Neurología Cognitiva

Functional validation of the PSEN1 R358P and PSEN1 T119I variants in Alzheimer's Disease: an in vitro study

2026-05-19T14:58:36Z

Functional validation of the PSEN1 R358P and PSEN1 T119I variants in Alzheimer's Disease: an in vitro study García Chialva, Diego; Cifarelli, Diego; Isaja, Luciana; Apecetche, Manuela; Martínes Ojeda, Laura; Itzcovich, Tatiana; Chrem Méndez, Patricio Alexis; Sevlever, Gustavo Emilio; Scassa, Maria; Surace, Ezequiel Ignacio; Romorini, Leonardo Background Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia worldwide. It is characterized by progressive neuronal degeneration and the accumulation of beta‐amyloid plaques (Aβ) and neurofibrillary tangles (NFT) in the brain. AD manifests in sporadic AD (sAD) and familial AD (fAD). fAD is associated with inherited genetic mutations affecting amyloid precursor protein (APP) processing, involving genes such as APP, PSEN1, and PSEN2. Method The identification of two novel PSEN1 variants, p.T119I and p.R358P in early‐onset AD patients at FLENI provided a unique opportunity to study their possible implications in fAD. Notably, the patient harboring the PSEN1 R358P variant also carried a novel SORL1 variant (Gly1536Asp). Noteworthy, genetic variants in SORL1 are now considered a major AD risk factor. To evaluate the role of these two novel PSEN1 variants in APP processing, we developed a cellular model using PSEN1 Knock‐Out (KO) HEK293T cells created through CRISPR/Cas9 technology. We assessed the Aβ 42 /Aβ 40 ratio (AD biomarker) in the supernatant of PSEN1 KO‐cells transfected with expression vectors coding for APP and either wild‐type PSEN1, the novel PSEN1 variants or PSEN1 A246E (a known pathogenic mutation). Result We observed a significant (p <0.05) increase in the Aβ 42 /Aβ 40 ratio in HEK293T cells transfected with PSEN1 A246E or PSEN1 R358P plasmids and a slight trend towards an increase in cells transfected with PSEN1 T119I vector. In the case of PSEN1 R358P‐transfected cells, the increase in the Aβ 42 /Aβ 40 ratio observed was primarily due to the decrease in Aβ 40 levels in the supernatant. Conclusion These findings suggest a potential pathogenic role for the PSEN1 R358P variant in fAD, independent of the co‐occurring SORL1 mutation.

Cortical asymmetry in autosomal dominant Alzheimer's disease progression

2026-05-07T13:04:56Z

Cortical asymmetry in autosomal dominant Alzheimer's disease progression Pérez-Millan, Agnès; Falgàs, Neus; Bosch, Beatriz; Borrego-Écija, Sergi; Antonell, Anna; Fernández-Villullas, Guadalupe; Esteller-Gauxax, Diana; Tort-Merino, Adrià; Bargalló, Núria; Balasa, Mircea; Lladó, Albert; Aguillon, David; Chrem Méndez, Patricio Alexis; Day, Gregory S.; Devenney, Emma; Huey, Edward D.; Ikeuchi, Takeshi; Jucker, Mathias; Kasuga, Kensaku; Dominantly Inherited Alzheimer Network (DIAN) The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer's disease to explore the brain asymmetry within the Alzheimer's disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer's disease progression in autosomal dominant Alzheimer's disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Executive Functions in Latin American Older Adults: Exploring the Concept Shifting Test and Its Relationship with the APOE Gene in a Cross‐Sectional Sample from the LatAm‐FINGERS Study

