Minute effects of sex on the aging brain: a multisample magnetic resonance imaging study of healthy aging and Alzheimer's disease

Abstract

Age is associated with substantial macrostructural brain changes. While some recent magnetic resonance imaging studies have reported larger age effects in men than women, others find no sex differences. As brain morphometry is a potentially important tool in diagnosis and monitoring of age-related neurological diseases, e.g., Alzheimer's disease (AD), it is important to know whether sex influences brain aging. We analyzed cross-sectional magnetic resonance scans from 1143 healthy participants from seven subsamples provided by four independent research groups. In addition, 96 patients with mild AD were included. Estimates of cortical thickness continuously across the brain surface, as well as volume of 17 subcortical structures, were obtained by use of automated segmentation tools (FreeSurfer). In the healthy participants, no differences in aging slopes between women and men were found in any part of the cortex. Pallidum corrected for intracranial volume showed slightly higher age correlations for men. The analyses were repeated in each of the seven subsamples, and the lack of age x sex interactions was largely replicated. Analyses of the AD sample showed no interactions between sex and age for any brain region. We conclude that sex has negligible effects on the age slope of brain volumes both in healthy participants and in AD.

Figure 1.

Volumetric differences between women and men. The bars illustrate the mean volume for women (red) and men (blue) separately for each of the brain volumes tested. The 95% confidence intervals are indicated. In the upper row, volumes are corrected for the effects of sample by means of regression analyses, and the standardized residuals are shown. In the middle row, the volumes are corrected for ICV in addition to sample, and in the final row they are corrected for total brain volume and sample. Men had significantly larger uncorrected volumes for all structures, and for several ICV-corrected structures, although the differences were much smaller in the latter cases. *p < 0.05.

Figure 2.

Scatter plots of age effects on cerebrum. The scatter plots show the individual data points and the aging pattern for women (red) and men (blue) for cerebral cortex and white matter after ICV corrections of the volumes (the y-axes denote z-scores of the residuals). The numbers above each plot are the R² for women (red) and men (blue), respectively, including the contributions from both linear and nonlinear terms. In addition, the three-dimensional renderings of several of the structures included in the present paper are shown above the plots, based on the average brain of ∼70 participants below 40 years.

Figure 3.

Scatter plots of age effects on subcortical structures. The scatter plots show the individual data points and the aging pattern for women (red) and men (blue) for selected subcortical structures after ICV corrections of the volumes (the y-axes denote z-scores of the residuals). The numbers above each plot are the R² for women (red) and men (blue), respectively, including the contributions from both the linear and the nonlinear terms. Above the plots, the three-dimensional renderings of the structures are shown, based on the average brains of ∼70 participants below 40 years. Note that these are rescaled for the figure, and so their size cannot be visually compared. The age effects did not differ between women and men.

Figure 4.

Scatter plots of aging patterns on CSF compartments. The scatter plots show the individual data points and the aging pattern for women (red) and men (blue) for the measured CSF compartments after ICV corrections of the volumes (the y-axes denote z-scores of the residuals). The numbers above each plot are the R² for women (red) and men (blue), respectively, including the contributions from both the linear and the nonlinear terms. CSF differed in age slope between women and men.

Figure 5.

Correlations with age in women and men. The lines illustrate the Pearson correlations between volume and age for women (red) and men (blue). The values are sorted by the coefficient strength for the raw volumes in women. With the exception of CSF, where men showed higher correlations, none differed significantly between women and men. 1, Lateral ventricles; 2, third ventricle; 3, inferior lateral ventricles; 4, CSF; 5, fourth ventricle; 6, brainstem; 7, cerebral WM; 8, cerebellum WM; 9, cerebellum cortex; 10, cerebellum cortex; 11, hippocampus; 12, pallidum; 13, amygdala; 14, thalamus; 15, accumbens; 16, TBV; 17, cerebral cortex; 18, putamen.

Figure 6.

Testing of effects of sex on cortical thickness. The figure shows that no effects of sex on cortical thickness were found when conventional procedures for multiple comparisons (FDR < 0.05) were used. Further, there were no significant differences in the age slopes of cortical thickness between women and men when the same threshold was used (FDR < 0.05). Top panel, The effects of sex on cortical thickness are shown as color-coded p-value maps, and projected onto a semi-inflated template brain. Blue-green indicates thinner cortex for men than women, while red-yellow indicates that women have thicker cortex (p < 0.05, uncorrected). The analyses were corrected for the effects of age and subsample. The middle panel illustrates that all effects vanish if a conventionally used procedure for correction for multiple comparisons is used (FDR < 0.05). Bottom panel, Red-yellow areas indicate that women have more age-related reduction in cortical thickness than men, while blue-green areas indicate the opposite. The analyses are corrected for the effect of subsample. When the results were thresholded at FDR < 0.05, all effects vanished.