Absence of Familial Association Between Dementia of Alzheimer Type and Down Syndrome

C. Berr, E. Borghi, M. 0. Rethore, J. Lejeune, and A. Alperovitch

American Journal of Medical Genetics 33:545-550 (1989)


Résumé :

The aim of this study was to test whether there is an excess of dementia of Alzheimer type (DAT) cases in Down syndrome (DS) relatives. We conducted a case-control study in families of DS children with classical trisomy 21. A control group was constituted of families of children referred to the same hospital for be-nign diseases. Families of 188 DS children and 185 controls were recruited. We obtained vital statistics on 1,850 (response rate 82%) grandparents and great-grandparents in the DS group and 1,525 (69%) in the control group. Rates of possible severe dementia were calculated on ancestors over age 60 years with available data on men-tal function, 1,336 in the DS group and 1,113 in the control group. Rates of possible severe dementia were similar in the two groups: 5.6% (78 cases) in DS and 6.2% (66 cases) in control. Dementia with insidious onset suggestive of DAT was observed in 2% (28 cases) of DS ancestors and 2.6% (28 cases) of control ances-tors. Our results argue against an excess of demen-tia cases with insidious onset suggestive of DAT in families of children with classical tri-somy 21.

Sommaire

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Introduction

Genetic models have been implicated previously in the etiology of dementia of Alzheimer type (DAT). Studies of pedigrees with multiple affected individuals have established the existence of a familial form of the disease with an apparent autosomal dominant pattern of inher-itance [Cook et al., 1979]. In addition, studies in families of DAT cases have shown an increased risk of dementia in first- and second-degree relatives of probands with DAT [Matsuyama et al., 1985]. It is of interest that such families appear to have a high risk not only of dementia but also of Down syndrome (DS). Heston et al. [1981] have studied medical disorders among the relatives of post-mortem confirmed DAT probands. When compared to the general population, these relatives show an in-creased frequency not only of DAT itself, but also of DS and immunoproliferative disorders. Heston's result were confirmed in a case control study by Heyman et al. [1984], who found an increased frequency of mental retardation, mainly related with DS, among relatives of clinically diagnosed patients as compared to controls. An excess of DS in DAT relatives has not been confirmed by others [Whalley et al., 1982; Chandra et al., 1987; Heymann et al., 1983; Breitner and Folstein, 1984; Amad-ucci et al., 1986; Huff et al., 1988]. As DS is not frequent (about 1.4 cases per 1,000 live births in the general population), large family sample sizes are necessary to evidence small differences in its frequency. Because the studies in the literature have sample-size limitations for this purpose, it is not clear whether the two disorders are associated in some families.

Other studies that support interest in the relationship between DAT and DS are those that show that nearly all individuals with DS develop Alzheimer-type changes in their brains by age 30 years [Whalley, 1982; Oliver and Holland, 1986]. Although the neuropathological studies are in general agreement, the proportion of individuals with DS who can be said to be demented and have the manifestations of DAT has not been as well established [Thase et al., 1984; Wisniewski et al., 1985].

Extensive research by molecular genetic techniques are now being conducted in DAT [St Georges Hyslop et al., 1987a,b; Tanzi et al., 1987; Delabar et al., 1986]. The results of studies on genes localized on chromosome 21 are conflicting. The aim of this study was to ascertain whether frequency of severe dementia, including possible DAT, was increased in the relatives of individuals with DS. We conducted a case-control study and compared the familial history of children with DS and controls.

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Materials and methods

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Selection of Cases and Controls

The study was conducted in the outpatient department of the Hopital Necker-Enfants Malades (Paris). Referred children were under age 18 years. Their parents (mother and/or father) were invited to participate in the study. Parents were interviewed at the hospital. Interviewers were not blind to the status of the child. Parents were not told of the specific interest in DAT but rather that the study concerned various health problems, particularly those related to aging, within families of children with various disorders. It was made clear that active coopera-tion of the family was needed, not only during this interview, but after as well in order to collect missing data. A form was used to record, at home, information that was not available at the time of the interview. Parents of children were encouraged to obtain data from their own parents when possible. Phone calls were made for verification and clarification of missing or incomplete responses.

