Altered brain white matter integrity in healthy carriers of the APOE epsilon4 allele: a risk for AD?
Persson J, Lind J, Larsson A, Ingvar M, Cruts M, Van Broeckhoven C, et al.;
Commented by , 25 Jul 2006
Aim of the study
To determine if changes in brain white matter explains the higher risk for cognitive impairment and dementia in carriers of the APOE ε4 allele.
Method
Sixty healthy volunteers ages 49 to 79 were studied using diffusion tensor imaging; 30 were homozygous for the APOE ε3 allele, 10 were homozygous for the APOE ε4 allele, 20 had the APOE ε34 allele combination. All groups were matched for gender, age and length of education. There were equivalent amounts of vascular risk factors.
Subjects were scanned using a single-shot spin echo EPI sequence, diffusion tensor imaging sequence was repeated four times, the averaged images were processed and fractional anisotropy maps were calculated. Separate univariate analysis of variance was used to examine the difference between carriers and non-carriers for each of the regions of interest.
Results
There was a decline in fractional anisotropy, a marker for white matter integrity, in the posterior corpus callosum of ε4 carriers compared to non-carriers [F(1,56) = 7.39, p<0.01]. This difference was found in younger as well as older subjects, using a cut off age of 65. There was no allelic dose effect. Additional sites of altered white matter integrity included the medial temporal lobe.
Professor Gauthier's comments
These findings suggest that increased genetic risk for developing AD is associated with changes in microscopic white matter integrity well before the onset of dementia. These results are consistent with observations made in anatomo-pathological or MRI studies.
There has been evidence for white matter changes in patients with AD, particularly in the posterior callosal fiber systems. It was logical to postulate that APOE ε4 carriers would present alterations in that brain region compared to ε3/4 and ε3/3 carriers. The technique of diffusion tensor imagery could thus become a non-invasive mean of studying prospectively persons at risk of developing AD and add to our understanding of the early stages of this condition.
An ethical issue is whether the participants have the right to know their APOE status as well as the individual results on various tests. Currently in the absence of proven disease-modifying treatment the usual practice has been in the consent form to clearly state that there will be no information shared from individual results, only group results.
The exception may be for incidental findings on neuroimaging that may have an impact on individuals, requiring permission a priori in the consent form for who to notify (ref. 1). On the other hand to potential availability of anti-amyloid and other long-term therapies may greatly modify what information is shared with research participants in future studies.
References
1. Illes J, Rosen AC, Huang L, Goldstein RA, Raffin TA, Swan G, et al. Ethical consideration of incidental findings on adult brain MRI in research. Neurology 2004; 62 (6); 888-890