Mara Dierssen

Intellectual disability (ID) characterizes numerous neurodevelopmental disorders, many of which also show increased obesity and metabolic comorbidities. Traditionally investigated independently, their coexistence suggests potentially shared pathogenic mechanisms, whose molecular and neural bases remain poorly understood. Down syndrome (DS), caused by trisomy 21, offers a genetically defined model for examining how altered gene dosage may affect cognition, feeding behavior, and energy homeostasis. Understanding these relationships could illuminate both the heterogeneous DS phenotype and metabolic vulnerability across ID-associated disorders. The locus coeruleus (LC), a major noradrenergic nucleus, regulates learning, memory, and energy balance. LC abnormalities have been reported in individuals with DS and corresponding mouse models, suggesting a potential contribution to both cognitive and metabolic phenotypes. Among chromosome 21 genes, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a compelling candidate. DYRK1A influences pancreatic β-cell mass and metabolic pathways while regulating neuronal development, synaptic function, and cognitive processes. Moreover, DYRK1A has been implicated in LC alterations in DS, although their functional consequences have primarily been investigated in cognition. Here, we review evidence connecting intellectual disability, obesity, LC function, and chromosome 21 gene dosage. We propose that DYRK1A-dependent changes in LC-noradrenergic signaling may contribute to cognitive impairment and potentially modify metabolic regulation in DS. Rather than assuming a single established causal pathway, this framework highlights a testable interaction between genetic dosage, neural circuitry, and environmental challenges that could explain divergent outcomes across physiological domains. Importantly, current experimental evidence more strongly supports a cognitive contribution than a direct causal role in metabolic and energy balance dysfunction.

Down syndrome (DS), or trisomy 21 (T21), represents the most common genetic cause of intellectual disability worldwide and is associated with a wide range of medical, developmental, and neurodegenerative conditions, including a universal predisposition to early-onset Alzheimer’s disease (AD). Since its establishment in 2014, the Trisomy 21 Research Society (T21RS) has provided a global forum for advancing DS research across disciplines and promoting translational efforts to improve health and quality of life. Every two years, T21RS hosts an international scientific meeting that brings together researchers, clinicians, self-advocates, families, and industry stakeholders. In 2024, the 5th T21RS International Conference was held in Rome, Italy, from June 5 to 8, under the theme “Promoting Research Excellence in Down Syndrome.” The meeting brought together about 500 scientists from 26 countries across five continents, and more than 900 attendees overall, including families and caregivers. The scientific program featured 5 keynote lectures, 2 satellite meetings, 17 symposia, 7 nano symposia, 2 workshops, and 1 industry-focused session, totaling more than 150 oral presentations. More than 230 abstracts were presented as posters. The conference covered research across the lifespan of individuals with DS, spanning genomic and epigenetic regulation, molecular and cellular mechanisms, preclinical and experimental models, cognition and behavior, neurodevelopment, aging and neurodegeneration, co-occurring medical conditions, and therapeutic interventions. Dedicated sessions focused on capacity-building in DS research and societal engagement were established. Significantly, T21RS promoted inclusivity by supporting 60 young investigator fellowships, providing childcare awards, and organizing a two-day program for families and caregivers in collaboration with Italian DS associations. This proceeding summarizes the main scientific highlights of the 5th T21RS International Conference, reflecting the latest advances in DS biology, clinical research, biomarker development, and therapeutic innovation.

Background: Individuals with Down syndrome (DS) are at an increased risk of obesity and, subsequently, its cardiometabolic and cognitive impacts. Caregivers play a critical role in managing health, yet their perceptions and behaviors have been poorly characterized. Methods: We performed a cross-sectional online survey of caregivers (n = 764) taking care of 48% females and 52% males with DS, conducted across European populations, predominantly in Spain and France. We assessed perceived obesity, perceived harmfulness of current weight, professional consultation, and confidence in promoting healthy behaviors. Associations were examined using chi-square tests, correlation analysis, and ordinal and logistic regression models. Results: Around one-third (32%) of caregivers perceived their family member with DS with obesity. Perceived obesity changed with age and was more frequently reported in female family members with DS. Awareness of general metabolic risk factors was high among caregivers, but half of respondents were unaware that abdominal fat affects brain health. Consultation with healthcare professionals was uncommon (57% “Never/Rarely/Sometimes”) even among those perceived with obesity. Conclusions: Caregivers demonstrate good general awareness about high energy food risks but limited knowledge of the link between obesity and brain health. Enhancing caregiver education and supporting behavioral change could promote healthier lifestyles in families with individuals with DS.

