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Introduction The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo‐controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60‐year‐old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non‐carriers who receive placebo. Methods Of the 252 enrolled, we present data on a total of 242 mutation carriers and non‐carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non‐carriers, 30 to 53 years of age. Carriers were significantly younger than non‐carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non‐carriers. Their demographic characteristics are representative of the local population.

Objective:Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer’s disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world’s largest ADAD kindred and sex differences in the relationship between SCD and memory performance.Methods:We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education.Results:Females in both groups had greater self-reported and study partner-reported SCD than males (allp< 0.001). In female mutation carriers, greater self-reported (p= 0.02) and study partner-reported SCD (p< 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p= 0.03), but not study partner-reported SCD (p= 0.11) was associated with worse verbal memory.Conclusions:Study partner-reported SCD may be a stronger indicator of memory decline in femalesversusmales in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

OBJECTIVE: Neuropsychologists continue to face challenges when assessing Spanish-speaking individuals due to limited availability of normative data. We developed comprehensive normative data stratified by age and education for a Spanish neuropsychological test battery used by the Grupo de Neurociencias de Antioquia (Colombia) and the Colombian Alzheimer’s Prevention Initiative Registry, which have followed large families at risk for autosomal-dominant Alzheimer’s disease (ADAD) since the 1990s. Approximately 75% of these individuals are cognitively-unimpaired and are not genetically predisposed to develop ADAD. METHODS: We conducted a retrospective study on neuropsychological evaluations from 2,673 cognitively unimpaired individuals (56% female), with ages ranging from 18 to 86 years and education from 1 to 25 years. Neuropsychological measures included the Consortium to Establish a Registry for Alzheimer’s Disease-Colombia, and other multi-domain Spanish tests. We examined associations between age, education, and sex with cognitive performance. RESULTS: Norms stratified by age and education are presented. Cognitive performance showed small associations with age and education and was unrelated to sex. CONCLUSIONS: We provided population-based norms for Spanish tests targeting multiple cognitive domains using a large Colombian sample. These normative data may be helpful for the neuropsychological characterization of Spanish speakers from Latin America in clinical and research settings.

Key Points Question How does lack of awareness (anosognosia) of memory impairment evolve in the Alzheimer disease (AD) trajectory? Findings In this cohort study of 2379 members of the Alzheimer’s Prevention Initiative Registry with a presenilin (PSEN1 E280A) variant for autosomal dominant AD, awareness of memory function was increased in carriers and noncarriers approximately 14 years before their estimated median age of dementia onset (49 years). In variant carriers only, awareness of memory function was reduced in the predementia stages, reaching anosognosia 6 years before dementia onset. Meaning The findings suggest that alteration of awareness of memory function in predementia stages may inform practitioners about AD progression., Importance Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. Objective To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. Design, Setting, and Participants This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer’s Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Main Outcomes and Measures Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. Results This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P, This cohort study investigates the evolution of anosognosia of memory decline in individuals with the PSEN1 E280A variant for autosomal dominant Alzheimer disease compared with family members without the variant.

Selected species of cyanobacteria and green algae have been reported to produce lipophilic polymethoxy-1-alkenes (PMAs) which were shown to exhibit in vivo teratogenicity. Considering that information on PMAs in Arthospira sp. (known commercially as Spirulina) and Chlorella sp. cultivated for food supplement production was essentially lacking, the present study screened Chlorella (n = 10) and Spirulina (n = 13) food supplements registered in the European Union. Mass spectrometry analysis of column fractionated extracts was performed. None of the four variants previously reported in some cyanobacteria and green algae, nor any potentially related structures were detected in the studied samples. Since the isolated lipophilic fractions contained various compounds, they were further screened for in vivo teratogenicity in Danio rerio embryo, and for the potential to induce oxidative stress and genotoxicity in the liver and neurotoxicity in the brain of adult zebrafish. None of the tested food supplements had detectable levels of PMAs or any potentially related structures. No teratogenicity was revealed except for spinal curvature induced by fractions obtained from two Chlorella products. Selected fractions revealed cytotoxicity as indicated by an increased level of reactive oxygen species, catalase activity, lipid peroxidation and increased frequency of DNA strand breaks in hepatic tissue. The majority (60%) of Chlorella fractions induced an increase in cholinesterase activity in zebrafish brain homogenate while exposure to 61.5% of Spirulina fractions was associated with its decrease. The present study confirms that Chlorella and Spirulina food supplements are free of teratogenic PMAs, although the observed in vivo toxicities raise questions regarding the quality of selected products.

Background There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. Objective We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. Methods 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). Results The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. Conclusions The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Background:This study aimed to determine Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery total score diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and dementia in familial Alzheimer's disease (FAD) with E280A mutation on presenilin-1 gene (PSEN1).Methods:A cross-sectional study was conducted in a cohort of PSEN1 E280A carriers and non-carriers assessed between January 1995 and February 2013. During the first neuropsychological assessment, 76 were having dementia, 46 had MCI, and 1,576 were asymptomatic. CERAD cut-off points were established for MCI and dementia using a Receiver Operating Characteristics (ROC) analysis, and were further analyzed according to education level in two groups: low education level (eight years or less), and high education level (over eight years).Results:The area under curve–ROC CERAD total score for dementia was 0.994 (95% CI = 0.989–0.999), and that for MCI was 0.862 (95% CI = 0.816–0.908). The dementia diagnosis cut-off point for the low education group was 54, (98.4% sensitivity, 92.6% specificity), and that for the high education group was 67 (100% sensitivity, 94.1% specificity). The MCI diagnosis cut-off point for the low education group was 66 (91.2% sensitivity, 56.4% specificity), and that for the high education group was 72 (91.7% sensitivity, 76.3% specificity).Conclusions:The CERAD total score is a useful screening tool for dementia and MCI in a population at risk of FAD.