Nearly all the parents approached agreed to participate. Only families that had lived in France for more than two generations were included. This restriction was necessary to reduce the risk of unreliable information due to language problems or to the removal of family. Children whose parents were separate or whose father was unknown were excluded.

The cases were children with DS. Each of them have been karyotyped. Nondisjunction of chromosome 21 dur-ing meiosis, leading to trisomy 21 in children, was at the origin of nearly 95% of the DS cases. The other cases were related to mosaicism (n = 6) or translocation of a portion of chromosome 21 on another chromosome (n = 3). Although the study of these two types of DS would have been interesting, the number of cases was too small to warrant a separate study of these cases and they were excluded. Thus, to study an homogeneous group of children, the cases included were restricted to those cases of DS related to classical trisomy 21.

The controls were children with normal phenotype referred to the outpatient departments of general pediatry and pneumology-allergology in the same hospital. They were affected by ordinary diseases, mostly asthma and allergy.

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Questionnaire

We recorded demographic and medical characteristics of the children and their parents (mother and father). A structured interview concerning the ancestors of the child (grandparents and great-grandparents) was arranged. We constructed a family pedigree recording all ancestors with available vital statistics (date of birth and death). For each ancestor, living or dead, we noted medical infor-mation in an open questionnaire. This information was obtained from members of the families without the aid of medical records.

The interviewers asked specifically for various symp-toms of mental deterioration. Possible dementia cases were identified by the presence of severe memory dis-turbance, language disorders, or disorientation leading to dependence on others. For relatives who met the criteria of possible dementia, the age at which the symptoms began was estimated. Description of onset (sudden or progressive) and progression of symptoms were noted. We considered only symptoms with an evolution longer than 6 months.

The possible dementia cases were subdivided into four groups according to mental history:

1. The possible DAT group consisted of cases with insidious onset, gradual progression of dementia, and absence of neurological symptoms.

2. The second group consisted of possible mental de-terioration due to stroke. It was composed of individuals with very sudden onset dementia with or without neuro-logical symptoms.

3. The Parkinson dementia (PD) group included Parkinson disease cases with a history or mental deteriora-tion.

4. The "undetermined" group gathered cases difficult to classify because of unspecific or unreliable history of dementia. This group probably included multi-infarct dementia (MID) and combined vascular and degenerative dementia (mixed dementia). A fraction of DAT cases was probably classified in this group. In addition, dementia due to specific condition or disorder known to sometimes cause dementia (essentially alcoholism and depression) were included in this group.

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Analysis

Statistical analysis of categorical data was performed using the chi-square test and eventually the Fisher exact probability test. Variance analysis was used to compare quantitative terms. Rates of dementia were standardized by time at risk for dementia. Crude rates are presented by age group (seven classes) along with their confidence interval.

On the hypothesis that rates of DAT were 3% in control families and 6% in DS families, 1,030 individuals in each group were required for a sufficient study power (a = ß = 5%).

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Results

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Sample Characteristics

One hundred ninety-four families in each group were included in this study. For six DS and nine controls, information was not obtained in spite of efforts to do so by post or phone. This study reports data on the families of 188 DS children and 185 controls.

Some of the characteristics of children and parents are shown in Table I. There were no significant differences in age or sex between DS children and controls. As expected, birth order in DS children was higher than in controls. Moreover, maternal and paternal age at birth were both elevated in the DS group.

Table I - Sample characteristics
DS cases(n == 188)Controls (n-185)P
Children
Mean age (years)7.47.9NS
Sex (% male)54.860.5NS
Mean birth order2.331.69<10-4
Parents
Mean maternal age at birth31.327.3<10-4
Mean paternal age at birth33.229.7<10-4
NS = nonsignificant P value.

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Available Family History

Relatives who reached the age of 60 years constituted the population at risk of dementia. Medical information recorded on ancestors under age 60 years did not show evidence of possible dementia cases. Only seven parents of IBS children and none of the parents of controls had reached the age of 60 years at the time of the interview. Hence, our analysis was restricted to grandparents and great-grandparents.