Background: Lifestyle factors such as diet and physical activity significantly impact on the risk of obesity in individuals with Down syndrome (DS). However, in the absence of national nutritional guidelines in individuals with DS, further work is needed to understand their dietary and physical activity patterns. In this work we retrieved caregivers’ responses on those aspects. Methods: We analyzed data from a cross-sectional online survey of caregivers of individuals with DS conducted as part of the GO-DS21 project and reported in the accompanying paper (nutrients-4216283) (n = 764). We explored physical activity patterns, dietary habits, beliefs around weight-loss interventions and caregiver confidence that family members with DS would engage in a healthier lifestyle. Associations were examined using correlation analysis, and cumulative and binary logistic regression models. Results: Caregivers reported that most individuals with DS exercised 1–3 times per week, with frequency declining with age. Males were more likely to exercise daily than females. Caregiver exercise frequency was positively correlated with that of their DS family member (ρ = 0.521, p < 0.001), suggesting clustering of shared health behaviors within households. In adjusted models, caregivers who exercised regularly had up to thirteen-fold higher odds of having a physically active family member with DS (aOR = 13.02, 95% CI: 7.40–24.06, p < 0.001). Fried food consumption and higher snack frequency were independently associated with perceived obesity status, while sugar-sweetened beverage consumption was not. Caregivers favored exercise as a weight-loss strategy, while anti-obesity drugs were endorsed by only 11% of caregivers primarily and were more likely to be endorsed when obesity was perceived (aOR = 4.21, 95% CI: 2.44–7.39, p < 0.001). Finally, caregiver confidence that their family member with DS would engage in healthier behaviors was associated with perceived obesity status and strongly associated with higher physical activity levels (aOR 14.68, 95% CI: 6.59–33.40, p < 0.001). Conclusions: In this large European caregiver survey, reported consumption of selected energy-dense foods was generally low, although fried food intake and higher snack frequency were associated with perceived obesity. Physical activity patterns were closely aligned between caregivers and individuals with DS, suggesting shared household health behaviors. These findings highlight the importance of involving caregivers and family environments in lifestyle interventions aimed at supporting physical activity and weight management in individuals with DS.

Background and Objectives: Treatment-resistant depression (TRD) is a major clinical challenge in the management of major depressive disorder (MDD). While pharmacogenetics has been suggested to be clinically useful in guiding antidepressant treatment, few studies have explored if and how pharmacogenes can be involved in TRD pathophysiology and its clinical outcomes. Material amd Methods: We explored the role of differences in metabolizer phenotypes, gene expression levels, and microRNAs of three key pharmacogenes (CYP2D6, CYP2C19, CYP2B6) in TRD pathophysiology and antidepressant response in a cohort of 300 patients with MDD from the PROMPT consortium. Results: CYP2D6 phenotype distribution did not differ significantly between TRD and non-TRD groups, but mRNA expression was significantly upregulated in TRD. Hsa-miR-26b-5p, a microRNA predicted to regulate CYP2D6, was significantly downregulated in TRD. For CYP2C19, intermediate metabolizers (IMs) were underrepresented in TRD versus non-TRD (IMs vs. normal metabolizers (NMs): χ² = 6.07, p = 0.019). microRNA hsa-let-7d-5p and hsa-miR-27a-3p, predicted to regulate CYP2C19, were significantly downregulated in TRD. No significant differences were found for CYP2B6. Conclusions: This study contributes valuable insights to the PROMPT project on how pharmacokinetic gene variants and their expression and regulatory mechanisms may influence antidepressant response and resistance in MDD.

Extensive evidence suggests overlapping pathological mechanisms in the brain of individuals with Parkinson’s disease dementia, Down syndrome dementia, and Alzheimer’s disease. For these neurodegenerative dementias, we observed that the chronological age did not align with their biological age, which was determined based on hippocampal transcript levels (i.e., transcriptional age). Subsequently, we performed a transcriptomic analysis that corrected for the transcriptional age in the hippocampus of affected individuals, highlighting common underlying pathogenic mechanisms. There were 45 common differentially expressed genes (DEGs), whereas enriched functional terms were related to lysine N -methyltransferase activity and intermediate filament. Co-expression network analysis displayed a module that was significantly downregulated in the non-demented control group only. This module identified EHMT2 and LMNB2 as hub genes, which were also common DEGs. Overall, these findings uncover shared functional insights in the hippocampus, while specifically highlighting EHMT2 and LMNB2 as potential universal biomarkers or disease-altered targets across neurodegenerative dementias.

Summary: Down syndrome (DS) is associated with widespread molecular alterations, including aberrant gene expression, which not only affects chromosome 21 genes but perturbs the whole transcriptome. The genome-wide nature of this alteration suggests that it might be epigenetically mediated, which may also offer therapeutic opportunities given the reversibility of epigenetic modifications. Here, we show that decreased global acetylation level in the hippocampus of the trisomic mouse model Ts65Dn is associated with decreased chromatin accessibility at gene promoters in hippocampal neurons. Strikingly, pharmacological restoration of histone acetylation using the clinically approved histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) normalized transcriptomic, epigenetic and cortico-hippocampal memory deficits in trisomic mice. This rescue was mediated by an unexpected heterochromatization of the supernumerary chromosome. Altogether, our results identify an unanticipated epigenetic mechanism linking histone acetylation dynamics to chromosomal dosage homeostasis.

Introduction/background: Individuals with Down syndrome (DS) face a higher and earlier risk of overweight and/or obesity than the general population, influenced by factors like limited physical activity, suboptimal diet, stress, and sleep disorders. Despite the impact these lifestyle factors can have, there is a significant lack of robust, evidence-based guidelines for managing overweight and obesity in these individuals, particularly for the adult population. Results: Based on findings from an observational study across three European sites, within the EU Horizon-2020 GO-DS21 project, in this short communication, we highlight some key insights for developing effective prevention and management strategies for overweight and obesity in people with Down syndrome. Conclusions: In general terms, effective overweight and obesity management demands a holistic approach, integrating tailored diet and physical activity and actively addressing co-occurring health conditions. Moreover, the active participation of the family and peers is crucial for promoting sustainable healthy habits and for enhancing the overall quality of life of people with Down syndrome.