 |
|
A Family Study of Alzheimer Disease and Early- and Late-Onset Depression in Elderly Patients
Reinhard Heun, MD;
Andreas Papassotiropoulos, MD;
Frank Jessen, MD;
Wolfgang Maier, MD;
John C. S. Breitner, MD
Arch Gen Psychiatry. 2001;58:190-196.
ABSTRACT
| |
Background The substantial symptomatic overlap between depression and dementia
in old age may be explained by common genetic vulnerability factors.
Methods We investigated this idea by comparing the occurrence of both disorders
in first-degree relatives of 78 patients with Alzheimer disease (AD), of 74
with late-onset depression (onset age of  60 years), of 78 with early-onset
depression, of 53 with comorbid lifetime diagnoses of AD/depression, and of
162 population control subjects. Diagnostic information on their 3002 relatives
was obtained from structured direct assessments and from family history interviews.
Results The 90-year lifetime incidence of primary progressive dementia was significantly
higher in relatives of patients with AD (30%) and comorbid AD/depression (27%)
than in relatives of patients with early-onset (21%) or late-onset (26%) depression,
or of controls (22%) (P = .01). Lifetime incidence
of depression was significantly higher in relatives of patients with early-onset
depression (13%) than in relatives of patients with AD (10%) or controls (9.0%)
(P = .006). Lifetime incidence of depression was
similar in control relatives and in relatives of those patients with comorbid
AD/depression (8.6%). Relatives of patients with late-onset depression also
showed similar occurrence of depression until the age of 80 years, but the
figure increased sharply thereafter to 19.1% by the age of 90 years.
Conclusions Primary progressive dementia and early-onset depression represent clinical
entities with distinct inheritance. Late-onset depression does not share substantial
inheritance in common with dementia or with early-onset depression, but does
show modest familial clustering.
INTRODUCTION
DEPRESSION IS common in old age,1, 2
and cognitive dysfunction, including severe memory deficit, is frequent in
elderly patients with depression.3, 4, 5, 6, 7
Likewise, depressive symptoms are often seen in those with Alzheimer disease
(AD).8, 9, 10 The cause
of such symptom overlap in geriatric depression and AD is unclear, but it
may reflect common genetic antecedents. Especially when genetic causes are
suspected, family studies can inform the causative classification of psychiatric
disorders in that relatives of subjects with one causative entity should show
an increased risk of this, but not other, conditions. By contrast, when 2
or more syndromes have common genetic antecedents, their relatives should
show increased risks of all such related syndromes, but not of other disorders.11
Such reasoning presupposes significant familial aggregation for the
disorders in question, eg, AD and depression. This presupposition is justified
for AD and for early-onset depression (EOD), but is less secure for late-onset
depression (LOD). First-degree relatives of patients with AD show a 2- to
3-fold increased occurrence of primary progressive dementias (PPDs), as contrasted
with control relatives.12, 13, 14, 15, 16, 17, 18, 19, 20
Similarly, increased risks have been reported for depression in relatives
of (mostly young) patients with bipolar I and II disorder and for relatives
of patients with early-onset unipolar depression.21, 22, 23, 24
When the proband's onset of depression is later, the findings are less consistent.
Maier and colleagues25 showed a higher risk
of depression in first-degree relatives of patients with LOD (onset age of 60
years) than in relatives of controls. Other groups25, 26, 27, 28, 29
have reported lower loads of depression in relatives of probands with LOD
than in relatives of patients with EOD, but there are exceptions.30 Brodaty and coauthors31
observed lower risks of depression in parents, but not in siblings, of patients
with LOD.
Few studies have examined the familial aggregation of AD and depression
simultaneously. The available studies32, 33, 34, 35, 36
have often shown increased occurrence of depression and other psychiatric
disorders among the relatives of patients with AD, and vice versa. Two groups37, 38 reported an increase in depression
among relatives of probands with AD, specifically when the latter had comorbid
depression. Another study39 confirmed this
finding only for female probands with AD. Important limitations of these studies,
and probable reasons for their inconsistent results, may be their limited
size (in most instances) and their investigation of only 1 or 2 disorders
in patients or their relatives. Most studies also used the family history
method rather than more precise family study methods, in which ill relatives
are directly examined.
To our knowledge, we undertook the first family study of PPD and depressive
syndromes among relatives of probands with AD, EOD, and LOD, among relatives
of patients with comorbid AD/depression, and among relatives of matched population
controls. We investigated the following hypotheses:
- Alzheimer disease and EOD have different genetic
antecedents and, therefore, different patterns of familial aggregation. Accordingly,
relatives of probands with AD will have higher loads of PPD than relatives
of patients with EOD or controls. Relatives of probands with EOD will show
more depression than relatives of patients with AD or controls.