Table II records the number of ancestors traced and the information available on them. The response rate for vital statistics on ancestors was significantly higher in DS families than in control families. In control families, we obtained significantly more information on females than on males. Because of the lack of reliable data on mental function, we had to exclude 6.6% of ancestors over age 60 years in the DS group and 4.6% in the control group (P < .05). All dementia rates have been calculated for this remaining population of ancestors over age 60 years for whom data on mental function were available; 1,336 subjects in the DS group and 1,113 subjects in the control group.

As parents of DS children were older than were the parents of controls, the "age effect" led to differences in the vital statistics of grandparents and great-grandparents.

1. More ancestors were deceased in the DS families. Being born earlier than the ancestors of controls, they were more "likely to be dead." Mean age at death of female ancestors was similar between the DS and control group. Male DS relatives died at an age older than did male control ancestors (P < .05).

2. For subjects alive at the time of the study, we found, similarly, an older age in DS ancestors than in the control ancestors. This increase was observed for both sexes.

Nevertheless, the same percentage of subjects over age 60 was observed in both groups.

Table II. Available Family History
Male ancestorFemale ancestorTotal ancestor
DSControlDSControlDSControl
No. ancestors with vital statistics (a)918 (81.4%)***lc 734(66.1%)932 (82.6%)***791 (71.3%)1,850 (82.%)***1,525 (68.7%)
% deceased72.3%***66.6%59.1%*49.3%65.7%***57.6%
Mean age at death67.9*66.372.172.269.868.9
Mean age at time of study68.7*66.969.868.869.4*68.1
No. ancestors with age over 60 years (b)692 (75.4%)532 (72.5%)739 (79.3%)635 (80.3%)1,431 (77.4%)1,167 (76.5%)
Ancestors over age 60 years with available data on mental function (c)641 (92.7%)501 (94.2%)695 (94.0%)*612 (96.4%)1,336 (93.4%)*1,113 (95.4%)
a Response rate. b Percent of ancestors with vital statistics; c Percent of ancestors over age 60 years. P values for comparison between DS ancestors and control ancestors: * P a0.05, ** P a 0.01, *** P a 001.

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Dementia in Ancestors Over Age 60 Years

Delay between age 60 years and age at death or age at time of interview was considered as the time at risk for dementia. This time was significantly greater in DS than in control ancestors for both sexes (Table III).

After a standardization by this risk time, similar rates of possible dementia, 5.55% in DS ancestors and 6.19% in control ancestors, were found. A higher frequency of dementia was noted for females in both groups.

There was no aggregation of cases in families. The 78 cases in DS were found in 63 families, 11 families with two cases and two families with three cases. The 66 cases in controls were found in 52 families, eight families with two cases, three families with three cases.

Study of dementia rates by classes according to clinical history did not show any difference between the two groups. The insidious onset form, suggestive of DAT, was present in 1.96% of DS ancestors and 2.63% of control ancestors. An excess of cases in females was again found in the two groups. Only one family with two possible DAT cases related at first degree was reported in the DS group compared to three in the control group.

Distribution by age class for possible dementia of all types is presented in Figure 1. Ascending values from 0.5% before age 65 years to 10.6% after age 90 years were observed in the DS group. Similarly, rates varied from 0.5% before age 65 years to 16.1% after age 90 years in controls. In two age classes, we noted significant differences: between ages 70 and 74 years, more possible dementia cases were reported in DS families, but conversely, between ages 75 and 79 years, the increase was in control families. Possible DAT rates by age group are presented in Figure 2. They increased similarly with age in the two groups.

Age of onset was sometimes difficult to determine and was not estimated for all the subjects ( 74 of the 78 DS relative cases; 54 of the 66 control relative cases). Of the dementia cases in DS families, 13 (17.6%) began before age 70 years compared to three (5.6%) in control families (P < .05). But of the 13 cases with onset before age 70 years, eight were possible dementia due to stroke, two PD, two "undetermined," and only one a possible DAT. Of the five cases in DS relatives who began before age 60 years, two were possible dementia suggestive of stroke, one a PD, and two "undetermined."

