The demographics of the subjects in each diagnostic group are shown in . As expected, the females predominate in the AD group, and the PD subjects are predominantly male and younger. Gender differences were also seen in the control group (female predominant) and the AD/PD group (male predominant). We performed a univariate t test for age and univariate chi-square tests for race and gender comparing the control group to the three case groups. See for results.
Demographics by diagnostic study group
shows the number of participants in each study group with positive family histories of AD and PD. Including all known relatives in the analysis, the frequency of reported AD family history was higher in the AD case group (33.5%) than in the other three study groups (25.9% for controls, 21.4% for AD/PD, and 21.0% for PD). This frequency difference is significant between the AD group and all three other groups: PD (p<0.001), AD/PD (p< 0.008), and control (p<0.04). In addition, the frequency of AD family history is higher in the control group (25.9%) than in the PD case group (21.0%) and in the AD/PD case group (21.4%); however, this difference is not statistically significant with p values of 0.14 and 0.35, respectively. Similarly, the frequency of reported PD family history was significantly higher in the PD case group (27.2%) than in the other three study groups (15.1% for AD/PD p<0.005, 12.3% for control p<0.0001, and 7.6% for AD p<0.0001). The frequency of PD family history was significantly higher in the control group (12.3%) than in the AD case group (7.6%; p<0.04).
Familial risk of AD and PD (intergroup analysis)
Logistic regression analysis was used to calculate the OR for the family history of AD or PD in the three case groups compared to controls (). As expected, AD subjects had a significantly increased risk of having a positive family history of AD when compared to the control subjects [1.9; 1.3–2.7 95% confidence interval (CI)]. Similarly, the PD patients had a significantly increased risk of a family history of PD when compared to controls (2.4; 1.5–3.9 95% CI). There was no crossed risk of either AD or PD; that is, AD cases did not show an increased risk of a family history of PD, and PD cases did not show an increased risk of a family history of AD. In fact, PD patients had a lower risk of familial AD than controls (0.6; 0.4–0.9 95% CI). AD/PD subjects showed no differences in risk of family history of either AD or PD as compared to control subjects.
As the reliability of reported medical information may be dependent upon the distance between the proband and relatives, a separate analysis of crossed risk of AD and PD was performed using only the data from the first-degree relatives (). Multivariate results were generally unchanged when comparing the analyses including only first-degree relative family history to the analyses including all relatives, although there were the expected lower frequencies of positive family histories for both diseases when only including first-degree relatives. Three of the univariate results changed when comparing analyses including only first-degree relative to those including all relatives. The AD family history reported in the PD case group was significantly lower than in the control group (p<0.03) when only first-degree relatives were included. When including all relatives, this difference was not significant (p<0.14). The PD family history reported in the AD/PD case group was significantly different from that reported by the PD case group when including only first-degree relatives (p<0.005) vs (p<0.2) when all relatives were included. And lastly, the AD case group did report significantly less PD family history than controls when only first-degree relatives were included (p<0.04) vs (p<0.27) when all relatives were included. These changes in significance do not alter the conclusions drawn from this analysis. Hence, the results of the intergroup analysis showed that AD and PD subjects have substantial increased risks of having the same disease in their family, but among all cases, there was no evidence for increased crossed risk.
To investigate the possible presence of a subset of cases with increased susceptibility to both AD and PD, we stratified the subjects in each diagnostic group by presence or absence of AD in their family history (including all relatives). We then performed an intragroup analysis comparing the frequency of a family history of PD in those with or without a family history of AD. As shown in , for probands with either AD or PD, those with a family history of AD were more likely to have a family history of PD. For example, AD cases with a positive family history of AD also exhibited an increased frequency of a positive family history of PD [11.1 vs 5.8%; OR 1.7 (0.9–3.1, 95% CI)] when compared to AD cases without a family history of AD. The increased crossed risk was also observed for PD cases with a positive family of AD [35.8 vs 24.9%; OR 1.7 (1.1–2.6, 95% CI)] when compared to PD cases without a family history of AD. The crossed risk was also observed in control cases, but the results did not reach statistical significance [17% vs 10.7%; OR 1.7 (0.7–4.1, 95% CI)]. No crossed risk of AD and PD was observed for those cases with AD/PD overlap syndrome, suggesting that either these are mechanistically distinct cases, a mixture of cases with several causes, or that the sample size was insufficient to detect a true difference [14.8 vs 15.2%; OR 0.8 (0.2–3.0, 95% confidence interval)].
Shared risk of AD and PD among those with family history of neurodegenerative disease (intragroup analysis)
The sensitivity of a family history report is dependent upon the recall and knowledge of the informant. As the identity of the informant was not recorded for all subjects, we are unable to analyze that data for the entire cohort. To address the possibility of bias based on the identity of the informant among groups, we examined this information for a random 20 subjects in each group. The subject was the sole provider of the family history for 100% of the controls, 70% of the PD subjects, 15% of the AD subjects, and 25% of the AD/PD subjects. The other 30% of PD subjects were assisted by at least one other family member. In the AD and AD/PD groups, 65% were assisted by at least one other family member. In the remaining 20% of AD cases and 10% of AD/PD cases, another family member was the sole provider. These results provide evidence for a notable difference in informants between the four study groups. Given the reduced involvement of the proband in reporting their family history, we would expect the family history reported in the AD and AD/PD groups to be less complete than in the PD and control groups.