- Late-onset depression belongs to the broad spectrum
of depressive disorders. Therefore, relatives of probands with LOD will show
more depression than relatives of controls, but they will not show higher
risks of PPD than relatives of patients with EOD or controls.
- Alternatively, LOD belongs to the broad spectrum
of dementing disorders. Therefore, relatives of patients with LOD will show
more PPD than relatives of probands with EOD or controls, but they will not
show more depression than relatives of patients with AD or controls.
- Patients with a history of AD/depression (comorbid
cases) are genetically vulnerable to dementia and depression. Therefore, the
relatives of such comorbid probands will show more PPD than the relatives
of patients with EOD or controls, and more depression than the relatives of
probands with AD or controls.
PATIENTS AND METHODS
RECRUITMENT OF PATIENTS, CONTROLS, AND THEIR FIRST-DEGREE RELATIVES
Between January 1, 1992, and October 31, 1995, and between January 1,
1996, and December 31, 1998, we recruited in sequence patients aged 60 years
or older from the clinics of the University of Bonn, Bonn, and the University
of Mainz, Mainz, Germany, respectively. The resulting patient sample included
78 with AD, 78 with EOD, 74 with LOD (onset age of 60 years), and 53 with
AD/depression (comorbid patients). In the same years, we recruited 162 control
subjects who were group matched to the patient sample on age, sex, and educational
background. With the support of the cities' census agencies, we used a weighted,
stratified, systematic sampling approach to select matched controls at random
from the inhabitants' registers of the 2 communities (Table 1). We contacted the control subjects by mail or, if they
did not respond, by telephone to administer a personal interview. The patients
and controls were asked to provide names and addresses for all first-degree
relatives. All procedures involving contact with human subjects were approved
by the relevant local ethics committees, and informed consent was obtained
for each stage of direct contact. We also asked the relatives whom we interviewed
to obtain assent from their unavailable family members for their inclusion
in the analyses.
|
|
|
|
Description of 445 Patients and Control Subjects and 2792 First-Degree
Relatives by Diagnoses of Patients and Controls*
|
|
|
Because PPD is rare before the age of 50 years (in 1775 relatives aged
<50 years, only 1 showed PPD), we required that all patients and controls
have at least one first-degree relative aged 50 years or older available for
interview. Among eligible patients, the participation rate was then 87%.40 Without prior information on the availability of
control relatives, we could not calculate a comparable participation rate
among eligible controls. Nonparticipant patients were broadly similar to participants
on age, sex, and marital status, but had slightly higher educational attainment.40 Educational background was similar, however, for
each group of patients and for controls. As expected, patients with EOD were
slightly younger than the other groups (Table 1).
Given the high prevalence of many mental disorders, several investigators41, 42, 43 have noted that the
use of disease-free controls can artificially inflate distinctions in case-control
comparisons. Others44 have, therefore, proposed
that selected (disease-free) and unselected controls should be used, but this
approach creates additional statistical comparisons. Because we were interested
in comparing risks in various relative groups vs the general population, we
followed the conservative practice of not requiring that controls be disease
free. An unselected general population control panel also enabled the use
of a single large group of control relatives for all comparisons. Accordingly,
our 162 control individuals included 22 with dementia, 8 with EOD, and 9 with
past or current LOD.
FIRST-DEGREE RELATIVES
Two first-degree relatives asked not to be included in the study, and
their data were consequently excluded from analysis. The 445 study probands
then had 3002 first-degree relatives (Table
1). We could not learn whether 210 (7.0%) of these relatives were
living or dead but assumed that many were long deceased or lost to follow-up,
probably as a result of wartime conditions. Of the remaining 2792 relatives,
1236 (44.3%) were deceased (Table 1). We succeeded in interviewing 775 (49.8%) of the remainder. Living relatives
of probands with EOD were somewhat younger, while educational attainment was
slightly lower among interviewed relatives of patients with LOD (Table 1). We interviewed a higher proportion
of female than male relatives (52.7% vs 43.5%;  21
= 14.2; P<.001), but there were no important differences
in sex composition of the various relative groups. Ostensibly psychiatrically
ill relatives of control subjects (but not of patients) were less available
for interview than their healthy counterparts.40
To prevent an awareness bias when comparing relatives of patients and controls,
we, therefore, included source of information (interview vs family history
information only) as a covariate in the survival analyses. We also made separate
comparisons using interviewed and unavailable relatives and obtained identical
results.
