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Background Colombia hosts the largest Autosomal‐Dominant Alzheimer's Disease (ADAD) kindred caused by the PSEN1‐E280A genetic variant, with full penetrance. This ADAD is well‐characterized in terms of clinical and biomarker research, but Electroencephalography (EEG) as a biomarker is still under development. EEG facilitates understanding brain function and electrophysiological changes in ADAD. Dual‐task (DT) paradigms, particularly during gait and upper extremity function, are useful biomarkers to determine cognitive impairments, due to neurodegenerative disorders such as Alzheimer's disease. EEG and DT are non‐invasive, portable, and feasible in outpatient settings, making them highly accessible for clinical practice. Method The study sample includes two groups, asymptomatic carriers (n = 37) and non‐carriers (n = 42) of the PSEN1‐E280A variant. EEG data were recorded during a dual‐task paradigm involving two tasks. The first task was a motor task (single‐task) involving upper extremity flexion‐extension. The second was a motor‐cognitive task (dual‐task), which included subtraction by 7 (DTS7), by 1 (DTS1) or verbal fluency with animals (DTAN). EEG signals were collected using the OpenBCI system from frontal and central regions. Data were processed and spectral and neural dynamics features were extracted. Dual‐task cost (DTC) was calculated as the difference between metric values under dual‐task and single‐task conditions, computed across channels and frequency bands for each feature. The extracted metrics were statistically analyzed using Cohen's‐D effect size and Mann‐Whitney U‐tests to assess differences. Result The most notable effect sizes were observed in entropy for Beta1 and Beta3 bands in frontal regions for the DTS7 and DTS1 tasks, Beta2 relative power in C4 during DTAN, Theta modulation in the Theta and alpha‐1 bands in frontal regions during DTS7, and Alpha2 modulations in the same task. Conclusion The proposed experiment effectively extracted brain information that differentiates between carriers and non‐carriers of the PSEN1‐E280A variant. DTC values in the alpha band (frontal and central regions) and the beta band (central regions) exhibited larger effect sizes, suggesting that these areas are sensitive to preclinical cognitive and motor differences. The experimental paradigm and data‐processing pipeline ensured the acquisition of EEG data with meaningful neurological information. This combination of novel biomarkers enhances non‐invasive and portable tools for identifying ADAD carriers during preclinical stages.

Graph metrics have been used to evaluate functional connectivity in Alzheimer's disease (AD). It has been found that nodal and global graph metrics are altered in subjects with AD and MCI compared to controls. In subjects with mutations associated with autosomal dominant Alzheimer's disease (ADAD), these metrics may vary depending on the stage within the disease continuum. This study aimed to evaluate the characteristics of graph metrics in the DMN specifically in asymptomatic subjects carrying the PSEN1 E280A mutation. 32 asymptomatic carriers (aC) and 25 non-carrier controls (nC) matched by sex, age and education status, underwent rs-fMRI acquisition for 10 minutes. Pre-processing of images was performed with CONN toolbox and RSN were extracted with Schaefer atlas with 79 ROI for DMN. Graph metrics were extracted with GRETNA toolbox, with a range of sparsity thresholds from 0.05-0.5 for all metrics. A non parametric t-test wilcoxon and linear mixed model (LMM) were performed, with corrections for multiple comparisons with Bonferroni. Significant differences were found in education (p-value < 0.001, confidence interval 95% 1.43 - 5.15), but not for age and sex. Betwenness Centrality (Bc) was higher in nC tan aC (p-value 0.0051, Cohen's d estimate: -0.011 CI95% -0.030 to 0.007) and Modularity (Q) (p-value 0.042, Cohen's d estimate: -0.15 CI95% -0.318 to 0.0136). Regarding the LMM, differences were observed in the intercepts of nodal graph metrics, but no differences were found between groups. However, when examining each intercept individually, it was shown that clustering coefficient, betweenness centrality, local efficiency, and degree centrality increase the slope in nC, while they decrease it in aC. At the global graph level, no differences were found between aC and nC groups. Bc idifferentiates between aC and nC. It is higher in nC, indicating that, at a local level, there is a greater number of nodes through which more connections pass, making them central to DMN connectivity. The local changes in aC are attributed to pathophysiological alterations in information distribution and the reorganization of DMN to distribute information across RSN and preserve cognitive functions.

