Carmona‐Iragui, María

Abstract INTRODUCTION Sleep and circadian rest–activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS‐associated AD continuum remain uncharacterized. METHODS We analyzed 7‐day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group‐specific associations. RESULTS DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

AbstractINTRODUCTIONSelf‐reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.METHODSWe 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.RESULTSSymptomatic 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.DISCUSSIONFemales 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.

AbstractBackgroundAccumulating evidence indicates that biological sex may influence clinical manifestation within the spectrum of frontotemporal lobar degeneration (FTLD), implying differences in cognitive reserve. Nonetheless, investigations into the impact of biological sex during the preclinical and minimally symptomatic stages of FTLD are lacking.MethodWe included 275 mutation carriers (158 females; 127 with C9orf72, 68 with GRN, and 80 with MAPT mutations) and 161 non‐carrier familial controls (97 females) from the ALLFTD Consortium (Staffaroni et al., Nat Medicine 2022). Participants underwent magnetic resonance imaging (MRI; 348 baseline, 338 longitudinal) and neuropsychological evaluations (394 baseline, 507 longitudinal). Behavioral symptoms were characterized with the Revised Self‐Monitoring Scale (RSMS) and the Neuropsychiatric Inventory (NPI severity scores). MRI‐derived regional volume estimates (RVE) were computed. Cognitive measures and RVE were normalized against sex‐matched controls. Cognitive composites (language, executive function, and visuospatial function) were calculated by averaging raw scores for each domain. Clinical characteristics and RVE comparisons were made between male and female participants. We adopted the residuals approach to explore behavioral and cognitive reserve by fitting a linear regression model for executive z‐scores as the response value and age, education, and RVE as explanatory variables.ResultIn mutation carriers, sex was not a significant differentiator in age, education level, disease severity, or mutation frequency. Most mutation carriers (188, 68%) were asymptomatic or mildly symptomatic at baseline. However, female mutation carriers exhibited significantly lower visuospatial performance at baseline (Cohen's d = ‐0.34, 95% CI[‐0.58, ‐0.09], p=.001). This difference remained significant among asymptomatic GRN mutation carriers (Cohen’s d = ‐0.73, 95% CI[‐1.22, ‐0.23], p=0.003) but not in other mutations. Following the residuals approach, female mutation carriers showed higher executive performance than males for the same amount of both frontotemporal and global atrophy as quantified by RVE (Cohen's d=0.45, 95 % CI[0.22, 0.67], p<.001). The observed higher executive reserve in women was particularly pronounced in C9orf72 carriers (Cohen's d=0.77, 95% CI[0.35, 1.20], p<.001) but not significant in GRN (p=0.48) and MAPT carriers (p=0.07). No differences in behavioral reserve reached statistical significance.ConclusionFemale sex might modulate early cognitive performance and confer higher executive reserve in FTLD mutation carriers.

Abstract INTRODUCTION A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti‐amyloid clinical trials. METHODS In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity—a novel marker of cortical microstructure—changes in 389 participants from the Dominantly Inherited Alzheimer Network. RESULTS In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations. DISCUSSION These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.