Department of Psychiatry, Institute of Psychiatry, London
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff
Institute for Health of the Elderly, Newcastle, UK
Department of Psychological Medicine, Institute of Psychiatry, London, UK
![]() |
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Correspondence: Dr N. Tunstall, Department of Psychiatry, Institute of Psychiatry, London SE5 8AF
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To determine the familial (genotypic) influence on phenomenology (phenotype) in Alzheimer's disease.
Method Affected sibling pairs with Alzheimer's disease were assessed for a range of cognitive and non-cognitive symptoms. Resemblance for phenotypic characteristics was estimated using intraclass correlations for continuous traits and by pairwise concordance for dichotomous traits. The relationship between age of onset and APOEgenotype was examined using linear regression analysis.
Results Significant familial effects on age of onset (intraclass correlation 0.41) and mood state (intraclass correlation 0.26), and a relatively high pairwise concordance for agitation (excess concordance 0.1) were found. The APOE locus was found to account for 4% of the variance in age of onset.
Conclusions Substantial familial influence on age of onset, depression and agitation suggests that genotype does influence phenotype in Alzheimer's disease. Establishing the molecular basis for this phenotypic variation may prove relevant to other neuropsychiatric disorders.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Clinical assessment
The standardised interview schedule consisted largely of informant-based
scales and batteries with established reliability; of relevance to the present
report are: the CAMDEX (Roth et
al, 1986), from which age of onset data were obtained; the
Cornell Scale for Depression in Dementia (CSDD;
Alexopoulos et al,
1988); and the Manchester and Oxford Universities Scale for the
Psychopathological Assessment of Dementia (MOUSEPAD;
Allen et al, 1996).
The CSDD is a clinician-administered instrument that utilises information from
interviews with both the patient and an informant. Total CSDD scores correlate
highly with depressive subtypes classified according to Research Diagnostic
Criteria (RDC). The MOUSEPAD is a 59-item instrument that measures
psychopathology and behavioural changes in dementia; it has established
reliability, sensitivity and validity
(Allen et al,
1996).
APOE genotyping
Deoxyribonucleic acid was extracted from venous blood and APOE
genotype was determined using standard methods
(Wenham et al,
1991).
Data analysis
Phenotypic data relating to age of onset and behavioural and psychiatric
signs and symptoms of dementia were analysed using the Statistical Package for
the Social Sciences. The behavioural variables were treated as separate from
one another. Support for this approach is given by a factor analysis of
behavioural changes in dementia that identified three robust syndromes
overactivity, aggressive behaviour and psychosis that were stable
across time (Hope et al,
1997). Variability in continuous phenotypic traits was partitioned
into betweenand within-family variation using analysis of variance, in order
to distinguish familial from non-familial sources of variation; intraclass
correlations were calculated to quantify the proportion of trait variance
accounted for by familial effects, and hence to estimate the strength of
familial influences on these traits. Because case-finding for this sample
involved recruiting families with two or more living affected siblings, it
necessarily excluded deceased affected siblings and siblings potentially at
risk but currently below the age range of susceptibility for the disorder.
However, age of onset data on deceased affected siblings were included where
obtainable. For all other data points, only those clinical variables directly
assessed with a living subject were utilised. The relationship between age of
onset and APOE alleles was examined using linear regression
analysis.
For each dichotomous trait, a pairwise concordance for its presence (the number of pairs in which both siblings are positive for the trait of interest, divided by the total number of pairs) was calculated, as was the expected value under the null hypothesis that familial effects are not operating (calculated as the square of the prevalence of the trait in question).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Current mood state
Data on current mood state (measured using position on the Cornell scale)
was obtained on 86 pairs. The intraclass correlation for familial influence on
variation in this dimension was 0.26 (P<0.05).
