Department of Psychological Medicine, University of Wales College of Medicine, Cardiff
Institute of Psychiatry, London
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff
Correspondence: Dr M. B. Liddell, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4xN, UK. E-mail: liddellmb{at}cardiff.ac.uk
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ABSTRACT |
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Aims To provide information for old age psychiatrists wishing to advise relatives of their risk of developing Alzheimer's disease.
Method A selective review of the key literature on the genetic epidemiology of Alzheimer's disease.
Results Currently a DNA diagnosis is attainable in some 70% of families with autosomal dominant Alzheimer's disease. In first-degree relatives of most cases, risk is increased some three- or four-fold relative to controls, but only one-third of this is realised in the average life span. Apolipoprotein E genotyping cannot be used as a predictive test and confers only minimal diagnostic benefit.
Conclusions Pedigrees with familial Alzheimer's disease should be referred to a Regional Centre for Medical Genetics. Accurate risk prediction is not possible in the vast majority of pedigrees with Alzheimer's disease, although it is possible for the psychiatrist to give a rough estimate of the risk, which can reasonably the couched in reassuring terms.
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INTRODUCTION |
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AUTOSOMAL DOMINANT FAMILIAL ALZHEIMER'S DISEASE |
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SUGGESTED APPROACH FOR HIGHLY FAMILIAL FORMS OF ALZHEIMER'S DISEASE |
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Predictive or prenatal testing is potentially feasible in families with FAD but will depend upon the availability of DNA from at least one affected individual in order to establish which mutation is causing disease in that family. It is worth stating that genetic counselling is a highly specialised area and it is strongly recommended that psychiatrists do not involve themselves without the appropriate training.
The study by Campion et al (1999) analysed DNA from 34 families with FAD (obtained from all over France) for causative mutations. Probably pathogenic mutations were found in the PSEN1 gene in 19 families, mutations within the APP gene in another 5 and no mutations in the PSEN1, PSEN2 or APP genes in the remaining 10 families. Thus, individuals from FAD pedigrees need to be informed that there is a 30% chance that, with the current state of our knowledge, no causative mutation will be found. If no mutation is found then, if the pedigree is strongly suggestive of an autosomal dominant disorder, the geneticist may choose to go on to search for mutations in genes associated with similar conditions prion protein (PrP) in CJD and tau in frontaltemporal dementias, for example. Yet another factor to consider is that there has been one report of apparent non-penetrance of a PSEN1 mutation in a healthy 68-year-old member of a FAD pedigree (Rossor et al, 1996). Notwithstanding these caveats, in the absence of any preventive treatment, the take-up for predictive testing is likely to be low, as has been the case in Huntington's disease (Binedell et al, 1998).
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SUGGESTED APPROACH FOR NON-MENDELIAN ALZHEIMER'S DISEASE |
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When faced with someone who is worried about their risk of developing Alzheimer's disease it is often worth pointing out that we are all at some risk of developing Alzheimer's disease provided that we live long enough. The large Rotterdam study suggests that the risk at age 55 years of developing dementia in the following 35 years is 0.26 for a woman and 0.15 for a man (Ott et al, 1998). In this study 73% of dementia was wholly or partially attributable to Alzheimer's disease. The large continuing Framingham study yields somewhat lower lifetime risks of Alzheimer's disease after the age of 65 years: 6.3% for men and 12% for women, with a corresponding risk for all dementia of 10.9% and 19%, respectively (Seshadri et al, 1997). Many epidemiological studies suggest that women are at increased risk of Alzheimer's disease. The reasons for this are not clear, but increased longevity compared to men, increased survival with the disease and some increase in intrinsic vulnerability probably all play a part.
Prevalence studies tell us that dementia doubles every 5 years after the age of 65 years up to the age of around 85 years, after which time the rate of increase appears to slow (Heeren et al, 1991; Skoog et al, 1993; Ritchie & Kildea, 1995; Breitner et al, 1999; von Strauss et al, 1999). It is likely that some of this slowing is due to very old people not living as long with their dementia as younger sufferers do, although it is also possible that survivors into late old age are relatively resistant to developing dementia (Drachman, 1994). Prevalence data are summarised in Table 1.
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In fact, two nearly completely ascertained community-based studies, one from Japan and one from The Netherlands, found that the prevalence of dementia in centenarians was very high: 70% in the Japanese and 88% in the Dutch sample (Asada et al, 1996; Blansjaar et al, 2000). Asada et al (1996) attributed some 76% of the dementia to Alzheimer's disease and demonstrated that the 6-month mortality rate was 27% for the centenarians with dementia, whereas none of the non-demented centenarians died.
