The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

Down syndrome (DS) is an intellectual disability (ID) disorder in which language and specifically, verbal fluency are strongly impaired domains; nearly all adults show neuropathology of Alzheimer's disease (AD), including amyloid deposition by their fifth decade of life. In the general population, verbal fluency deficits are considered a strong AD predictor being the semantic verbal fluency task (SVFT) a useful tool for enhancing early diagnostic. However, there is a lack of information about the association between the semantic verbal fluency pattern (SVFP) and the biological amyloidosis markers in DS. In the current study, we used the SVFT in young adults with DS to characterize their SVFP, assessing total generated words, clustering, and switching. We then explored its association with early indicators of dementia, adaptive behavior and amyloidosis biomarkers, using the Dementia Questionnaire for Persons with Intellectual Disability (DMR), the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and plasma levels of Aβ peptides (Aβ40 and Aβ42), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Aβ42 concentrations, a higher DMR score and impaired communication skills (ABAS-II). The total word production and switching ability in SVFT were good indicators of plasma Aβ42 concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS.

Down syndrome (DS) individuals present increased risk for Alzheimer's disease (AD) neuropathology and AD-type dementia. Here, we investigated the use of green tea extracts containing (-)-epigallocatechin-3-gallate (EGCG), as co-adjuvant to enhance the effects of environmental enrichment (EE) in Ts65Dn mice, a segmental trisomy model of DS that partially mimics DS/AD pathology, at the age of initiation of cognitive decline. Classical repeated measures ANOVA showed that combined EE-EGCG treatment was more efficient than EE or EGCG alone to improve specific spatial learning related variables. Using principal component analysis (PCA) we found that several spatial learning parameters contributed similarly to a first PC and explained a large proportion of the variance among groups, thus representing a composite learning measure. This PC1 revealed that EGCG or EE alone had no significant effect. However, combined EE-EGCG significantly ameliorated learning alterations of middle age Ts65Dn mice. Interestingly, PCA revealed an increased variability along learning sessions with good and poor learners in Ts65Dn, and this stratification did not disappear upon treatments. Our results suggest that combining EE and EGCG represents a viable therapeutic approach for amelioration of age-related cognitive decline in DS, although its efficacy may vary across individuals.