DIAGNOSTIC ASSESSMENT
The clinical examination of the patients consisted of personal and family
histories, neurological and medical assessments, an extensive laboratory workup,
electroencephalography, computed tomography or magnetic resonance imaging,
and other tests if indicated. The patients, controls, and their available
first-degree relatives were assessed using the Composite International Diagnostic
Interview45 to assign lifetime DSM-III-R diagnoses for major psychiatric disorders.46
To detect and diagnose dementia, we interviewed patients, controls, and their
relatives older than 50 years using the Structured Interview for the Diagnosis
of Dementia of the Alzheimer Type, Multi-Infarct Dementia and Dementias of
Other Aetiology.47 Both instruments include
the Mini-Mental State Examination.48 To detect
depression and dementia in living and deceased relatives, we also used the
Family History Questionnaire49 and the Family
Dementia Risk Questionnaire.14, 50
We obtained family history information from spouses and all interviewed relatives.
The interviewers were medical students in their final years of training or
junior physicians. They had been trained in a 4-week clinical clerkship on
a geropsychiatric ward, and had participated in a comprehensive training course,
including at least 10 supervised training interviews. The interviewers were
"blind" to the patients' (and control subjects') diagnoses. To maintain this
blindness, they did not ask for information about the probands. Final diagnoses
and age at onset were assigned using the best-estimate procedure51
according to the consensus judgment of 2 experienced psychiatrists (R.H. and
A.P.) who remained blind to the identity of all probands and relatives.
We rarely obtained identical diagnoses for a relative from combinations
of 2 or more direct interviews or family history interviews. We, therefore,
combined lifetime diagnoses into broad categories for which agreement was
high. Diagnoses of major depression included DSM-III-R
codes 296.20 to 296.36. We diagnosed PPD (codes 290.00-290.30) rather than
AD in relatives because the latter can only be diagnosed after a clinical
workup. Interrater reliability of the direct interview data was satisfactory
for major depression (Cohen  = 0.67; 95% confidence interval, 0.37-1.00)
and for PPD (Cohen = 1.00; 95% confidence interval, 0.78-1.00). Interinformant
reliability of family history–based diagnoses was moderate for PPD (Cohen
= 0.58; 95% confidence interval, 0.48-0.68) but weaker for depression (Cohen
= 0.26; 95% confidence interval, 0.14-0.38).52
Compared with direct interview results, family history data showed limited
sensitivity but good specificity, namely, sensitivity and specificity of 20.8%
and 98.4% for dementia and 34.0% and 97.1% for depression, respectively. These
sensitivity estimates reflect the comparison of family history information
obtained from all available informants vs a direct interview of those who
could participate in the latter. The sensitivity of family history interviews
increased substantially with severity or duration of illness.53
The low sensitivity of family history information will reduce observed lifetime
incidence, but it should not affect comparisons of risks across relatives
of various patient groups or controls unless the sensitivity varied according
to the diagnosis in the proband. To control for the latter effect, we included
the source of information (direct assessment vs family history data) as a
covariate when comparing survival curves. Like Kendler and colleagues,54 we found increased sensitivity in the reporting of
depression by relatives who had themselves experienced a depressive illness.53 To avoid spurious familial aggregation resulting
from this problem, we discarded the family history information obtained from
93 relatives with one of the diagnoses under study. Other diagnostic information,
including direct interview results, remained available for these relatives.
STATISTICAL ANALYSES
Group comparisons used the 2 statistic, analysis of
variance, and the Scheffé tests. To compare the risks of depression
and PPD in relatives of the various groups of patients and controls, we calculated
Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression
analyses were then used according to the study hypotheses.55
We cite resulting hazard ratios (HRs) instead of corresponding 2 values for individual comparisons if the HR can be interpreted, ie,
if P .05 and df = 1.
For clarity, the final analyses were restricted to include only variables
with significant influence on familial loads for depression and PPD, namely,
sex and source of information (family history vs direct interview). Because
proportional hazards analysis relies on the (not necessarily justified) assumption
of proportionality in the effects of various predictor variables across multiple
groups, we also examined differences among the several Kaplan-Meier curves
using distribution-free Mantel-Haenszel statistics56
(the weakness of this method being its lack of consideration to covariates
or to examination of interaction effects). Unless otherwise stated, all 2 statistics have 1 df. The conventional threshold
for statistical significance ( ) was taken as P<.05
(2 tailed). A priori power calculations had shown that we would then need
about 60 families in each group to afford a probability of 80% (ß = .20)
of detecting significant differences among the survival curves.