Background In sporadic Alzheimer's Disease (AD), the cholinergic basal forebrain degenerates early, but seems to be preserved in the Colombian PSEN1‐E280A genetic mutation for familial AD. In two cross‐sectional studies analyzing basal forebrain volume and connectivity from the API Colombia cohort, we found no reduction in basal forebrain volume or connectivity in carriers, but observed reduced thalamic volume. Confirming these findings in other groups with the same genetic mutation, such as those in the Colombia‐Boston (COLBOS) biomarker study, will help determine whether the new hypothesis about basal forebrain preservation in familial AD holds true. Method We used multi‐modal imaging (MRI, amyloid and tau‐PET) data of 57 cognitively unimpaired individuals from the COLBOS study comprising PSEN1‐E280A carriers (n = 27) and non‐carriers (n =30). Staging of functional impairment was done using the Functional Assessment Staging Tool (FAST). Volumetry analyses were performed using basal forebrain, hippocampus and thalamus as regions of interest. We used Bayesian multiple regression with both flat and informed priors to test the hypothesis of preservation. As a secondary analysis, we investigated the associations of amyloid and tau pathology with brain volumes. Result We found evidence for no effect of mutation carrier status on basal forebrain volume (BF₁₀: flat = 0.076; inf =0.54) and hippocampal volume (BF₁₀: flat =0.16; inf =1.05). In contrast, we observed moderate evidence for an effect of mutation carrier status on thalamus volume, with smaller volumes in mutation carriers (BF₁₀: flat =5.42; inf =8.74) (Figure 1). Lastly, we found strong evidence against an effect of amyloid status on basal forebrain and hippocampus, but moderate evidence for an effect on thalamic volume (Figure 2A). Similarly, tau pathology was not associated with basal forebrain, but showed associations with thalamus and hippocampus. (Figure 2B). Conclusion Our findings show that in the PSEN1‐E280A cohort, the cholinergic basal forebrain and hippocampus are not affected early in the disease, whereas the thalamus is, pointing to important considerations for treatment target selection in this group. These results should be further explored in other autosomal dominant AD mutations.

In sporadic Alzheimer's Disease (AD), the cholinergic basal forebrain degenerates early, but seems to be preserved in the Colombian PSEN1-E280A genetic mutation for familial AD. In two cross-sectional studies analyzing basal forebrain volume and connectivity from the API Colombia cohort, we found no reduction in basal forebrain volume or connectivity in carriers, but observed reduced thalamic volume. Confirming these findings in other groups with the same genetic mutation, such as those in the Colombia-Boston (COLBOS) biomarker study, will help determine whether the new hypothesis about basal forebrain preservation in familial AD holds true. We used multi-modal imaging (MRI, amyloid and tau-PET) data of 57 cognitively unimpaired individuals from the COLBOS study comprising PSEN1-E280A carriers (n = 27) and non-carriers (n =30). Staging of functional impairment was done using the Functional Assessment Staging Tool (FAST). Volumetry analyses were performed using basal forebrain, hippocampus and thalamus as regions of interest. We used Bayesian multiple regression with both flat and informed priors to test the hypothesis of preservation. As a secondary analysis, we investigated the associations of amyloid and tau pathology with brain volumes. We found evidence for no effect of mutation carrier status on basal forebrain volume (BF₁₀: flat = 0.076; inf =0.54) and hippocampal volume (BF₁₀: flat =0.16; inf =1.05). In contrast, we observed moderate evidence for an effect of mutation carrier status on thalamus volume, with smaller volumes in mutation carriers (BF₁₀: flat =5.42; inf =8.74) (Figure 1). Lastly, we found strong evidence against an effect of amyloid status on basal forebrain and hippocampus, but moderate evidence for an effect on thalamic volume (Figure 2A). Similarly, tau pathology was not associated with basal forebrain, but showed associations with thalamus and hippocampus. (Figure 2B). Our findings show that in the PSEN1-E280A cohort, the cholinergic basal forebrain and hippocampus are not affected early in the disease, whereas the thalamus is, pointing to important considerations for treatment target selection in this group. These results should be further explored in other autosomal dominant AD mutations.

