Aug 2026· Brain Communications· Vol 8· 0 citations· 45 references
Medicine
TL;DR
Sex and educational attainment significantly affect the development and maintenance of cognitive reserve in individuals with genetic FTD, and underscore the importance of identifying disease-modifying interventions since the presymptomatic stages of the disease.
Abstract
Abstract Individuals with autosomal dominant frontotemporal dementia (FTD) exhibit considerable variability in disease onset and progression. Both modifiable and non-modifiable factors—such as sex, educational attainment or geographic region of residence—may contribute to this heterogeneity, potentially through their influence on cognitive reserve. The aim of the present study was to investigate the role of cognitive reserve modulators within the Genetic Frontotemporal dementia Initiative (GENFI) cohort. To this end, we used functional MRI (i.e. spatial chronnectome measures) and neurodegenerative markers (i.e. plasma neurofilament light chains levels) to determine disease stage using a Discriminative Event-Based Model (DEBM). We then examined how potential modulators influence the relationship between disease stage and cognitive performance. We analysed a total of 711 participants, including 106 patients with genetic FTD, 325 presymptomatic mutation carriers and 280 non-carriers healthy controls. Female participants showed a weaker association between disease stage and cognitive performance compared to males (P < 0.001), with difference becoming progressively more pronounced across symptomatic stages. Educational attainment exhibited a similar effect: individuals with higher education demonstrated an attenuated association compared to those with secondary or primary schooling (P < 0.001), with differences already detectable at prodromal disease stages. The effect of geographical region of residence was associated with education levels, but appeared to have an indirect and less strong influence. In summary, sex and educational attainment significantly affect the development and maintenance of cognitive reserve in individuals with genetic FTD. These findings underscore the importance of identifying disease-modifying interventions since the presymptomatic stages of the disease.
Background Hearing impairment (HI) has been identified as a potentially modifiable risk factor for dementia, yet its relationship with Alzheimer's disease (AD) neuropathology and the temporal directionality remain unclear, particularly in late life. Objective To examine cross-sectional and longitudinal associations between HI, clinical cognitive status, and AD biomarkers in community-dwelling older adults. Methods We included 474 DRIVES Project participants (mean age 73.5 ± 5.2 years). Hearing was assessed using the NIH Toolbox Words-in-Noise (WIN) test. Clinical cognitive status was assessed using Clinical Dementia Rating (CDR). AD biomarkers included cerebrospinal fluid (CSF) Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42 ratios and amyloid PET imaging. Multivariable linear, logistic, Cox proportional hazards, and Fine–Gray competing-risk models were used. Results HI was more prevalent among participants with mild cognitive impairment (MCI; defined as CDR = 0.5) than cognitively normal individuals (50% versus 24%, p < 0.001), and MCI status was independently associated with worse baseline WIN thresholds (β = 1.55 dB SNR; 95% CI 0.72–2.37). HI was not cross-sectionally associated with CSF amyloid or tau ratios or amyloid PET positivity. Longitudinally, baseline MCI was associated with a higher risk of incident HI (Cox HR = 2.63, 95% CI 1.48–4.67; Fine–Gray sHR = 2.79, 95% CI 1.06–7.40), whereas baseline HI was not associated with subsequent CDR progression. Conclusions In older adults, HI was associated with MCI but not core AD biomarkers or future CDR progression, suggesting that late-life HI may reflect cognitive vulnerability or broader brain aging rather than independently driving AD pathology.
