Performance on the Latin American version of the Face-Name Associative Memory Exam (LAS-FNAME) distinguishes individuals with Mild Cognitive Impairment from age-matched controls in a sample from Argentina.

INTRODUCTION: The Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) has shown promise in identifying cognitive changes in those at risk for Alzheimer's disease (AD). However, its applicability for Mild Cognitive Impairment (MCI) detection in the Latin American population remains unexplored. This study aims to analyze the psychometric properties in terms of validity and reliability and diagnostic performance of the LAS-FNAME for the detection of memory disorders in patients with amnestic MCI (aMCI). MATERIALS AND METHODS: The study included 31 participants with aMCI, diagnosed by a neurologist according to Petersen's criteria, and 19 healthy controls. Inclusion criteria for the aMCI group were to be 60 years of age or older, report cognitive complaints, have a memory test score (Craft Story 21) below a -1.5 z-score and have preserved functioning in activities of daily living. Participants completed LAS-FNAME and a comprehensive neuropsychological assessment. RESULTS: LAS-FNAME showed the ability to discriminate against healthy controls from patients with aMCI (AUC= 75) in comparison with a gold-standard memory test (AUC = 69.1). LAS-FNAME also showed evidence of concurrent and divergent validity with a standard memory test (RAVLT) (r = 0.58, p < .001) and with an attention task (Digit Span) (r = -0.37, p = .06). Finally, the reliability index was very high (α = 0.88). DISCUSSION: LAS-FNAME effectively distinguished aMCI patients from healthy controls, suggesting its potential for detecting early cognitive changes in Alzheimer's prodromal stages among Spanish speakers.

The MAPP Room Memory Test: Examining Contextual Memory Using a Novel Computerized Test in Cognitively-Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

Contextual memory, the ability to remember spatial or temporal features related to an event, is affected in Alzheimer's disease (AD). There is a shortfall of tests that measure contextual memory. To evaluate visuospatial contextual memory, we developed a computerized cognitive test, the MAPP Room Memory Test, which requires participants to identify in which visual scene target items were previously presented. We hypothesized that cognitively-unimpaired carriers of an autosomal dominant AD mutation (Presenilin-1 E280A, n=15) would perform more poorly on this test than non-carrier family members (n=31). Compared to non-carriers, the carriers had significantly worse delayed room recognition. The results indicate that the MAPP Room Memory Test may be sensitive to subtle cognitive changes associated with risk of AD. Future studies with larger samples using the MAPP Room Memory Test and biomarkers are needed to examine whether this test may also be sensitive to the earliest pathological changes in preclinical AD.

Memory for Semantically Related Objects Differentiates Cognitively Unimpaired Autosomal Dominant Mutation Carriers from Non-Carrier Family Members.

Early cognitive changes due to Alzheimer's disease (AD) include difficulties in semantic access and working memory. Using a computerized cognitive test developed by our group, called the Memory for Semantically Related Objects test (MESERO), we evaluated if cognitively unimpaired carriers of an autosomal dominant AD (ADAD) mutation performed worse on this test than non-carrier family members. 35 cognitively unimpaired ADAD mutation carriers and 26 non-carrier family members from a Colombian ADAD cohort took the MESERO on a laptop computer. Cognitively unimpaired ADAD carriers had significantly worse MESERO total scores than non-carrier family members, driven by worse performance in semantically-related object sets; group performances did not differ on semantically unrelated object sets. Findings suggest that MESERO performance may be sensitive to subtle cognitive changes associated with AD. Future MESERO research should examine performances between healthy older adults and people at risk for sporadic AD.

APOE3 Christchurch modulates tau phosphorylation and ß-catenin/Wnt/Cadherin signaling in induced pluripotent stem cell-derived cerebral organoids from Alzheimer's cases.

Alzheimer's disease (AD) is the most common cause of dementia among older adults. APOE3 Christchurch (R136S, APOE3Ch ) variant homozygosity was reported in an individual with extreme resistance to autosomal dominant AD due to the PSEN1 E280A mutation. This subject had a delayed clinical age at onset and resistance to tauopathy and neurodegeneration despite extremely high amyloid plaque burden. We established induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and from a non-protected kindred control (with PSEN1 E280A and APOE3/3 ). We used CRISPR/Cas9 gene editing to successfully remove the APOE3Ch to wild type in iPS cells from the protected case and to introduce the APOE3Ch as homozygote in iPS cells from the non-protected case to examine causality. We found significant reduction of tau phosphorylation (pTau 202/205 and pTau396) in cerebral organoids with the APOE3Ch variant, consistent with the strikingly reduced tau pathology found in the resistant case. We identified Cadherin and Wnt pathways as signaling mechanisms regulated by the APOE3Ch variant through single cell RNA sequencing in cerebral organoids. We also identified elevated ß-catenin protein, a regulator of tau phosphorylation, as a candidate mediator of APOE3Ch resistance to tauopathy. Our findings show that APOE3Ch is necessary and sufficient to confer resistance to tauopathy in an experimental ex-vivo model establishing a foundation for the development of novel, protected case-inspired therapeutics for tauopathies, including Alzheimer's.

