Microstructural White Matter Properties Mediate the Association between APOE and Perceptual Speed in Very Old Persons without Dementia

PLoS One. 2015 Aug 7;10(8):e0134766. doi: 10.1371/journal.pone.0134766. eCollection 2015.


Background: Reduced white matter integrity, as indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), has been related to poorer perceptual speed (PS) performance. As the ε4 allele has been associated with lower white matter integrity in old age, this represents a potential mechanism through which APOE may affect PS.

Objective: To examine whether the association between APOE and PS is mediated by white matter microstructure in very old persons without dementia.

Method: Participants were selected from the population-based SNAC-K study. After excluding persons with dementia, preclinical dementia, and other neurological disorders, 652 persons (age range 78-90) were included in the study, of which 89 had data on diffusion tensor imaging (DTI). We used structural equation modeling to form seven latent white matter factors (FA and MD) and one latent PS factor. Separate analyses were performed for FA and MD and mediational analyses were carried out for tracts where significant associations were observed to both APOE and PS.

Results: APOE was associated with white matter microstructure in 2 out of 14 tracts; ε4 carriers had significantly lower FA in forceps major and higher MD in the cortico-spinal tract. Allowing the white matter microstructure indicators in these tracts to mediate the association between APOE and PS resulted in a markedly attenuated association between these variables. Bootstrapping statistics in the subsample with DTI data (n = 89) indicated that FA in forceps major significantly mediated the association between APOE and PS (indirect effect: -0.070, 95% bias corrected CIs -0.197 to -0.004).

Conclusion: Lower white matter integrity may represent one of several mechanisms through which APOE affects PS performance in elderly persons free of dementia and preclinical dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apolipoprotein E4 / genetics*
  • Dementia / genetics
  • Dementia / pathology*
  • Diffusion Tensor Imaging
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Perception*
  • White Matter / pathology*


  • Apolipoprotein E4

Grants and funding

SNAC-K is financially supported by the Swedish Ministry of Health and Social Affairs, the participating County Councils and Municipalities, and the Swedish Research Council. This work was further funded by grants from the Swedish Council for Working Life and Social Research (EL, ML, LF, LB), the Swedish Research Council (EL, ML, LF, LB), Swedish Brain Power (LF, LB), Gun and Bertil Stohne’s foundation (GK), Osterman’s foundation (GK), the foundation for age-related diseases at Karolinska Institutet (EL), an Alexander von Humboldt Research Award (LB), and a donation from the af Jochnick Foundation (LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.