RESULTS
PPD IN RELATIVES
Figure 1 presents Kaplan-Meier
curves of estimated PPD-free survival among relatives of the various patient
and control groups. Proportional hazards regression analysis revealed significant
differences in disease-free survival among relatives of the different proband
groups (Wald 24 = 17.0; P
= .002). Risks were increased in relatives of patients with AD and of patients
with comorbid AD/depression compared with control relatives (HR, 2.38 [P<.001] and 2.06 [P = .01],
respectively). Sex had no significant influence on the risk of PPD (2 = 1.86; P = .17). Direct interviewing increased
the chance of detecting PPD compared with family history information (HR,
2.3; P<.001), but this effect disappeared if an
interaction term including source of data and sex was used. This term indicated
that direct interview diagnoses of PPD were more sensitive than family history
diagnoses in women (HR, 2.91; P<.001) but not
in men. When the analyses were stratified by source of information, the diagnosis
of the patient remained the only predictor for risk of PPD in relatives (for
interviewed subjects vs those diagnosed by family history, 24 = 11.4 [P = .02] vs 24 = 10.6 [P = .03]).
|
|
|
|
Figure 1. Primary progressive dementia (PPD)–free
survival up to the age of 90 years in first-degree relatives with known age
or age of death by lifetime diagnosis of patients and control subjects, ie,
in 520 relatives of 78 subjects with Alzheimer disease (AD), in 347 relatives
of 53 subjects with comorbid AD/depression, in 465 relatives of 78 subjects
with early-onset depression, in 440 relatives of 74 subjects with late-onset
depression, and in 1020 relatives of 162 controls.
|
|
|
Mantel-Haenszel statistics revealed similar results: the familial loads
of PPD were different for the various groups of relatives (log-rank test 24 = 12.9; P = .01). Relatives of
patients with AD showed increased risk of PPD compared with relatives of probands
with EOD or LOD and controls (log-rank tests: AD vs EOD, 2
= 5.65, P = .02; AD vs LOD, 2 = 4.41, P = .04; and AD vs controls, 2 = 14.64, P<.001). Relatives of comorbid patients also showed
increased risk of PPD compared with control relatives (log-rank 2 = 9.45; P = .002) and, suggestively, with
relatives of probands with EOD and LOD (log-rank 2 = 3.52
[P = .06] and 2.37 [P =
.12], respectively). Patients with AD and with comorbid AD/depression, therefore,
appear relatively distinct from patients with EOD and with LOD and from controls
for their familial loads of PPD. Relatives of patients with AD and of patients
with AD/depression had indistinguishable familial loads of PPD (2 = 0.10; P = .76), as did relatives of patients
with LOD and EOD and control subjects (LOD vs controls, 2
= 1.24; EOD vs controls, 2 = 0.62; and LOD vs EOD, 2 = 0.06; P .27 for all).
DEPRESSION IN RELATIVES
Figure 2 shows Kaplan-Meier
curves for depression-free survival by relatives of patients and controls.
Cox proportional hazards regression analysis again revealed that proband diagnosis
significantly influenced relatives' risk of depression (Wald 24 = 14.5; P = .006). For relatives of patients
with EOD vs control relatives, the HR was 1.64 (P
= .04), whereas for relatives of patients with AD, the HR was 0.57 (P = .05). Relatives of probands with LOD and with comorbid
AD/depression showed risks of depression similar to control relatives (2 = 0.88 and 0.01, respectively; P .34).
Female relatives showed more depression than male relatives (HR, 1.93; P<.001). Directly interviewed relatives also showed
an apparently increased risk vs those assessed only by family history information
(HR, 2.2; P<.001), but this effect did not vary
substantially across proband groups. A significant interaction between sex
and source of data (2 = 7.33; P =
.007) suggested that the difference in depression between female and male
relatives was greater in relatives assessed by family history than in those
who were interviewed (HR, 2.13 [P = .008] and 1.32
[P = .07], respectively). Interaction terms between
proband diagnosis and sex, or between diagnosis and source of data, were not
statistically significant (24 = 8.6 [P = .07] and 6.8 [P = .14], respectively).
|
|
|
|
Figure 2. Depression-free survival up to
the age of 90 years in first-degree relatives with known age or age of death
by lifetime diagnosis of patients and control subjects, ie, in 520 relatives
of 78 subjects with Alzheimer disease (AD), in 347 relatives of 53 subjects
with comorbid AD/depression, in 465 relatives of 78 subjects with early-onset
depression, in 440 relatives of 74 subjects with late-onset depression, and
in 1020 relatives of 162 controls.
