Our primary finding is that there was no significant difference in distress as measured with the IES instrument between those who underwent susceptibility testing and those who underwent deterministic testing. We also found that both susceptibility and deterministic genetic testing appeared to be well-tolerated using disclosure protocols that provided screening, education, counseling and follow-up. Of interest, individuals who tested positive for the APOE ε4 allele in the susceptibility protocol experienced more test-specific distress over the first year post-disclosure than those who tested negative, while individuals who tested negative for autosomal dominant dementia in the deterministic protocol experienced approximately the same degree of distress as those who tested positive.
Despite the lack of significant difference in mean IES scores between positive and negative groups in the deterministic protocol, our linear regression model showed that test result was the only significant variable in predicting the total and avoidance IES score outcome measure when controlling for other variables. Indeed, the linear regression model showed that the type of genetic testing did not play a significant predictive role in IES outcome, nor did age, gender, or time from disclosure. This suggests that the type of genetic testing may not greatly influence post-disclosure distress, despite the very different genetic implications of susceptibility versus deterministic testing.
Our results showed a statistically significant difference in IES scores between those who tested positive for APOE ε4 and those who tested negative for the genotype. However, it remains unclear whether this difference in distress as reflected by quantitative IES score is indicative of clinically perceivable differences in qualitative distress. While statistically significant, the numerical disparity between total IES score means of the APOE ε4+ and ε4− groups was only 3.7 points on a scale that ranges from 0 to 75. Furthermore, both groups showed mean IES scores in the low range of the scale. It is therefore difficult to interpret how the differences between the APOE groups detected by this study might be manifested clinically.
We were surprised to observe that those receiving negative test results with deterministic testing had average IES total scores that were nearly as high as those testing positive. These results may considered in light of the fact that subjects presenting for deterministic testing are more likely to have witnessed siblings and multiple family members affected by the disease, potentially resulting in “survivor guilt” even if they are spared a positive result upon predictive testing.26
Most participants in both protocols appeared to tolerate genetic testing well, with only a small minority of individuals having IES scores above a cut-off that could be considered clinically significant, and none of the participants in either study reporting severe adverse events such as suicide attempts. These observations are consistent with studies on the impact of disclosure in HD, breast cancer, and colon cancer,20, 26–40
along with more limited studies of other autosomal dominant diseases,22, 41
which have reported an overall ability of subjects to cope successfully with genetic test results when provided in the context of a formal genetic counseling and education protocol. HD studies are particularly relevant as this is a neurodegenerative disease for which there is worldwide experience. While initial surveys of anticipated responses and anecdotal reports on the impact of HD testing suggested the possibility of severe psychological risks,42–48
systematic studies are more reassuring. With respect to suicide after HD testing, a world-wide survey of catastrophic events among those who received testing for HD did not suggest that suicide was more common than the general population among persons receiving positive test results who were truly pre-symptomatic.49
With respect to the emotional toll of testing, there is extensive evidence and remarkable consensus that with appropriate screening, education, and counseling, individuals testing positive for HD may experience modestly increased anger, despair or distress in the first weeks or months after disclosure. However, in the longer term, they are not emotionally more distressed than they were before being tested. There is also evidence that those who receive a negative test experience substantial emotional relief.26–28, 30, 33, 34, 40, 50, 51
Since genetic testing is not widely available, participants in genetic testing studies represent persons who have actively sought out these services within research protocols. Research reports have suggested that those responding and willing to participate in genetic testing studies are likely to be individuals who are well-prepared to receive results, have often known for years of their high-risk status, and therefore tend to cope well in the immediate aftermath of receiving genotype disclosure.52, 53
This may account, in part, for the fact that no differences in distress were observed between deterministic and susceptibility protocols. Because of the selection bias inherent to genetic testing research, the findings of this and other genetic testing studies may not be generalizable to the population at large. However, one study has compared the impact of genetic testing for hemochromatosis in high-risk groups to the impact of population-based genetic testing for the same disorder, and found similar levels of distress in both groups.54
Although the disclosure for the hemochromatosis gene holds different health implications than might be expected in genetic testing for Alzheimer’s disease, this study may suggest that population-based genetic testing could be as well-tolerated as that in more prepared high-risk groups.
Our study is limited by small sample sizes, particularly in the deterministic protocol, which may not have revealed differences in psychological impact between protocols due to low statistical power. Therefore, the results of this pilot study should be considered preliminary. While small, however, the data in the deterministic protocol represent the largest study of its kind and the best information on genetic testing for dominantly inherited AD and frontotemporal dementia currently available.
The differences in the protocol design between the two studies compared in this research are also limiting factors. In particular, the inclusion of a support person at the genetic counseling sessions in the deterministic protocol was not a feature of the susceptibility protocol design. This may have resulted in more emotional and social support in the deterministic group, which could have influenced IES scores in the post-test period. Also of note, the response rate to IES questionnaires was higher in the susceptibility group than in the deterministic group. One person testing positive in the deterministic group specifically requested not to be contacted in follow-up. These differences in response rates may impose some bias on the results of our study, as those who are more distressed might be less likely to return IES questionnaires. While our small sample size necessitated considering the results of genetic testing for the TAU gene, which is related to frontotemporal dementia, as having similar psychological impact to disclosure of a deterministic genotype for AD, in reality these two dementias are not identical. As such, the impact of disclosure of the TAU genotype may in actuality have a different psychological impact that was not detected in our study, and may therefore have skewed the IES scores in the deterministic group.
The study population demographics may also introduce a limitation to our conclusions, as there was an overrepresentation of white, highly educated participants. These individuals are likely to be better equipped to understand the implications of complex genetic information than would less educated members of the general population. Additionally, there are other potentially significant factors influencing the individual response to genetic testing that were not accounted for in our analyses, such as baseline psychological functioning and social support.26, 55
Another limitation lies in the fact that we did not examine a broad range of psychological outcomes in this study, relying instead exclusively on the IES, which was the only validated measure common to both protocols. Finally, although the limited availability of data in the deterministic protocol necessitated comparison of IES outcomes at disparate post-disclosure time points, controlling for this variable in a linear regression model showed no significant impact of time from disclosure in prediction of IES scores.
Further research is needed on the long-term psychological impact of both susceptibility and deterministic testing for AD. Future studies should aim to analyze the consequences of genetic testing for potentially distressing diagnoses in larger clinical samples, and should attempt to elucidate the individual baseline psychological or demographic characteristics that may predict a poor response to genotype disclosure in candidates for genetic testing. Additional knowledge is also needed on the long-term impact of genetic testing for AD, to ascertain how distress may change as those who have received genotype disclosure progress closer towards the age of onset.
Clinical genetic testing paradigms to date have evolved from experiences with rare deterministic mutations such as HD. Yet, the future of genetic testing in clinical medicine is more likely to involve susceptibility testing in complex genetic disorders. Research on genetic testing in AD, where both types of genetic testing are available, may provide some insight into the changing parameters of genetic risk assessment in the future.