Thus, prevalence figures for dementia tell us that many of us are at some risk of developing dementia, provided that we live long enough. This is obviously too simplistic: most people do not expect to live into their mid-90s; a much more reasonable question is, "What is my chance of developing Alzheimer's disease by the age of 85 years?". Family studies in Alzheimer's disease can go some way towards allowing us to answer this question for the relatives of affected individuals.
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FAMILY STUDIES AND RISK OF DEMENTIA |
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Overall, the findings from studies based in memory clinics (that are likely to be centres of secondary referral) suggest that 30-48% of probands with Alzheimer's disease have a history of affected first-degree relatives compared with 13-19% of controls. This translates to 6-14% of the relatives of patients with Alzheimer's disease having a history of Alzheimer's disease compared with 3.5-7% of the first-degree relatives of healthy controls. KaplanMeier life table analysis has been used in these studies to infer that the cumulative risk of dementia by age 90 varies between 30 and 50% compared with between 10 and 23% in control relatives. However, as has been pointed out by Breitner, owing to competing causes of death, only about one-third of this theoretical familial predisposition to Alzheimer's disease is realised in the usual life span. This translates to an actual predicted risk of developing Alzheimer's disease in the first-degree relatives of probands with Alzheimer's disease of 15-19%, compared with 5% in controls (Breitner et al, 1988; Breitner, 1991).
The latest systematically ascertained twin studies on the heritability of Alzheimer's disease also tend to support the estimates of familial risk derived from family studies. Probandwise, concordance rates of about 40% and 84%, respectively, are seen in fraternal and identical twins (Bergem et al, 1997). Because fraternal twins are genetically equivalent to ordinary first-degree relatives, the observed morbid risk of developing Alzheimer's disease is similar to that estimated for first-degree relatives in family studies.
A study by Silverman et al (1994) suggested that, in large measure, the familial component of risk to the relatives of probands with Alzheimer's disease was expended by the end of the ninth decade, after which time the risk was very similar to that in controls. A number of other family history studies have suggested that familial factors are more prominent when onset is earlier (McGuffin et al, 1994). Thus, much of Alzheimer's disease in late old age may be considered as not very familial and merely an expression of one of the ways in which the ageing process is manifested in those few survivors into late old age.
The findings from these family studies can be used to advise relatives in only the broadest terms. One can do little more than to say that, on balance, the risk to the first-degree relatives of patients with Alzheimer's disease who developed the disorder at any time up to the age of 85 years is increased some threefold to fourfold relative to the risk in controls. This would seem to translate to a risk of developing Alzheimer's disease of between one in five and one in six, which, although an improvement on a risk of one in two, can still be rather frightening. In order to put this risk into better perspective, and to help allay the client's anxiety, it may be preferable to present the risk estimates in a graphical form, as is done in Fig. 1 (from Breitner et al, 1988). If this is done, clients can see that even at 78 years, the age of greatest risk, the actual predicted risk is only some 3% and that the cumulative risk (half the area under the curve f(x)·S(x)) from age 65 to 78 is probably less than 10%. In our experience many tell us that this is reassuring partly because their worries were about getting Alzheimer's disease in their fifties "because this is when familial Alzheimer's disease happens" or in their sixties/seventies, thus preventing them from enjoying retirement.
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In the case of patients with Alzheimer's disease who became demented late in old age, say by their 80s, relatives probably run the same 30-50% risk of developing dementia as anyone else who lives to the age of 90 years and beyond. Of course, it is possible that some of the same genes that confer longevity may also increase the risk of developing Alzheimer's disease. Like other disorders that reflect the combined action of several genes, the risk to relatives drops rapidly as the degree of genetic relatedness falls. Data are limited but the risk to second-degree relatives, such as grand-children, is probably less than twice the population levels (Heston et al, 1981).
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THE APOLIPOPROTEIN E EFFECT |
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The APOE 4 association with Alzheimer's disease has been replicated
in many laboratories around the world. A meta-analysis summarised the data and
demonstrated that the association was found in people of European, African
American, American Hispanic and Japanese origin
(Farrer et al, 1997).
Exactly how APOE
4 and the apoE4 protein influence the pathophysiology
of Alzheimer's disease is still unknown, but bearers of this risk allele
appear to get Alzheimer's disease earlier and develop a heavier amyloid
burden.