|
|
|
Mantel-Haenszel statistics supported these results. The familial load
of depression differed significantly by proband diagnoses (log-rank 24 = 14.5; P = .006). Relatives
of patients with EOD showed the most depression compared with relatives of
patients with AD and controls (log-rank 2 = 14.1 and 6.30,
respectively; P .01). However, comparisons of
relatives of probands with EOD vs LOD or comorbid AD/depression were inconclusive
(log-rank 2 = 1.41 [P = .23] and
2.45 [P = .12], respectively). Relatives of probands
with AD showed the lowest occurrence of depression (log-rank tests: AD vs
controls, 2 = 3.36, P = .07; AD vs
EOD, 2 = 14.1, P<.001; AD vs LOD, 2 = 6.72, P = .01; and AD vs comorbid AD/depression, 2 = 3.42, P = .06). Patients with LOD, comorbid
AD/depression, and controls did not differ in their familial loads of depression
(LOD vs controls, 2 = 1.12, P = .29;
comorbid patients vs controls, 2 = 0.06, P = .81; and LOD vs comorbid AD/depression, 2 = 0.35, P = .55). However, relatives of patients with LOD showed
a small, but significant, increase in LOD after the age of 80 years. Of 64
relatives of patients with LOD, 4 (6%) developed depression after this age,
as contrasted with 2 (2%) of 85 relatives of persons with AD, 1 (2%) of 65
such relatives of persons with EOD, and 0 of the 145 control relatives and
the 51 relatives of probands with comorbid AD/depression (24 = 11.5; P = .02).
COMMENT
In keeping with our first hypothesis, we found an increased risk of
PPD in the relatives of patients with AD and of patients with comorbid AD/depression,
compared with relatives of controls, but no such increase in relatives of
probands with EOD. The observed familial aggregation of PPD is in full agreement
with several earlier studies.12, 13, 14, 16, 17, 18, 19, 20
Like several other family studies on EOD,21, 22, 23, 24
we also found increased risk of depression in relatives of probands with EOD
vs relatives of controls, but there was no such effect in relatives of patients
with AD. These results suggest that AD and EOD are psychiatric disorders that
share few, if any, common genetic antecedents.
In contrast with Maier and colleagues,25
and in contrast with predictions of our second and third hypotheses, we found
that probands with LOD did not show significant familial loading of either
depression or PPD when compared with controls. Their relatives' occurrence
of depression tended to be lower than in relatives of patients with EOD, and
their load of PPD was substantially lower than in relatives of patients with
AD. These results do not support the notion that LOD shares familial factors
with either AD or EOD. There is, nevertheless, a slight but significant increase
in the loading of LOD in the relatives of probands with LOD that is evident
after the age of 80 years. These findings suggest that unique familial factors
may predispose to the development of LOD.
Our fourth hypothesis was confirmed only in part, in that patients with
comorbid AD/depression showed familial loading of PPD similar to that in patients
with uncomplicated AD, but they showed no substantial increase in familial
risk of depression.
The reduced risk of depression in relatives of patients with AD compared
with relatives of controls was unexpected. This difference persisted when
we restricted the control group to those free of disease. We conjecture that
some protective factor(s) might reduce the risk of depression in these relatives
of probands with AD or, alternatively, that our patients with AD and without
comorbid depression might represent individuals selected for the absence of
familial risk factors for depression. We favor the latter interpretation because
it is consistent with several family studies37, 38, 39
showing an increased risk of depression in relatives of subjects with comorbid
AD/depression compared with relatives of patients with uncomplicated AD. The
similar observed risks of depression in relatives of patients with comorbid
AD/depression and of controls might reflect the limited effect of familial
factors on relatives' risk of depression, rendering difficult their detection
in a comparison with population controls.
Selection bias and awareness bias are potential problems in this work,
as in all family studies. We succeeded in administering a direct interview
to only 775 of 3002 relatives, representing 49.8% of those living and 25.8%
of the entire sample. Our observed proportion of missing data (210 relatives,
or 7.0%) would be unlikely to bear substantially on results of survival analyses.
To examine possible differences in the reported occurrence of illness in direct
interview vs family history data, we compared results in a subsample of the
first 531 relatives studied. Except for the relatives of controls,40 we saw little effect of proband's diagnostic group
on relatives' availability for direct interview. Consequently, and because
the relatives' groups had comparable demographic characteristics, we doubt
that differential participation had any undue influence on comparisons of
disorders in the different relative groups.
The variables that affected the validity of diagnoses that relied on
family history were disorder in the informant, age, and sex. Accordingly,
we deleted information provided by diseased informants to prevent spurious
familial aggregation. Differences in the age distribution of relatives were
intrinsically considered through the use of survival analysis, while sex and
the source of information were controlled by including them as covariates.
All analyses, including those stratified by source of information (direct
interview vs family history) and the use of a design that compared several
groups of relatives (not only specific proband vs control relatives), led
to consistent results. We are, therefore, confident that our findings are
valid.
Our a priori power calculations relied on earlier studies that had compared
familial loads of dementia in patients with AD and controls, and of depression
in probands with EOD and controls. Accordingly, small differences between
disorders with intermediate familial loads would not be expected to reach
statistical significance. We, therefore, cannot exclude the possibility of
small increases of the familial loadings of PPD or depression in relatives
of subjects with LOD.