Dichotomous traits
For the dichotomous measures of behavioural disturbance at some point
during the clinical course, data were obtained on 99 pairs. As in previous
studies, we found a high rate of behavioural disturbance, with frequencies as
follows: agitation, 0.44; aggression, 0.44; psychosis, 0.41 (with delusions
and hallucinations showing frequencies of 0.36 and 0.30, respectively). The
pairwise concordance for each trait (with the excess (observedexpected)
concordance in parentheses) was as follows: agitation, 0.29 (0.1); aggression,
0.22 (0.03); psychosis, 0.21 (0.04).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Familial influence on mood state
Evidence of significant familial effects on current mood state within
Alzheimer's disease has been detected. This finding is of considerable
interest because the overrepresentation of depression in Alzheimer's disease
has not hitherto been adequately explained. Although aetiological models
suggest that genetic susceptibility and recent life stressors are the major
determinants of depression in adults, behavioural genetic work points to
genetic influence on variation in depressive symptoms as being greater in
older, compared with younger, nondemented individuals
(Gatz et al, 1992).
APOE is probably a risk factor for neither late-life depression nor
depression within Alzheimer's disease
(Cantillon et al,
1997; Schmand et al,
1998). However, an association between depression in Alzheimer's
disease and family history of affective disorder has been reported
(Pearlson et al,
1990; Lyketsos et al,
1996; Strauss & Ogrocki,
1996) suggesting the influence of genetic factors unrelated to
susceptibility for Alzheimer's disease.
Familial influence on behavioural disturbance
The finding of a significantly elevated pairwise concordance for agitation
suggests moderate genetic influence on this trait. Evidence points to relative
dopaminergic overactivity as a basis for agitation in Alzheimer's disease
(Sweet et al, 1997).
Candidates genes for propensity to agitation in Alzheimer's disease,
therefore, include those genes influencing the functioning of this system,
such as the dopamine receptors, polymorphisms in which have been reported to
be associated with aggression in Alzheimer's disease
(Sweet et al, 1998).
In the present study, only a very modest excess concordance for the presence
of aggression was detected. The interrelationship between agitation,
aggression and dopamine receptor variation warrants further study.
Genotype-phenotype correlation in Alzheimer's disease may identify
psychiatric genes
The rich phenotypic variability of Alzheimer's disease cannot be explained
exclusively by genetic variation but, nonetheless, this study does demonstrate
that familial factors exert significant influence upon the pattern of symptoms
experienced by individuals. Given that siblings are generally exposed to very
little shared environment in later life, it seems very unlikely that shared
environmental factors influence familial aggregation of symptoms in
Alzheimer's disease. It will be important to replicate this finding in other
studies and to examine different traits. Because phenotypic characteristics in
Alzheimer's disease are not stable over time, it will be important to study
larger sample sets over time.
Determining the genes that contribute to phenotypic variability in Alzheimer's disease will be important in understanding this disorder more fully. Behavioural disturbance is a major determinant of carer stress and an important target for therapy, and it is possible that better understanding of the underlying pathogenesis of behavioural disturbance may lead to improved clinical management. However, these findings may also have implications for other psychiatric genetic studies. One hypothesis following from our findings is that genetic vulnerability to psychiatric disorder is revealed by neurodegeneration. That is, some individuals may have a genetic propensity to depression, for example, but other factors protect against its development until the onset of Alzheimer's disease lowers the susceptibility threshold of these individuals. Our study suggests that in the search for genes for depression, and possibly other psychiatric disorders, Alzheimer's disease may prove a more fertile hunting ground.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
APPENDIX: ESTIMATION OF INTRACLASS CORRELATION FROM SIBSHIPS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Alexopoulos, G. S., Abrams, R. C., Young, R. C., et al (1988) Cornell Scale for Depression in Dementia. Biological Psychiatry, 23, 271-284.[Medline]
Allen, N. H. P., Gordon, S., Hope, T., et al (1996) Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD). British Journal of Psychiatry, 169, 293-307.[Abstract]
Breitner, J. C. & Folstein, M. F. (1984) Familial Alzheimer Dementia: a prevalent disorder with specific clinical features. Psychological Medicine, 14, 63-80.[Medline]
Cantillon, M., Harwood, D., Barker, W., et al (1997) No association between apolipoprotein E genotype and late-onset depression in Alzheimer's disease. Biological Psychiatry, 41, 246-248.[CrossRef][Medline]
Donner, A. (1986) A review of inference procedures for the intraclass correlation coefficient in the one-way random effects model. International Statistical Review, 54, 67-82.