Colombia hosts the largest Autosomal-Dominant Alzheimer's Disease (ADAD) kindred caused by the PSEN1-E280A genetic variant, with full penetrance. This ADAD is well-characterized in terms of clinical and biomarker research, but Electroencephalography (EEG) as a biomarker is still under development. EEG facilitates understanding brain function and electrophysiological changes in ADAD. Dual-task (DT) paradigms, particularly during gait and upper extremity function, are useful biomarkers to determine cognitive impairments, due to neurodegenerative disorders such as Alzheimer's disease. EEG and DT are non-invasive, portable, and feasible in outpatient settings, making them highly accessible for clinical practice. The study sample includes two groups, asymptomatic carriers (n = 37) and non-carriers (n = 42) of the PSEN1-E280A variant. EEG data were recorded during a dual-task paradigm involving two tasks. The first task was a motor task (single-task) involving upper extremity flexion-extension. The second was a motor-cognitive task (dual-task), which included subtraction by 7 (DTS7), by 1 (DTS1) or verbal fluency with animals (DTAN). EEG signals were collected using the OpenBCI system from frontal and central regions. Data were processed and spectral and neural dynamics features were extracted. Dual-task cost (DTC) was calculated as the difference between metric values under dual-task and single-task conditions, computed across channels and frequency bands for each feature. The extracted metrics were statistically analyzed using Cohen's-D effect size and Mann-Whitney U-tests to assess differences. The most notable effect sizes were observed in entropy for Beta1 and Beta3 bands in frontal regions for the DTS7 and DTS1 tasks, Beta2 relative power in C4 during DTAN, Theta modulation in the Theta and alpha-1 bands in frontal regions during DTS7, and Alpha2 modulations in the same task. The proposed experiment effectively extracted brain information that differentiates between carriers and non-carriers of the PSEN1-E280A variant. DTC values in the alpha band (frontal and central regions) and the beta band (central regions) exhibited larger effect sizes, suggesting that these areas are sensitive to preclinical cognitive and motor differences. The experimental paradigm and data-processing pipeline ensured the acquisition of EEG data with meaningful neurological information. This combination of novel biomarkers enhances non-invasive and portable tools for identifying ADAD carriers during preclinical stages.

Background Graph metrics have been used to evaluate functional connectivity in Alzheimer's disease (AD). It has been found that nodal and global graph metrics are altered in subjects with AD and MCI compared to controls. In subjects with mutations associated with autosomal dominant Alzheimer's disease (ADAD), these metrics may vary depending on the stage within the disease continuum. This study aimed to evaluate the characteristics of graph metrics in the DMN specifically in asymptomatic subjects carrying the PSEN1 E280A mutation. Methods 32 asymptomatic carriers (aC) and 25 non‐carrier controls (nC) matched by sex, age and education status, underwent rs‐fMRI acquisition for 10 minutes. Pre‐processing of images was performed with CONN toolbox and RSN were extracted with Schaefer atlas with 79 ROI for DMN. Graph metrics were extracted with GRETNA toolbox, with a range of sparsity thresholds from 0.05‐0.5 for all metrics. A non parametric t‐test wilcoxon and linear mixed model (LMM) were performed, with corrections for multiple comparisons with Bonferroni. Results Significant differences were found in education (p‐value < 0.001, confidence interval 95% 1.43 – 5.15), but not for age and sex. Betwenness Centrality (Bc) was higher in nC tan aC (p‐value 0.0051, Cohen's d estimate: ‐0.011 CI95% ‐0.030 to 0.007) and Modularity (Q) (p‐value 0.042, Cohen's d estimate: ‐0.15 CI95% ‐0.318 to 0.0136). Regarding the LMM, differences were observed in the intercepts of nodal graph metrics, but no differences were found between groups. However, when examining each intercept individually, it was shown that clustering coefficient, betweenness centrality, local efficiency, and degree centrality increase the slope in nC, while they decrease it in aC. At the global graph level, no differences were found between aC and nC groups. Conclusion Bc idifferentiates between aC and nC. It is higher in nC, indicating that, at a local level, there is a greater number of nodes through which more connections pass, making them central to DMN connectivity. The local changes in aC are attributed to pathophysiological alterations in information distribution and the reorganization of DMN to distribute information across RSN and preserve cognitive functions.