The observed familial aggregation of psychiatric disorders may be explained
by shared environmental factors and by genetic risk factors that influence
the illness susceptibility.57 Broadly speaking,
different disorders are likely to vary in the degree to which genetic and
shared environmental factors contribute to their familial aggregation. Even
so, genetic vulnerability factors are probably more important than shared
environment when onset is characteristically in late life, as in AD and LOD.
It is also likely that these prevalent late-onset conditions have heterogeneous
causes and tend mostly to result from complex interactions of common genetic
and environmental risk factors. These arguments should not detract substantially
from the reported results and conclusions, which were based on comparisons
across multiple groups of relatives. We acknowledge that our study could have
been improved with inclusion of APOE (apolipoprotein
E) genotypes for our probands and their relatives. Such genotypes were not
included herein because we did not collect blood samples at the beginning
of the study, and because some interviewed family members were reluctant to
provide blood samples. Despite these limitations, we suggest that this is
the largest and most comprehensive study yet published on familial aggregation
and coaggregation of the common psychiatric disorders of old age. Our results
suggest broadly that a family history of AD, EOD, and LOD all indicate an
increased familial risk for the same, but not other, psychogeriatric disorders.
AUTHOR INFORMATION
Accepted for publication August 16, 2000.
This study was supported by grant HE 2318/1-2 from the German Research
Foundation.
From the Department of Psychiatry, University of Bonn, Bonn, Germany
(Drs Heun, Papassotiropoulos, Jessen, and Maier); and the Department of Mental
Hygiene, The Johns Hopkins School of Public Health, Baltimore, Md (Dr Breitner).
Corresponding author and reprints: Reinhard Heun, MD, Department
of Psychiatry, University of Bonn, Venusberg, D-53105 Bonn, Germany (e-mail: heun{at}uni-bonn.de).
REFERENCES
| |
1. Copeland JRM. Depression of older age: origins of the study. Br J Psychiatry. 1999;174:304-306.
FREE FULL TEXT
2. Wittchen H-U, Knäuper B, Kessler RC. Lifetime risk of depression. Br J Psychiatry Suppl. 1994;(26):16-22.
3. O'Connor DW, Pollitt PA, Roth M. Coexisting depression and dementia in a community survey of the elderly. Int Psychogeriatr. 1990;2:45-53.
FULL TEXT
| PUBMED
4. O'Connor DW, Pollitt PA, Roth M, Brook CPB, Reiss BB. Memory complaints and impairment in normal, depressed, and demented
elderly persons identified in a community survey. Arch Gen Psychiatry. 1990;47:224-227.
FREE FULL TEXT
5. Deijen JB, Orlebeke JF, Rijsdijk FV. Effect of depression on psychomotor skills, eye movements and recognition-memory. J Affect Disord. 1993;29:33-40.
FULL TEXT
|
ISI
| PUBMED
6. Lichtenberg PA, Ross T, Millis SR, Manning CA. The relationship between depression and cognition in older adults:
a cross-validation study. J Gerontol B Psychol Sci Soc Sci. 1995;50:P25-P32.
7. Yaffe K, Blackwell T, Gore R, Sands L, Reus V, Browner WS. Depressive symptoms and cognitive decline in nondemented elderly women:
a prospective study. Arch Gen Psychiatry. 1999;56:425-430.
FREE FULL TEXT
8. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease, III: disorders of mood. Br J Psychiatry. 1990;157:81-86.
FREE FULL TEXT
9. Newman SC. The prevalence of depression in Alzheimer's disease and vascular dementia
in a population sample. J Affect Disord. 1999;52:169-176.
FULL TEXT
|
ISI
| PUBMED
10. Emery VO, Oxman TE. Update on the dementia spectrum of depression. Am J Psychiatry. 1992;149:305-317.
FREE FULL TEXT
11. Kendell RE. Clinical validity. Psychol Med. 1989;19:45-55.
ISI
| PUBMED
12. Heston LL, Mastri AR, Anderson VE, White J. Dementia of the Alzheimer type. Arch Gen Psychiatry. 1981;38:1085-1090.
FREE FULL TEXT
13. Heyman A, Wilkinson WE, Hurwitz BJ, Schmechel D, Sigmon AH, Weinberg T, Helms MJ, Swift M. Alzheimer's disease: genetic aspects and associated clinical disorders. Ann Neurol. 1983;14:507-515.
FULL TEXT
|
ISI
| PUBMED
14. Breitner JCS, Folstein MF. Familial Alzheimer dementia: a prevalent disorder with specific clinical
features. Psychol Med. 1984;14:63-80.
ISI
| PUBMED
15. Breitner JCS, Folstein MF, Murphy EA. Familial aggregation in Alzheimer dementia-I: a model for the age-dependent
expression of an autosomal dominant gene. J Psychiatr Res. 1986;20:31-43.