Table III. Dementia in Ancestors Over Age 60 Years: No. Cases and Rates Standardized by Time at Risk of Dementia
Male ancestorsFemale ancestorsAll ancestors
DS (n = 641)Control (n = 501)DS (n = 695)Control (n = 612)DS (n = 1,336)Control (n = 1,113)
Mean time at risk for dementia (after age 60 years)14.5*13.216.9*15.715.8*14.6
All dementia29 (4.27%)16 (3.41%)49 (6.70%)50 (8.52%)78 (5.55%)66 (6.19%)
Subtypes
Progressive onset6 (0.94%)5 (1.08%)22 (3.02%)23 (3.91%)28 (1.96%)28 (2.63%)
Sudden onset14 (2.15%)2 (0.44%)14 (1.88%)10 (1.74%)28 (2.0%)12 (1.14%)
Parkinson dementia (PD)4 (0.58%)1 (0.22%)3 (0.43%)1 (0.14%)7 (0.50%)2 (0.17%)
Undetermined5 (0.71%)8 (1.67%)10 (1.37%)16 (2.74%)15 (1.08%)24 (2.24%)
P value for comparison between DS ancestors and control ancestors: * P a 0.05.


Fig. 1 - Dementia rate by age group (seven classes)


Fig. 2 - Rate of progressive dementia suggestive of dementia of Alzheimer type (DAT) by age group (seven classes)

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Dementia in Grandparents Over Age 60 Years

Second-degree relatives were analyzed separately. Demographic data were available for mast of the grandparents: 98% in the DS group and 95% in the control group. We obtained sufficient data on mental function of 505 grandparents (95.5% of the 529 who reached age 60 years) in the DS group and 453 (94.2% of the 481 who reached age 60 years) in the control group. Mean tine at risk for dementia was greater, for both sexes, in grandparents of DS children than in those of the control (Table IV). After standardization by time at risk, rate of dementia in DS grandparents was significantly higher than in controls: 3.63 vs. 0.90% (P < .01). This increase was significant for grandfathers (4.93 vs. 0.45%, P < .01) but not for grandmothers (2.78 vs. 1.38% ).

No possible DAT cases were described in DS grandfathers or in the control grandfathers. Nine of the 13 cases (69%) were related to mental deterioration due to stroke. They were observed in the maternal branch of the families for ten of the 13 cases.

Table IV. Dementia in Grandparents Over Age 60 Years: No. Cases and Rates Standardize by Time at Risk for Dementia
GrandfathersGrandmothersAll grandparents
DS (n = 258)Control (n = 220)DS (n = 247)Control (n = 233)DS (n = 505)Control(n = 453)
Mean time at risk for dementia (after age 60 years)11.1**9.311.5***8.611.3***9.0
All dementia13 (4.93%)***1 (0.45%)9 (2.78%)3 (1.38%)22 (3.63%)**4 (0.90%)
Progressive onset dementia suggestive of DAT003 (0.90%)03 (0.43%)0
P values for comparison between DS ancestors and control ancestors: P a 0.05, ** P a 0.01, *** P a .001.

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Dementia in Ancestors of Children With Maternal Age Under 35 Years

Elevated maternal age at birth is considered to be the most important risk factor for DS, and it is hypothesized that the mechanism at the origin of trisomy 21 (nondisjunction of chromosome 21 originated from the mother in 80% of the cases) might differ according to maternal age at birth [Penrose, 1983; Erickson, 1978].

We compared families of DS children with maternal age under 35 years to families of controls with same maternal age. There were 118 DS children and 167 controls with mother's age under 35 years at birth. Available data on mental function were provided for 93.5% (n = 857) of the DS ancestors with age over 60 years and 95% (n = 982) of the control group's ancestors (Table V).

Dementia rates standardized by time at risk were similar in the two groups: 4.98% in the DS and 6.36% in the control group. No excess of possible DAT cases was observed.

Of the cases with known age of onset (42 in DS, 50 in controls), an earlier onset was noted for Down syndrome, seven cases (four possible dementia due to stroke, two PD, one "undetermined") before age 70 years compared to two (possible dementia due to stroke) in control ancestors (P = .05).