Semere Bekena, R. Singh, Subrata Pal et al.· Journal of Alzheimer's Disea...· 0 citations
IMPORTANCE Autopsy evidence on sex-specific associations of education with neuropathology and cognition is limited. OBJECTIVE To test sex differences in education associations with neuropathologic burden and cognition. DESIGN Cohort study of data collected from September 2005 through August 2024. SETTING Multicenter autopsy cohort from the National Alzheimer's Coordinating Center. PARTICIPANTS Adults aged 55 years or older; cross-sectional eligibility required a final CDR-SB assessment within 2 years before death, and longitudinal eligibility additionally required at least 3 assessments. EXPOSURES Years of formal education. MAIN OUTCOMES AND MEASURES Neuropathologic measures and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Linear regression and mixed-effects models tested associations and interactions of education with sex, neuropathology, and linear and quadratic time. Benjamini-Hochberg correction addressed multiple comparisons. RESULTS Among 2592 participants (mean [SD] age at death, 81.6 [10.8] years; 1188 [45.8%] female), 1969 contributed to longitudinal analyses. In female participants, higher education was associated with lower Thal amyloid phase, diffuse plaques, neuritic plaques, and Braak stage ({beta} range, -0.097 to -0.071; qFDR<.026); none was significant among male participants. Education-by-sex interactions supported differences in Thal amyloid phase, and diffuse and neuritic plaques ({beta} range, -0.119 to -0.097; qFDR<.045). Education was unrelated to final CDR-SB among female ({beta}, -0.007; 95% CI, -0.052 to 0.038; P=.767) and male participants ({beta}, -0.026; 95% CI, -0.071 to 0.019; P=.254), with no education-by-sex interaction (P=.660). The education-by-Braak-stage-by-sex interaction indicated that higher education was associated with a weaker Braak stage-CDR-SB association among females than males ({beta}, -0.104; 95% CI, -0.171 to -0.038; qFDR=.022). Longitudinally, education was unrelated to linear CDR-SB change in either sex. Education-by-quadratic-time associations were observed among females ({beta}, 0.002; 95% CI, 0.001-0.003; P<.001) and male participants ({beta}, 0.001; 95% CI, 0-0.002; P=.037). The corresponding interaction with sex was also significant (P=.043). CONCLUSIONS AND RELEVANCE Among female participants, higher education was associated with lower selected Alzheimer's disease neuropathologic measures and weaker associations of tau pathology with cognition. Longitudinal trajectories were nonlinear, with slower earlier decline followed by later acceleration at higher education levels.
S. Raeesi, Y. Zeighami, C. Morrison et al.· medRxiv· 0 citations
About 50% of amyotrophic lateral sclerosis (ALS) patients develop cognitive-behavioural impairment, yet longitudinal studies diverge on onset and extent of decline. Cognitive reserve (CR) may modulate cognitive trajectories, although longitudinal evidence remains limited. We aim to characterize cognitive trajectories in ALS and healthy aging and to examine the role of CR proxies in shaping cognitive change over time. About 268 participants (169 patients, 99 controls) were evaluated twice over 6 to 18 months using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Mixed models were used to predict initial ECAS performance (ECAS1), and cognitive slope (ECAS2-ECAS1) using CR proxies (education, work and leisure), ECAS21-ECAS12 interval, demographics (age, sex, psychiatric medication) and clinical factors (disease duration, onset-region, respiratory capacity, functional decline, C9orf72 mutation and behavioural symptoms). In patients, education (p < .001) and leisure (p < .001) positively predicted ECAS1. However, longitudinally, education and leisure had negative main effects on cognition, protecting against decline through interactions with clinical variables. In controls, more education and leisure predicted better cognition through main effects and interactions. CR appears to exhibit a dynamic, phase-dependent influence in patients and controls, supporting initial cognitive performance and potentially offering subtle protection as disease progresses. The observed non-linear effects of all CR proxies and subgroup-specific effects highlight the importance of considering clinical context, time and initial cognition when evaluating CR's role in ALS.