2026-05-19T14:13:49Z

Executive Functions in Latin American Older Adults: Exploring the Concept Shifting Test and Its Relationship with the APOE Gene in a Cross‐Sectional Sample from the LatAm‐FINGERS Study Melillo Cardoso, Davi; Vasconcelos Friedlander, Clarisse; Sanches Yassuda, Monica; Cruz de Souza, Leonardo; Crivelli, Lucía; Kimie Suemoto, Claudia; Martin, Maria Eugenia; Calandri, Ismael Luis; Acosta‐Baena, Natalia; Surace, Ezequiel Ignacio; Damian, Andrés; Da Graça Morais Martin, Maria; Vigil‐Martinez, Ana; Henrique Cançado, Gustavo; Salinas‐Contreras, Rosa Maria; Custodio, Belen; Cusicanqui, María Isabel; Delgado, Carolina; Sevlever, Gustavo Emilio; Allegri, Ricardo Francisco Background Latin America (LA) faces high vulnerability to dementia risk factors. Early detection of cognitive decline, particularly in executive functions (EF), is crucial. The Trail Making Test (TMT) has limitations, while the Concept Shifting Test (CST) offers potential advantages but lacks LA adaptation. This study examines CST's correlation with other EF tests and its relationship with APOE‐ε4 in older adults. Methods Cross‐sectional analysis of LatAm‐FINGERS baseline data, including TMT, CST, Stroop Test, and fluency tasks. APOE genotyping used PCR‐RFLP analysis. Jamovi software (v2.3) analyzed correlations (p < 0.05). Results Sample: 1,143 individuals from 11 LA countries. Mean age = 67.4 years (±4.7), education = 13.2 years (±3.5), 73.9% women, 57.3% mixed‐race. 21.4% carried APOE‐ε4 allele. Mean CST shifting score: 16.0 (±19.3). Significant correlations with age (𝜌=0.085; p = 0.009) and education (𝜌 = ‐0.201; p <0.001). No sex differences (p = 0.172). CST shifting score showed moderate correlation with TMT‐flexibility (𝜌=0.372; p <0.001), weak correlations with Stroop (𝜌=‐0.175; p <0.001), semantic (𝜌=‐0.133; p <0.001) and phonemic fluency (𝜌=‐0.184; p <0.001). No significant differences in CST shifting (p = 0.951) or TMT‐flexibility (p = 0.767) between APOE‐ε4 groups. Conclusions Weak correlations between CST shifting, Stroop‐flexibility, and fluency tasks suggest they assess different EF aspects. The moderate CST‐TMT correlation may indicate refined cognitive flexibility measurement in CST. While useful for EF assessment in LA, CST doesn't replace TMT. Diverse tools are crucial for early dementia detection. The lack of association between APOE‐ε4 and cognitive scores emphasizes the importance of assessment regardless of genetic risk.

Cognitive and neuroimaging trajectories in the behavioral variant of Alzheimer's disease

2026-03-05T15:56:12Z

Cognitive and neuroimaging trajectories in the behavioral variant of Alzheimer's disease Calandri, Ismael Luis; Phillips, Jeffrey S.; Tideman, Pontus; Singleton, Ellen Hanna; La Joie, Renaud; van der Flier, Wiesje M.; Jonkman, Laura E.; Hansson, Oskar; Rabinovici, Gil D.; Pijnenburg, Yolande A. L.; Ossenkoppele, Rik; Mastenbroek, Sophie E. Background The behavioral variant of Alzheimer's disease (bvAD) is a rare atypical presentationcharacterized by early and prominent behavioral changes, clinically akin to the behavioral variant of fronto‐temporal dementia (bvFTD). The natural history of bvAD is poorly understood. This study investigates the progression of bvAD in a multinational cohort, comparing bvAD with matched bvFTD and typical AD (tAD) groups. Method We analyzed 81 bvAD participants from four centers and matched them by age, sex, and education to bvFTD (n = 80), tAD (n = 81), and controls (n = 78). Participants completed longitudinal clinical assessments and underwent repeated structural MRI. We combined neurocognitive variables into domain‐specific composites. Furthermore, we extracted cortical thickness and volumetric MRI data using FreeSurfer andcomputed atemporal AD‐signature and a frontal region‐of‐interest. Linear mixed models were used to evaluate cognitive and neuroimaging trajectories. The model coefficients are presented as standardized (β), and the effect is assessed through estimated marginal means (EMM). Result Demographic features are shown in Table 1. Subjects with bvAD exhibited significant decline in executive function (β=‐0.62, 95%CI[‐1.02, ‐0.22], p = 0.03, EMM=‐0.19), memory (β=‐1.62, 95%CI[‐1.90, ‐1.33], p < 0.001, EMM=‐0.49), language (β=‐0.95, 95%CI[‐1.31, ‐0.59], p < 0.01, EMM=‐0.18), and visuospatial function (β=‐0.80, 95%CI[‐1.31, ‐0.28], p < 0.05) compared to controls. Compared to bvFTD, individuals with bvAD showed relatively greater memory (p = 0.005) and language (p = 0.04) preservation over time, while no significant differences were observed in visuospatial function (p = 0.65) or executive function (p = 0.4). In contrast, bvAD did not differ significantly from tAD in memory (p = 0.1), language (p = 0.6), visuospatial function (p = 0.99), or executive function. Individuals with bvAD exhibited significant decline in the AD‐signature (β=‐0.91, 95%CI[‐1.34, ‐0.48], EMM=‐0.49) and frontal ((β=‐0.66, 95%CI[‐1.16, ‐0.15], EMM=‐0.29) regions‐of‐interest compared to controls. Compared to tAD, no significant differences were found in both regions of interest (p = 0.61, p = 0.91). Compared to bvFTD, individuals with bvAD showed significantly greater atrophy in the AD‐signature regions (p = 0.02) and significantly less atrophy in frontal lobe (p = 0.03). Conclusion The progression of bvAD differs both cognitivelyand anatomically from bvFTD, while showing a progression pattern that is very similar to tAD. These results underscore the importance of investigating AD pathology in the context of cognitive‐behavioral decline.