Farrer, L. A., Cupples, L. A., Haines, J. L., et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium [see comments]. Journal of the American Medical Association, 278, 1349-1356.[Abstract]
Gatz, M., Pedersen, N. L., Plomin, R., et al (1992) Importance of shared genes and shared environments for symptoms of depression in older adults. Journal of Abnormal Psychology, 101, 701-708.[CrossRef][Medline]
Harvey, R., Ellison, D., Hardy, J., et al
(1998) Chromosome 14 familial Alzheimer's disease: the
clinical and neuropathological characteristics of a family with a leucine->
serine (L250S) substitution at codon 250 of the presenilin 1 gene.
Journal of Neurology, Neurosurgery and Psychiatry,
64, 44-49.
Holmes, C., Arranz, M. J., Powell, J. F., et al
(1998) 5-HT2A and 5-HT2C receptor
polymorphisms and psychopathology in late onset Alzheimer's disease.
Human Molecular Genetics,
7,
1507-1509.
Hope, T., Keene, J., Fairburn, C., et al (1997) Behaviour changes in dementia 2: Are there behavioural syndromes? International Journal of Geriatric Psychiatry, 12, 1074-1078.[CrossRef][Medline]
Lampe, T. H., Bird, T. D., Nochlin, D., et al (1994) Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred. Annals of Neurology, 36, 368-378.[Medline]
Lyketsos, C. G., Tune, L. E., Pearlson, G., et al (1996) Major depression in Alzheimer's disease. An interaction between gender and family history. Psychosomatics, 37, 380-384.[Abstract]
McKhann, G., Dracman, D., Folstein, M., et al (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology, 34, 939-944.[Abstract]
Meyer, M. R., Tschanz, J. T., Norton, M. C., et al (1998) APOE genotype predicts when - not whether - one is predisposed to develop Alzheimer's disease. Nature Genetics, 19, 321-322.[CrossRef][Medline]
Mullan, M., Houlden, H., Crawford, F., et al (1993) Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology. American Journal of Medical Genetics, 48, 129-130.[Medline]
Pearlson, G. D., Ross, C. A., Lohr, W. D., et al (1990) Association between family history of affective disorder and the depressive syndrome of Alzheimer's disease. American Journal of Psychiatry, 147, 452-456.[Abstract]
Roth, M., Tym, E., Mountjoy, C. Q., Huppert, F. A., et al (1986) CAMDEX. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry, 149, 698-709.[Abstract]
Schmand, B., Hooijer, C., Jonker, C., et al (1998) Apolipoprotein E phenotype is not related to late-life depression in a population-based sample. Social Psychiatry and Epidemiology, 33, 21-26.
Slooter, A. J., Cruts, M., Kalmijn, S., et al
(1998) Risk estimates of dementia by apolipoprotein E
genotypes from a population-based incidence study: The Rotterdam Study.
Archives of Neurology,
55,
964-968.
Strauss, M. E. & Ogrocki, P. K. (1996) Confirmation of an association between family history of affective disorder and the depressive syndrome in Alzheimer's disease. American Journal of Psychiatry, 153, 1340-1342.[Abstract]
Sumi, S. M., Bird, T. D., Nochlin, D., et al (1992) Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology, 42, 120-127.[Abstract]
Sweet, R., Pollock, B. G., Mulsant, B., et al (1997) Association of plasma homovanillic acid with behavioural symptoms in patients diagnosed with dementia: a preliminary report. Biological Psychiatry, 42, 1016-1023.[CrossRef][Medline]
Sweet, R., Nimgaonkar, V. L., Kamboh, M. I., et al
(1998) Dopamine receptor genetic variation, psychosis, and
aggression in Alzheimer's disease. Archives of
Neurology, 55,
1335-1340.
Wenham, P. R., Price, W. H. & Blandell, G. (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet, 337, 1158-1159.[Medline]
Received for publication March 29, 1999. Revision received July 26, 1999. Accepted for publication July 27, 1999.