Publications
1. Seyedsalehi, Aida; Warrier, Varun; Bethlehem, Richard A I; Perry, Benjamin I; Burgess, Stephen; Murray, Graham K
Educational attainment, structural brain reserve and Alzheimer's
disease: a Mendelian randomization analysis Journal Article
In: Brain, vol. 146, no. 5, pp. 2059–2074, 2023.
Abstract | BibTeX | Tags: Alzheimer's disease; MRI; Mendelian randomization; brain reserve; educational attainment
@article{Seyedsalehi2023-zu,
title = {Educational attainment, structural brain reserve and Alzheimer's
disease: a Mendelian randomization analysis},
author = {Aida Seyedsalehi and Varun Warrier and Richard A I Bethlehem and Benjamin I Perry and Stephen Burgess and Graham K Murray},
year = {2023},
date = {2023-05-01},
journal = {Brain},
volume = {146},
number = {5},
pages = {2059–2074},
publisher = {Oxford University Press (OUP)},
abstract = {Higher educational attainment is observationally associated with
lower risk of Alzheimer's disease. However, the biological
mechanisms underpinning this association remain unclear. The
protective effect of education on Alzheimer's disease may be
mediated via increased brain reserve. We used two-sample
Mendelian randomization to explore putative causal relationships
between educational attainment, structural brain reserve as
proxied by MRI phenotypes and Alzheimer's disease. Summary
statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's
disease (35 274 cases, 59 163 controls) and 15 measures of grey
or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted
univariable Mendelian randomization analyses to investigate
bidirectional associations between (i) educational attainment
and Alzheimer's disease; (ii) educational attainment and
imaging-derived phenotypes; and (iii) imaging-derived phenotypes
and Alzheimer's disease. Multivariable Mendelian randomization
was used to assess whether brain structure phenotypes mediated
the effect of education on Alzheimer's disease risk. Genetically
proxied educational attainment was inversely associated with
Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95%
confidence interval 0.60, 0.80). There were positive
associations between genetically predicted educational
attainment and four cortical metrics (standard deviation units
change in imaging phenotype per one standard deviation increase
in genetically predicted years of schooling): surface area 0.30
(95% confidence interval 0.20, 0.40); volume 0.29 (95%
confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95%
confidence interval 0.11, 0.25); local gyrification index 0.21
(95% confidence interval 0.11, 0.31)]; and inverse associations
with cortical intracellular volume fraction [-0.09 (95%
confidence interval -0.15, -0.03)] and white matter
hyperintensities volume [-0.14 (95% confidence interval -0.23,
-0.05)]. Genetically proxied levels of surface area, cortical
volume and intrinsic curvature were positively associated with
educational attainment [standard deviation units change in years
of schooling per one standard deviation increase in respective
genetically predicted imaging phenotype: 0.13 (95% confidence
interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19)
and 0.12 (95% confidence interval 0.04, 0.19)]. We found no
evidence of associations between genetically predicted
imaging-derived phenotypes and Alzheimer's disease. The inverse
association of genetically predicted educational attainment with
Alzheimer's disease did not attenuate after adjusting for
imaging-derived phenotypes in multivariable analyses. Our
results provide support for a protective causal effect of
educational attainment on Alzheimer's disease risk, as well as
potential bidirectional causal relationships between education
and brain macro- and micro-structure. However, we did not find
evidence that these structural markers affect risk of
Alzheimer's disease. The protective effect of education on
Alzheimer's disease may be mediated via other measures of brain
reserve not included in the present study, or by alternative
mechanisms.},
keywords = {Alzheimer's disease; MRI; Mendelian randomization; brain reserve; educational attainment},
pubstate = {published},
tppubtype = {article}
}
Higher educational attainment is observationally associated with
lower risk of Alzheimer's disease. However, the biological
mechanisms underpinning this association remain unclear. The
protective effect of education on Alzheimer's disease may be
mediated via increased brain reserve. We used two-sample
Mendelian randomization to explore putative causal relationships
between educational attainment, structural brain reserve as
proxied by MRI phenotypes and Alzheimer's disease. Summary
statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's
disease (35 274 cases, 59 163 controls) and 15 measures of grey
or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted
univariable Mendelian randomization analyses to investigate
bidirectional associations between (i) educational attainment
and Alzheimer's disease; (ii) educational attainment and
imaging-derived phenotypes; and (iii) imaging-derived phenotypes
and Alzheimer's disease. Multivariable Mendelian randomization
was used to assess whether brain structure phenotypes mediated
the effect of education on Alzheimer's disease risk. Genetically
proxied educational attainment was inversely associated with
Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95%
confidence interval 0.60, 0.80). There were positive
associations between genetically predicted educational
attainment and four cortical metrics (standard deviation units
change in imaging phenotype per one standard deviation increase
in genetically predicted years of schooling): surface area 0.30
(95% confidence interval 0.20, 0.40); volume 0.29 (95%
confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95%
confidence interval 0.11, 0.25); local gyrification index 0.21
(95% confidence interval 0.11, 0.31)]; and inverse associations
with cortical intracellular volume fraction [-0.09 (95%
confidence interval -0.15, -0.03)] and white matter
hyperintensities volume [-0.14 (95% confidence interval -0.23,
-0.05)]. Genetically proxied levels of surface area, cortical
volume and intrinsic curvature were positively associated with
educational attainment [standard deviation units change in years
of schooling per one standard deviation increase in respective
genetically predicted imaging phenotype: 0.13 (95% confidence
interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19)
and 0.12 (95% confidence interval 0.04, 0.19)]. We found no
evidence of associations between genetically predicted
imaging-derived phenotypes and Alzheimer's disease. The inverse
association of genetically predicted educational attainment with
Alzheimer's disease did not attenuate after adjusting for
imaging-derived phenotypes in multivariable analyses. Our
results provide support for a protective causal effect of
educational attainment on Alzheimer's disease risk, as well as
potential bidirectional causal relationships between education
and brain macro- and micro-structure. However, we did not find
evidence that these structural markers affect risk of
Alzheimer's disease. The protective effect of education on
Alzheimer's disease may be mediated via other measures of brain
reserve not included in the present study, or by alternative
mechanisms.