FULL TEXT
|
ISI
| PUBMED
16. Huff FJ, Auerbach J, Chakravarti A, Boller F. Risk of dementia in relatives of patients with Alzheimer's disease. Neurology. 1988;38:786-790.
FREE FULL TEXT
17. Farrer LA, O'Sullivan DM, Cupples LA, Growdon JH, Myers H. Assessment of genetic risk for Alzheimer's disease among first-degree
relatives. Ann Neurol. 1989;25:485-493.
FULL TEXT
|
ISI
| PUBMED
18. Korten AE, Jorm AF, Henderson AS, Broe GA, Creasey H, McCusker E. Assessing the risk of Alzheimer's disease in first-degree relatives
of Alzheimer's disease cases. Psychol Med. 1993;23:915-923.
ISI
| PUBMED
19. Silverman JM, Li G, Zaccario ML, Smith CJ, Schmeidler J, Mohs RC, Davis KL. Patterns of risk in first-degree relatives of patients with Alzheimer's
disease. Arch Gen Psychiatry. 1994;51:577-586.
FREE FULL TEXT
20. Silverman JM, Raiford K, Edland S, Fillenbaum G, Morris JC, Clark CM, Kukull W, Heyman A. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD):
part VI. Neurology. 1994;44:1253-1259.
FREE FULL TEXT
21. Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI Jr, Goldin LR, Bunney WE Jr. A family study of schizoaffective, bipolar I, bipolar II, unipolar,
and normal control probands. Arch Gen Psychiatry. 1982;39:1157-1167.
FREE FULL TEXT
22. Weissman MM, Kidd KK, Prusoff BA. Variability in rates of affective disorders in relatives of depressed
and normal probands. Arch Gen Psychiatry. 1982;39:1397-1403.
FREE FULL TEXT
23. Heun R, Maier W. The distinction of bipolar II disorder from bipolar I and recurrent
unipolar depression: results of a controlled family study. Acta Psychiatr Scand. 1993;87:279-284.
ISI
| PUBMED
24. Winokur G, Coryell W, Keller M, Endicott J, Leon A. A family study of manic-depressive (bipolar I) disease: is it a distinct
illness separable from primary unipolar depression? Arch Gen Psychiatry. 1995;52:367-373.
FREE FULL TEXT
25. Maier W, Lichtermann D, Minges J, Heun R, Hallmayer J, Klingler T. Unipolar depression in the aged: determinants of familial aggregation. J Affect Disord. 1991;23:53-61.
FULL TEXT
|
ISI
| PUBMED
26. Hopkinson G. A genetic study of affective illness in patients over 50. Br J Psychiatry. 1964;110:244-254.
27. Bland RC, Newman SC, Orn H. Recurrent and nonrecurrent depression. Arch Gen Psychiatry. 1986;43:1085-1089.
FREE FULL TEXT
28. Herrmann N, Lieff S, Silberfeld M. The effect of age of onset on depression in the elderly. J Geriatr Psychiatry Neurol. 1989;2:182-187.
29. Conwell Y, Nelson JC, Kim KM, Mazure CM. Depression in late life: age of onset as marker of a subtype. J Affect Disord. 1989;17:189-195.
FULL TEXT
|
ISI
| PUBMED
30. Greenwald BS, Kramer-Ginsberg E. Age-at-onset in geriatric depression: relationship to clinical variables. J Affect Disord. 1988;15:61-68.
FULL TEXT
|
ISI
| PUBMED
31. Brodaty H, Peters K, Boyce P, Hickie I, Parker G, Mitchell P, Wilhelm K. Age and depression. J Affect Disord. 1991;23:137-149.
FULL TEXT
|
ISI
| PUBMED
32. Van Ojen R, Hooijer C, Bezember D, Jonker C, Lindeboom J, Van Tilburg W. Late-life depressive disorder in the community, II: the relationship
between psychiatric history, MMSE and family history. Br J Psychiatry. 1995;166:316-319.
FREE FULL TEXT
33. Fahim S, van Duijn CM, Baker FM, Launer L, Breteler MMB, Schudel WJ, Hofman A. A study of familial aggregation of depression, dementia and Parkinson's
disease. Eur J Epidemiol. 1998;14:233-238.
FULL TEXT
|
ISI
| PUBMED
34. Martin RL, Gerteis G, Gabrielli WF Jr. A family-genetic study of dementia of Alzheimer type. Arch Gen Psychiatry. 1988;45:894-900.
FREE FULL TEXT
35. Li G, Shen YC, Li YT, Chen CH, Zhau YW, Silverma JM. A case-control study of Alzheimer's disease in China. Neurology. 1992;42:1481-1488.
FREE FULL TEXT
36. Lawlor BA, Sunderland T, Mellow AM, Hill JL, Newhouse PA, Murphy DL. Family history of depression and alcoholism in Alzheimer patients and
age-matched controls. Int J Geriatr Psychiatry. 1989;4:327-331.