Background Limited access to diagnostic technologies in low and middle‐income countries hinders the early detection of Alzheimer's Disease (AD). Advances in digital neuropsychology have enabled the development of tools like NavegApp, a serious game‐based platform that evaluates allocentric navigation, mental rotation, and visuospatial memory—domains affected during the preclinical and prodromal stages of AD. While previous studies have confirmed NavegApp's usability and content validity, further evidence of its construct validity and diagnostic accuracy is required to support its potential implementation in primary care settings. The analysis of cognitive changes during these early disease stages, particularly in individuals carrying causative mutations for early‐onset familial AD, is essential to advance the clinical utility of innovative digital cognitive markers. Therefore, the main objective of this study was to evaluate the construct validity and diagnostic accuracy of NavegApp's spatial cognition metrics across the AD spectrum. Method A retrospective observational study was conducted with 226 participants classified into five groups, including presymptomatic and symptomatic PSEN1‐E280A carriers. Construct validity was assessed by examining correlations between NavegApp metrics and standard neuropsychological assessments. Group performance differences were analyzed using effect size estimates, controlling for sex, education, and age, while diagnostic accuracy was evaluated using ROC curve analysis. Result NavegApp's spatial cognition metrics demonstrated moderate associations with general cognitive status, memory, and visuospatial domains. Diagnostic accuracy analysis revealed excellent discriminative capacity for identifying symptomatic PSEN1‐E280A carriers compared to asymptomatic participants, particularly in allocentric navigation (AUC‐ROC = 0.94–0.97). However, diagnostic performance for early preclinical detection was limited (AUC‐ROC = 0.66). In contrast, metrics showed acceptable accuracy for distinguishing sporadic MCI from healthy elder controls (AUC‐ROC = 0.77). Conclusion The findings demonstrate the feasibility of NavegApp as an innovative digital tool with potential applications in cognitive screening, particularly in underserved populations. Further research is needed to validate its clinical utility in broader settings and to explore the variability of cognitive changes across the AD spectrum. This evidence could inform its integration into clinical workflows for the preclinical and prodromal detection of AD.

Background Colombia hosts the largest Autosomal‐Dominant Alzheimer's Disease (ADAD) kindred caused by the PSEN1‐E280A genetic variant, with full penetrance. This ADAD is well‐characterized in terms of clinical and biomarker research, but Electroencephalography (EEG) as a biomarker is still under development. EEG facilitates understanding brain function and electrophysiological changes in ADAD. Dual‐task (DT) paradigms, particularly during gait and upper extremity function, are useful biomarkers to determine cognitive impairments, due to neurodegenerative disorders such as Alzheimer's disease. EEG and DT are non‐invasive, portable, and feasible in outpatient settings, making them highly accessible for clinical practice. Method The study sample includes two groups, asymptomatic carriers (n = 37) and non‐carriers (n = 42) of the PSEN1‐E280A variant. EEG data were recorded during a dual‐task paradigm involving two tasks. The first task was a motor task (single‐task) involving upper extremity flexion‐extension. The second was a motor‐cognitive task (dual‐task), which included subtraction by 7 (DTS7), by 1 (DTS1) or verbal fluency with animals (DTAN). EEG signals were collected using the OpenBCI system from frontal and central regions. Data were processed and spectral and neural dynamics features were extracted. Dual‐task cost (DTC) was calculated as the difference between metric values under dual‐task and single‐task conditions, computed across channels and frequency bands for each feature. The extracted metrics were statistically analyzed using Cohen's‐D effect size and Mann‐Whitney U‐tests to assess differences. Result The most notable effect sizes were observed in entropy for Beta1 and Beta3 bands in frontal regions for the DTS7 and DTS1 tasks, Beta2 relative power in C4 during DTAN, Theta modulation in the Theta and alpha‐1 bands in frontal regions during DTS7, and Alpha2 modulations in the same task. Conclusion The proposed experiment effectively extracted brain information that differentiates between carriers and non‐carriers of the PSEN1‐E280A variant. DTC values in the alpha band (frontal and central regions) and the beta band (central regions) exhibited larger effect sizes, suggesting that these areas are sensitive to preclinical cognitive and motor differences. The experimental paradigm and data‐processing pipeline ensured the acquisition of EEG data with meaningful neurological information. This combination of novel biomarkers enhances non‐invasive and portable tools for identifying ADAD carriers during preclinical stages.