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CLINICAL SIGNIFICANCE OF APOLIPOPROTEIN E GENOTYPE |
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The consensus of opinion appears to be that APOE genotype determines
when rather than whether one succumbs to
Alzheimer's disease. For example, the Cache County study
(Meyer et al, 1998,
Breitner et al, 1999)
on an elderly population of almost 5000 found 22 cases of Alzheimer's disease
among 141 APOE 4 homozygotes, 118 among 1452 APOE
4 heterozygotes
and 80 among 3339 not bearing the APOE
4 allele. There appeared to be a
plateau in each group's survival curve beyond which no new cases of
Alzheimer's disease were seen. For APOE
4 homozygotes no new cases were
seen after the age of 84 years, with nine individuals surviving without
Alzheimer's disease for a combined total of a further 37 years. For APOE
4 heterozygotes the last onset of Alzheimer's disease was at 99 years,
with four long-term survivors. The last onset of dementia in individuals
without the APOE
4 allele was at age 95 years, with 31 surviving free of
dementia for a combined total of 100 years thereafter. This differential
effect of APOE genotype on the age of maximum risk of Alzheimer's disease is
also suggested in the APOE meta-analysis of Farrer et al
(1997) and also in the study
by Asada et al
(1996).
A Bayesian analysis has been used by Seshadri et al (1995) to relate the APOE genotype to the lifetime risk of developing Alzheimer's disease. When the estimates of dementia risk derived from the Framingham study (Seshadri et al, 1997) are substituted in the analysis, somewhat lower risk estimates, which are stratified according to gender, are obtained (Table 2).
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These estimates suggest that, at most, some 50% of APOE 4 homozygotes
will develop Alzheimer's disease within their lifetime. These predictions
agree well with the general population-based study of Henderson et al
(1995), which suggested that
the risk of developing dementia by age 90 years in APOE
4 homozygotes
was about 50%.
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POSSIBLE CLINICAL USES OF APOE GENOTYPING IN ALZHEIMER'S DISEASE |
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Some claims have been made that APOE genotyping may be an aid to diagnosing
Alzheimer's disease. The study by Mayeux et al
(1998) suggested that for
patients referred to specialised assessment centres for Alzheimer's disease,
APOE genotyping used in combination with clinical criteria might improve the
specificity of the diagnosis. The data show that whereas the demonstration of
one or more APOE 4 allele in a person suspected of suffering with
dementia slightly increases the accuracy of a clinical diagnosis of
Alzheimer's disease, the absence of an APOE
4 allele has little value in
either endorsing or refuting a clinical diagnosis of Alzheimer's disease.
Thus, even in a selected group of patients, presumably all with a high a
priori chance of Alzheimer's disease, APOE genotyping seems to confer
negligible diagnostic benefit.
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GENETIC COUNSELLING AND ALZHEIMER'S DISEASE |
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RECOMMENDATIONS |
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Late-onset Alzheimer's disease
For late-onset Alzheimer's disease there is wide agreement that there is no
genetic test available, but genetic testing is not the same as genetic
counselling. The absence of a test should not mean that relatives are denied
information and the opportunity to discuss their concerns. So, when asked
"am I likely to get Alzheimer's disease?" by the relative of a
patient with late-onset Alzheimer's disease, how should one answer? In most
cases of Alzheimer's disease it is only possible to advise relatives of their
risk in the broadest terms. Extrapolating from family history studies, it is
possible to say that the risk to the children is in the region of one in five
to one in six and one should be prepared to illustrate what this means in an
easy to understand graphical form. We believe that it is permissible for such
a broad estimate of risk to be imparted by a consultant or doctor not
specifically trained in genetic counselling.
Occasionally, psychiatrists encounter families with several siblings affected by late-onset Alzheimer's disease and a history of dementia in previous generations. Such families almost certainly exhibit high genetic loading, but there are few reliable data on whether and to what extent risk increases with the number of affected relatives, although studies of other common disorders suggest that this is likely to be the case. However, it should be borne in mind that the number of affected relatives may well depend on factors affecting longevity as well as on the degree of genetic loading for Alzheimer's disease, and it may not be advisable or possible to base discussion on risk estimates that are increased when several relatives have been affected in late old age. There is also preliminary evidence for substantially increased risk in the offspring of parents who both have a diagnosis of Alzheimer's disease (Bird et al, 1993). In such pedigrees, if relatives request further information, it may be worth taking a detailed family history and consulting with a clinical geneticist.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication February 14, 2000. Revision received June 26, 2000. Accepted for publication June 28, 2000.