Introduction: Cognitive decline could begin 20 years before the diagnosis of dementia. Besides age, several factors related to medical, socioeconomic, and behavioral and genetic condition may be associated with cognitive decline. The aim of this systematic review was to summarize evidence on the risk and protective factors for cognitive decline in people under 65 years old. Methods: A systematic review was conducted using a search strategy in MEDLINE and Embase, including longitudinal studies to analyze the effect of protective or risk factors on cognitive decline in a population under 65 years old. Results: A total of 22 studies were included in this review. Factors such as diabetes, hyperinsulinemia, overweight or obesity, metabolic syndrome, education, physical activity, cognitive stimulation, marital status and diet, could be related to cognitive decline before 65 years of age. Conclusions: Cardiovascular risk factors and lifestyle conditions may be associated with cognitive decline before 65 years of age. However, the quality of the evidence was low. Introducción: Se ha señalado antes del diagna que el deterioro cognitivo comienza 20 años antes del diagnóstico de la demencia. Además de la edad, diversos factores médicos, socioeconómicos y conductuales pueden estar asociados al declive cognitivo. El objetivo de esta revisión sistemática es resumir la evidencia de factores de riesgo o protectores relacionados con el declive cognitivo en población menor de 65 años. Métodos: Se realizó una revisión sistemática mediante una estrategia de búsqueda en bases de datos MEDLINE y Embase, incluyendo estudios con diseño longitudinal que analizaran el efecto de factores protectores o de riesgo en el declive cognitivo de población adulta menor de 65 años. Resultados: Se incluyeron 22 estudios en la presente revisión. Factores como diabetes mellitus, hiperinsulinemia, sobrepeso u obesidad, síndrome metabólico, nivel educativo, actividad física, estimulación cognitiva, estado civil y calidad de la dieta podrían estar relacionados con el declive cognitivo antes de los 65 años. Conclusiones: Factores de riesgo cardiovasculares y de estilos de vida pueden estar asociados al declive cognitivo en menores de 65 años. Sin embargo, la calidad de la evidencia es baja.

Importance Data from an autosomal dominant Alzheimer disease (ADAD) kindred were used to track the longitudinal trajectory of cognitive decline associated with preclinical ADAD and explore factors that may modify the rate of cognitive decline. Objectives To evaluate the onset and rate of cognitive decline during preclinical ADAD and the effect of socioeconomic, vascular, and genetic factors on the cognitive decline. Design, Setting, and Participants We performed a retrospective cohort study from January 1, 1995, through June 31, 2012, of individuals from Antioquia, Colombia, who tested positive for the ADAD-associated PSEN1 E280A mutation. Data analysis was performed from August 20, 2014, through November 30, 2015. A mixed-effects model was used to estimate annual rates of change in cognitive test scores and to mark the onset of cognitive decline. Main Outcomes and Measures Memory, language, praxis, and total scores from the Consortium to Establish a Registry for Alzheimer Disease test battery. Chronologic age was used as a time scale in the models. We explore the effects of sex; educational level; socioeconomic status; residence area; occupation type; marital status; history of hypertension, diabetes mellitus, and dyslipidemia; tobacco and alcohol use; and APOE e4 on the rates of cognitive decline. Results A total of 493 carriers met the inclusion criteria and were analyzed. A total of 256 carriers had 2 or more assessments. At the time of the initial assessment, participants had a mean (SD) age of 33.4 (11.7) years and a mean (SD) educational level of 7.2 (4.2) years. They were predominantly female (270 [54.8%]), married (293 [59.4%]), and of low socioeconomic status (322 [65.3%]). Word list recall scores provided the earliest indicator of preclinical cognitive decline at 32 years of age, 12 and 17 years before the kindred’s respective median ages at mild cognitive impairment and dementia onset. After the change point, carriers had a statistically significant cognitive decline with a loss of 0.24 (95% CI, −0.26 to −0.22) points per year for the word list recall test and 2.13 (95% CI, −2.29 to −1.96) points per year for total scores. Carriers with high educational levels had an increase of approximately 36% in the rate of cognitive decline after the change point when compared with those with low educational levels (−2.89 vs −2.13 points per year, respectively). Onset of cognitive decline was delayed by 3 years in individuals with higher educational levels compared with those with lower educational levels. Those with higher educational level, middle/high socioeconomic status, history of diabetes and hypertension, and tobacco and alcohol use had a steeper cognitive decline after onset. Conclusions and Relevance Preclinical cognitive decline was evident in PSEN1 E280A mutation carriers 12 years before the onset of clinical impairment. Educational level may be a protective factor against the onset of cognitive impairment.