Colombia hosts the largest Autosomal-Dominant Alzheimer's Disease (ADAD) kindred caused by the PSEN1-E280A genetic variant, with full penetrance. This ADAD is well-characterized in terms of clinical and biomarker research, but Electroencephalography (EEG) as a biomarker is still under development. EEG facilitates understanding brain function and electrophysiological changes in ADAD. Dual-task (DT) paradigms, particularly during gait and upper extremity function, are useful biomarkers to determine cognitive impairments, due to neurodegenerative disorders such as Alzheimer's disease. EEG and DT are non-invasive, portable, and feasible in outpatient settings, making them highly accessible for clinical practice. The study sample includes two groups, asymptomatic carriers (n = 37) and non-carriers (n = 42) of the PSEN1-E280A variant. EEG data were recorded during a dual-task paradigm involving two tasks. The first task was a motor task (single-task) involving upper extremity flexion-extension. The second was a motor-cognitive task (dual-task), which included subtraction by 7 (DTS7), by 1 (DTS1) or verbal fluency with animals (DTAN). EEG signals were collected using the OpenBCI system from frontal and central regions. Data were processed and spectral and neural dynamics features were extracted. Dual-task cost (DTC) was calculated as the difference between metric values under dual-task and single-task conditions, computed across channels and frequency bands for each feature. The extracted metrics were statistically analyzed using Cohen's-D effect size and Mann-Whitney U-tests to assess differences. The most notable effect sizes were observed in entropy for Beta1 and Beta3 bands in frontal regions for the DTS7 and DTS1 tasks, Beta2 relative power in C4 during DTAN, Theta modulation in the Theta and alpha-1 bands in frontal regions during DTS7, and Alpha2 modulations in the same task. The proposed experiment effectively extracted brain information that differentiates between carriers and non-carriers of the PSEN1-E280A variant. DTC values in the alpha band (frontal and central regions) and the beta band (central regions) exhibited larger effect sizes, suggesting that these areas are sensitive to preclinical cognitive and motor differences. The experimental paradigm and data-processing pipeline ensured the acquisition of EEG data with meaningful neurological information. This combination of novel biomarkers enhances non-invasive and portable tools for identifying ADAD carriers during preclinical stages.

Background The Alzheimer’s Disease Colombian kindred is the world’s largest autosomal dominant cohort with Early Onset Familiar Alzheimer’s Disease (EOAD) due to a single genetic variant. These families have been studied for decades, identifying the disease progression from early subclinical stages to late dementia stages. Such cognitive and functional decline impacts the mental and physical well‐being of families and caregivers and to our knowledge, how being part of these families affects reproductive desire and contraception has not been studied. Therefore, we aim to explore if sociodemographic data, exposure to the dementia progression of relatives, and knowledge about EOAD is associated with reproductive desire and contraceptive practices in the Colombian kindred. Method A cross‐sectional study using a web‐based questionnaire emphasizing socio‐economic status, educational background, relationship with affected relatives, knowledge about EOAD, reproductive health (marital status, number of children, desire to conceive), and contraception (and long‐acting contraceptive methods (LAC)), was sent to cognitively unimpaired individuals from the PSEN1‐E280A Colombian kindred. All responders were included (N = 191). Result Of all, 58.6% were female, age rank goes from 18 to 47 years, 87% had any contraceptive method, only 29% of the participants had LACs, 2.6% of the participants would like to have children even if they were PSEN1‐E280A carriers, and 94% of the participants were interested in being part of genetic counseling programs. The use of LACs was associated with being single and considering that having a family member with EOAD had a negative impact on them. Not wanting to have children or not wanting more children after an unwanted pregnancy was associated with having lived with an EOAD patient, having a higher knowledge of the disease, being single, and considering that having a family member with EOAD had a negative impact on them. Conclusion This exploratory study shows that the experience of being part of a family with EOAD can influence sexual and reproductive health. This may be mediated by knowledge about the disease and the experiences of each individual. Further studies on the effect of these factors and possible ways to intervene are needed.