Visual working memory for semantically related objects in healthy adults. / Memoria de trabajo visual para objetos relacionados semánticamente en adultos sanos.

INTRODUCTION: Few studies have examined how manipulating the semantic relationship between objects impacts visual working memory accuracy or reaction time. AIM: To characterize how the semantic relatedness of visual objects impacts working memory accuracy and reaction time in healthy adults using a newly developed mobile-tablet cognitive task. SUBJECTS AND METHODS: A delayed matching to sample paradigm on the tablet task was studied in a sample of 76 community-dwelling adult participants from Spain and Colombia. The tablet task included 80 unique sets of either four or six semantically related or semantically unrelated objects. The accuracy and reaction time of the participants on the task were recorded for analysis. RESULTS: When objects were semantically related, reaction time was greater in the six object sets relative to the four object sets. Age was positively associated with reaction time, but not accuracy across all four task conditions. Participants with fewer years of formal education than the sample median (16 years) exhibited worse response accuracy and slower reaction time on both the four and six semantically related conditions relative to participants with 16 or more years of formal education. CONCLUSIONS: Findings from this study suggest that when objects are semantically related (versus unrelated) and object load is increased, more processing time is needed to determine whether an object was or was not in the encoded set. The results also suggest that greater educational attainment -which likely relates with greater exposure to more technologies- is related with faster and more accurate responses on some task conditions.

TITLE: Memoria de trabajo visual para objetos relacionados semánticamente en adultos sanos.Introducción. Pocos estudios han examinado cómo la manipulación de la relación semántica entre objetos puede influir en el desempeño o el tiempo de reacción en tareas de memoria de trabajo visual. Objetivo. Caracterizar cómo la relación semántica de los objetos afecta el desempeño o el tiempo de reacción en una tarea de memoria de trabajo en adultos sanos utilizando una tarea cognitiva diseñada para el uso con tableta. Sujetos y métodos. Se usó una tarea de emparejamiento demorado (delayed matching to sample) con una muestra de 76 participantes adultos de España y Colombia. La tarea incluyó 80 conjuntos únicos de cuatro o seis objetos relacionados/no relacionados semánticamente. Se registraron las respuestas y el tiempo de reacción de los participantes. Resultados. Cuando los objetos estaban semánticamente relacionados, el tiempo de reacción fue mayor en la condición de seis objetos con respecto a la condición de cuatro objetos. La edad se asoció positivamente con el tiempo de reacción, pero no con la precisión de las respuestas. Los participantes con menos años de educación formal tuvieron un peor de­sempeño y un tiempo de reacción más lento en las condiciones somáticamente relacionadas en relación con los participantes con 16 años o más de educación formal. Conclusión. Los resultados sugieren que, cuando los objetos están semánticamente relacionados y aumenta su número, se necesita más tiempo de procesamiento para determinar si un objeto está o no en el grupo de objetos codificado. Además, un mayor nivel educativo se relaciona con respuestas más rápidas y un mejor desempeño en ciertas condiciones de la tarea.

Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred.

The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.

Event-related potential markers of brain changes in preclinical familial Alzheimer disease.

OBJECTIVES: Event-related potentials (ERPs) can reflect differences in brain electrophysiology underlying cognitive functions in brain disorders such as dementia and mild cognitive impairment. To identify individuals at risk for Alzheimer disease (AD) we used high-density ERPs to examine brain physiology in young presymptomatic individuals (average age 34.2 years) who carry the E280A mutation in the presenilin-1 (PSEN1) gene and will go on to develop AD around the age of 45. METHODS: Twenty-one subjects from a Colombian population with familial AD participated: 10 presymptomatic subjects positive for the PSEN1 mutation (carriers) and 11 siblings without the mutation (controls). Subjects performed a visual recognition memory test while 128-channel ERPs were recorded. RESULTS: Despite identical behavioral performance, PSEN1 mutation carriers showed less positivity in frontal regions and more positivity in occipital regions, compared to controls. These differences were more pronounced during the 200-300 msec period. Discriminant analysis at this time interval showed promising sensitivity (72.7%) and specificity (81.8%) of the ERP measures to predict the presence of AD pathology. CONCLUSIONS: Presymptomatic PSEN1 mutation carriers show changes in brain physiology that can be detected by high-density ERPs. The relative differences observed showing greater frontal positivity in controls and greater occipital positivity in carriers indicates that control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items, whereas carriers appear to rely more upon perceptual details of the items to distinguish between them. These findings also demonstrate the potential usefulness of ERP brain correlates as preclinical markers of AD.