Table V. Dementia in Relatives of Proband With Maternal Age at Birth < 35 Years: No. Cases and Rates Standardized by Time at Risk for Dementia
Male ancestorsFemale ancestorsAll ancestors
DS (n = 415)Control (n = 445)DS (n = 442)Control (n = 537)DS (n = 857)Control (n = 982)
Mean time at risk for dementia (after 60)13.813.316.5*15.215.214.4
All dementia15 (3.58%)14 (3.28%)29 (6.25%)46 (9.02%)44 (4.98%)60 (6.36%)
Progressive onset dementia suggestive of DAT6 (1.40%)4 (0.92%)12 (2.54%)23 (4.49%)18 (2.02%)27 (2.85%)
P value for comparison between DS ancestors and control ancestors: P a.05.

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Discussion

The present study found no excess of severe dementia in the families of DS cases compared with the families of controls. Among the various types of dementia, we did not observe an increased frequency of occurrence of possible DAT in ancestors of probands with DS.

In discussing these negative results, some aspects of the study should be considered. First, ascertainment of dementia cases is affected by 1) the motivation of the respondents to collect vital statistics and medical information on their families; and 2) the personal bias of the respondent (or the interviewer) regarding the reporting of dementia cases. The respondents of FMS cases provided more vital statistics on their families than did the controls. However, comparable information about medical history and mental functioning in ancestors over age 60 years was obtained for both DS cases and controls. Strict guidelines were defined to minimize the effect of the interviewer regarding the diagnosis of dementia, and mild and moderate dementing conditions were excluded. Although some of these might be true dementia cases, there is no reason to suspect that comparability is affected by this underestimating. However, it seems easier to obtain information of an equal quality for families of both DS cases and the controls if ascertainment is restricted to severe demented illness. Thus, the proportion of false-positive and false-negative errors in the diagnosis of dementia cases in families is likely to be identical in both groups. Because interviewers were aware of the hypothesis of the study, we cannot totally exclude a recall bias. This could have led to an overdetection of dementia cases in DS families, but the negativity of our results is against such a bias.

The frequency of occurrence of dementia observed in this study is about 6%. This frequency increased more than tenfold between ages 60 and 90 years in relatives of both DS and controls. These endings are comparable to prevalence rates for severe dementia that have been reported in other studies [Mölsä et al., 1982; Kay et al., 1964]. Despite inherent differences in study design, which make a direct comparison of our results with those of other studies difficult, this similarity provides confirmatory evidence for the reliability of our data. The present study, similar to previous studies [Sulkava et al., 1985; Broe et al., 1976], found higher rates of severe dementia in females.

The assignment of type of dementia, based on the reporting of history of onset and progression of the dementing disorder, was made with great caution. On the whole, less than 40% of demented cases were diagnosed as probable DAT, a proportion that is very close to those found in other epidemiological studies [Mölsä et al., 1982; Sulkava et al., 1985; Rorsman et al., 1986].

An important concern in interpreting these negative results is whether the study power was sufficient to detect a difference in the frequencies of occurrence. In this study, the number of subjects in each group was large and sufficient to detect weak association between DS and dementia (study power = .97).

In this study, we observed very few early-onset dementia cases, that is, before age 60 years. The slight excess of cases with onset before age 70 years observed in DS relatives was related mostly to the cases with onset suggestive of possible dementia due to stroke and not to possible early-onset DAT cases. Yatham et al. [ 1988] suggested recently that the rate of presenile DAT cases was higher in relatives of DS probands than in the general population and discussed this result with respect to the very small number of presenile dementia cases (n = 4) that they observed. Our study did not find a similar increase.

One possible explanation of differences between our results and those observed in studies conducted by Heston et al. [1981] and Heyman et al. [1984] is that DAT could be associated with some special conditions of DS. For example, in families of DAT, translocation or duplication of part of chromosome 21 could be looked for. We think that this hypothesis is not very likely, but it cannot be totally excluded. When the investigation is focused on classical free trisomy 21, there is no evidence of excess of DAT in ancestors of Down syndrome patients.


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