Sara Simão, Miguel Oliveira Santos, M. Gromicho et al.· Journal of Neuropsychology· 0 citations
Background Subjective cognitive decline (SCD) is increasingly recognized in some cases as an early clinical stage in the Alzheimer's disease continuum, yet the factors that predict which individuals will progress to objective impairment remain poorly understood. Objective We evaluated risk factor differences and cognitive domain markers associated with progression in participants with subjective cognitive decline (SCD) at baseline from the NYU Alzheimer's Disease Research Center. Methods We included SCD non-decliners (n = 27), who remained stable, and decliners (n = 24), who progressed to mild cognitive impairment or worse, between the second to sixth yearly follow-up visits. Adjusted mixed-effects models examined group differences and associations between demographic, APOE status, psychometric test performance and comorbidities with longitudinal-decline. Results Overall, mean (SD) age was 67.4 (9.2) and total follow-up time was 5.1 (1.8) years. Lower education (14.9 (3.2) versus 17.3 (2.1)), Hispanic ethnicity (50.0% versus 11.0%), and hypercholesterolemia (adjusted odds ratio: 6.67) were risk factors for progression in SCD, p ≤ 0.05, whereas APOE status was not. Notably, SCD decliners were at increased risk for both amnestic and non-amnestic cognitive-decline with psychometric changes in memory, executive, and language domains (p < 0.001 for all). Conclusions These findings inform further work on SCD outcomes and related biomarkers, as well as preventive studies that target modifiable risk factors for SCD progression.
O. Bubu, Alfred K. Mbah, Mark A. Bernard et al.· Journal of Alzheimer's Disea...· 0 citations
Background: The interaction between sex, APOE ε4 status, and clinical progression in Alzheimer’s Disease (AD) remains a subject of debate. While females are often considered at higher risk for AD, the underlying structural neuroanatomical trajectories and how they are modulated by genotype are not fully elucidated. This study aims to evaluate how sex and the APOE ε4 genotype interact to influence longitudinal brain atrophy across three clinical groups. Methods: We analyzed longitudinal data from 2400 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), stratified by clinical group (i.e., cognitively normal, mild cognitive impairment, and AD), sex, and APOE ε4 carrier status. Using Type III Sum of Squares ANCOVA, we modeled the longitudinal variation in brain volume, controlling for baseline brain volume, and baseline severity of neurocognitive impairment and age at entry. Results: While main effects of sex and APOE genotype were not significant, the triple interaction (APOE * Sex * Clinical Group) was marginally significant (p = 0.051). Post hoc analysis revealed a distinct pattern of structural dimorphism within the AD cohort among APOE ε4-negative individuals with females exhibiting significantly greater structural preservation compared to males (Mean difference = 11.32, p = 0.051). Among APOE ε4 carriers, atrophy trajectories for males and females were statistically indistinguishable (p = 0.922), potentially suggesting that the ε4 allele exerts a dominant neurodegenerative influence that overrides sex-specific physiological differences. Conclusions: These emerging findings highlight the importance of jointly considering biological sex and APOE ε4 status to improve the characterization of Alzheimer’s disease heterogeneity and support precision medicine approaches.
Wanessa Michelin, Joana O. Pinto, B. Peixoto· Life· 0 citations
OBJECTIVES
The presence of a hexanucleotide expansion in the gene C9orf72 confers a higher risk of developing ALS and FTD with associated cognitive and behavioral change, although penetrance is incomplete, and many gene carriers never exhibit any clinical signs during their lifetime. To date, there have been few studies investigating additional factors such as age, years of education, gender, and their influence on cognition and behavior in people with ALS (pwALS), particularly those with a hexanucleotide expansion in the gene C9orf72.
METHODS
We selected 104 consenting pwALS from the Irish ALS register, comprising 52 C9orf72 positive participants and 52 C9orf72 negative controls matched on age, years of education, and gender. Cognitive functioning was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), while behavioral changes were examined using the Beaumont Behavioral Inventory (BBI).
RESULTS
No significant differences in ECAS performance were observed across the two groups, with the exception of visuospatial performance, which was more impaired in those carrying the C9orf72 repeat expansion (p = .001). Similarly, there was no difference in behavoural scores between the 2 groups.
CONCLUSIONS
These findings suggest that the presence of the C9orf72 repeat expansion does not presage the development of significant cognitive or behavioral impairment early in the disease stage when controlled for age, years of education, and gender. When interpreting these results, it is important to consider the relatively small sample size, and the exclusion criteria of previous clinically significant comorbidities.
Seán O'Farrell, Maria Christina Holland, C. Peelo et al.· Amyotrophic Lateral Sclerosi...· 0 citations
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