Sex differences in the executive and behavioral reserve of autosomal dominant frontotemporal dementia

Abstract

Introduction: Self-reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.

Methods: We analyzed 394 genetic-FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI-based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes. We used the residuals of linear regression models, which predict each participant's cognitive and behavioral performance levels relative to cortical thickness, as a proxy for reserve. We then modeled sex differences in longitudinal trajectories with linear mixed-effects models.

Results: Symptomatic females with genetic FTD had lower frontal cortical thickness than males, and the C9orf72 subgroup showed lower-than-expected frontal cortical thickness for a given level of executive functioning. Differences in cognitive reserve between sexes peaked near symptom onset but diminished thereafter.

Discussion: Females with genetic FTD showed higher cognitive reserve than males, suggesting that self-reported sex modulates resilience to frontotemporal neurodegeneration.

Highlights: Females with genetic FTD showed higher cognitive reserve than males. Those differences were particularly pronounced in the C9orf72 and GRN subgroups. The higher cognitive reserve in females declined as the disease progressed.

Keywords: cognitive reserve; diagnosis; frontotemporal dementia; magnetic resonance imaging; neuroimaging; progression; resilience; survival.

FIGURE 1

Cortical thickness reduction in symptomatic FTD mutation carriers. Comparison of cortical thickness reduction in symptomatic (Clinical Dementia Rating plus National Alzheimer's Coordinating Center Behavior and Language Domains ≥ 0.5) pathogenic mutation carriers and healthy controls of the same self‐reported sex. (A) Group difference in cortical thickness between male FTD mutation carriers and healthy male controls. (B) Group difference in cortical thickness between female FTD mutation carriers and healthy female controls. (C) Net effect size shows greater cortical thinning in females carrying FTD mutations than in males. The effect size was obtained after subtracting the effect size map in panel B from the one in panel A. (D) Cortical areas where a significant group by sex interaction was found. The result was obtained from a 2‐way ANOVA analysis with group (pathogenic mutation carrier or healthy control) and sex at birth (female or male) as main factors and age and years of education as covariates. Colored areas represent the p‐values of the interaction between the pathogenic mutation carrier status (carrier vs. non‐carrier) and self‐reported sex (man vs. woman). ANOVA, analysis of variance; FTD, frontotemporal dementia; HC, healthy controls.

FIGURE 2

Comparison of cognitive reserve between females and males carrying FTD mutations. The predicted cognitive performance for a certain level of cortical thinning in each subject was obtained using the individual residuals as a proxy of cognitive reserve. The model included data from all the mutation carriers at baseline. Differences in residuals between females and males were calculated with Welch t‐tests. Panels show the linear model (A) and violin plot for the residuals (B). FTD, frontotemporal dementia.

FIGURE 3

Comparison of social cognitive reserve between females and males carrying FTD mutations. The predicted social cognitive performance for a certain level of cortical thinning in each subject was obtained using the individual residuals as a proxy of cognitive reserve. The model included data from all the mutation carriers at baseline. Differences in residuals between females and males were calculated with Welch t‐tests Panels show the linear model (A) and violin plot for the residuals (B). FTD, frontotemporal dementia; IRI, Interpersonal Reactivity Index.

FIGURE 4

Comparison of the cognitive reserve trajectories between females and males carrying FTD mutations. The image shows the differences in the executive function composite between males and females carrying FTD mutations through time, stratified by symptomatic status. The executive function composite obtained from every participant at each visit during the follow‐up was included as the dependent variable, correcting for cortical thickness to quantify the individual reserve as the disease progresses. Time, age at baseline, and years of education were included as fixed effects, as well as the interaction between self‐reported sex and symptomatic status with time. The model included random intercepts and slopes. The model included repeated measures from the mutation carriers during follow‐up. The vertical line represents the mean time of symptom onset for the participants who transitioned from asymptomatic to symptomatic stage during the follow‐up period. FTD, frontotemporal dementia.