37. Pearlson GD, Ross CA, Lohr WD, Rovner BW, Chase GA, Folstein MF. Association between family history of affective disorder and the depressive
syndrome of Alzheimer's disease. Am J Psychiatry. 1990;147:452-456.
FREE FULL TEXT
38. Strauss ME, Ogrocki PK. Confirmation of an association between family history of affective
disorder and the depressive syndrome in Alzheimer's disease. Am J Psychiatry. 1996;153:1340-1342.
FREE FULL TEXT
39. Lyketsos CG, Tune LE, Pearlson G, Steele C. Major depression in Alzheimer's disease: an interaction between gender
and family history. Psychosomatics. 1996;37:380-384.
FREE FULL TEXT
40. Heun R, Burkart M, Maier W. Selection biases during recruitment of patients and relatives for a
family study in the elderly. J Psychiatr Res. 1995;29:491-504.
FULL TEXT
|
ISI
| PUBMED
41. Breitner JCS, Murphy EA, Woodbury MA. Case-control studies of environmental influences in diseases with genetic
determinants, with an application to Alzheimer's disease. Am J Epidemiol. 1991;133:246-256.
FREE FULL TEXT
42. Kendler KS. The super-normal control group in psychiatric genetics: possible artifactual
evidence for coaggregation. Psychiatr Genet. 1990;1:45-53.
43. Weissman MM, Merikangas KR, John K, Wickramaratne P, Prusoff BA, Kidd KK. Family-genetic studies of psychiatric disorders: developing technologies. Arch Gen Psychiatry. 1986;43:1104-1116.
FREE FULL TEXT
44. Tsuang MT, Fleming JA, Kendler KS, Gruenberg AS. Selection of controls for family studies. Arch Gen Psychiatry. 1988;45:1006-1008.
FREE FULL TEXT
45. World Health Organization. Composite International Diagnostic Interview. Geneva, Switzerland: Division of Mental Health, World Health Organization;
1990.
46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
47. Zaudig M, Mittelhammer J, Hiller W, Pauls A, Thora C, Morinigo A, Mombour W. SIDAM: a structured interview for the diagnosis of dementia of the
Alzheimer type, multi-infarct dementia and dementias of other aetiology according
to ICD-10 and DSM-III-R. Psychol Med. 1991;21:225-236.
ISI
| PUBMED
48. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state
of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
49. Andreasen NC, Endicott J, Spitzer RL, Winokur G. The family history method using diagnostic criteria: reliability and
validity. Arch Gen Psychiatry. 1977;34:1229-1235.
FREE FULL TEXT
50. Silverman JM, Breitner JCS, Mohs RC, Davis KL. Reliability of the family history method in genetic studies of Alzheimer's
disease and related dementias. Am J Psychiatry. 1986;143:1279-1282.
FREE FULL TEXT
51. Leckman JF, Sholomskas D, Thompson WD, Belanger A, Weissman MM. Best estimate of lifetime psychiatric diagnosis. Arch Gen Psychiatry. 1982;39:879-883.
FREE FULL TEXT
52. Heun R, Müller H. Interinformant reliability of family history information on psychiatric
disorders in relatives. Eur Arch Psychiatry Clin Neurosci. 1998;248:104-109.
FULL TEXT
|
ISI
| PUBMED
53. Heun R, Maier W, Müller H. Subject and informant variables affecting family history diagnoses
of depression and dementia. Psychiatry Res. 1997;71:175-180.
FULL TEXT
|
ISI
| PUBMED
54. Kendler KS, Silberg JL, Neale MC, Kessler RC, Heath AC, Eaves LJ. The family history method: whose psychiatric history is measured? Am J Psychiatry. 1991;148:1501-1504.
FREE FULL TEXT
55. Cox DR, Oakes D. Analysis of Survival Data: Monographs on Statistics
and Applied Probability 21. London, England: Chapman & Hall; 1984.
56. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies
of disease. J Natl Cancer Inst. 1959;22:719-748.
57. Khoury MJ, Beaty TH, Cohen BH. Fundamentals of Genetic Epidemiology: Monographs
in Epidemiology and Biostatistics. Vol 19. New York, NY: Oxford University Press Inc; 1993.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Research Agenda for DSM-V: Diagnostic Categories and Criteria for Neuropsychiatric Syndromes in Dementia
Jeste et al.
J Geriatr Psychiatry Neurol 2006;19:160-171.
ABSTRACT
Variability of Familial Risk of Alzheimer Disease Across the Late Life Span
Silverman et al.
Arch Gen Psychiatry 2005;62:565-573.
ABSTRACT
| FULL TEXT
|
