research has the potential for harm as well as for good. In order that these developments are used for the benefit of our patients and their relatives and to ensure that no harm is done, old age psychiatrists should be prepared to remain abreast of the science and to take a lead role in the development of services together with our geneti- cist colleagues.

SIMON LOVESTONE Institute of Psychiatry, London


Post-script

‘In a fascinating illustration of the speed of molecular genetics in this area, within weeks of the identification of S182, a remarkably similar gene on chromosome 1 was identified, mutations in which result in early onset autosomal dominant Alzheimer’s disease in the Volga German group of families (Levy-Lahad E. et al. (1995) A familial Alzheimer’s disease locus on chromosome 1. Science. 269, 970-972; and Levy-Lahad E. et al. (1 995) A candidate gene for chromosome 1 familial Alzheimer’s disease locus. Science. 269, 973-977). The fact that both these genes are similar in structure and both cause Alzheimer’s disease strongly suggests a common biological mechanism and homology with the intracellular signalling receptors (Levitan and Greenwald (1995) Facilita- tion of LIN-12 mediated signalling by SEL- 12. A. Elegans S182 Alzheimer’s disease gene. Nature. 377, 351-354) probably indicates that the future of neurobiological research into Alzheimer’s disease for the next few years will concentrate upon signal transduction mechanisms’.

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editorial review. the genetics of alzheimer’s disease— new opportunities and new challenges

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