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Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD. Given the variability in the timing of pathology and symptoms, we discuss the evidence supporting the role of genetic, biological, socio‐behavioral, lifestyle, and environmental factors in resistance and resilience to DSAD. We also consider how co‐occurring health conditions in DS may influence resistance and resilience, and how methods from AD research can be applied to DSAD. Ultimately, this framework aims to guide future research and translate findings into clinical interventions to improve outcomes in DSAD. Highlights Definitions of resistance and resilience in the genetic form of Alzheimer's disease (DSAD) are proposed for guiding the field. Variability in the timing of AD pathology and symptoms suggests the potential for resistance and resilience mechanisms in DSAD. Genetic, biological, socio‐behavioral, lifestyle, and environmental factors have the potential to build resistance or resilience in DSAD. Future research will require longitudinal and experimental designs, life course approaches, and large cohort studies.

Background Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL + ), APOE E4 carriership (APOE4 + ), and extremely low CSF Aβ42 concentrations (A L ). We hypothesize that studying the CSF proteome of Alzheimer’s disease (AD) dementia patients from a high-risk group (MBL + APOE4 + A L ) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers. Methods We utilized CSF proteomic data of AD ( n  = 156) and cognitively unimpaired individuals (CU n  = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk ( n  = 13) was compared to low-risk AD group ( n  = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n  = 14, low risk n  = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression. Results Ninety-four proteins differentiated in the high-risk group compared to low-risk ( p  < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p  = 0.014, vs. CU: FC = 2.4, p  < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p  = 0.046, vs. CU: FC = 0.5, p  < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p  = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p  = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins ( R  > 0.8). Conclusions The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting.

Accumulating evidence suggests that meditation practices have positive effects on brain ageing overall. The cingulate is known to be recruited during meditation, but research into possible effects of meditation on the ageing of the cingulate is currently missing. Thus, the present study was designed to help close this knowledge gap, with particular focus on the subgenual cingulate, a region involved in emotional regulation and autonomic and endocrine functions, making it potentially relevant for meditation. Here, we investigated differences in age-related gray matter loss between 50 long-term meditation practitioners (28 male, 22 female), aged between 24 and 77, and 50 age- and sex-matched controls. Areas of interest were four subregions of the subgenual cingulate gyrus (areas 25, 33, s24, and s32) defined as per the Julich-Brain atlas. Our study revealed a significant age-related decline in all subregions in both meditators and controls, but with significantly lower rates of annual tissue loss in meditators, specifically in left and right area s32 and right area 25. These regions have been shown to play a role in mood regulation, autonomic processing, and the integration of emotion and cognitive processes, which are all involved in and impacted by meditation. Overall, the results add further evidence to the emerging notion that meditation may slow the effects of ageing on the brain.

With rising global life expectancy, early identification of dementia risk is crucial for implementing timely interventions. This study assesses the value of neuropsychological measures in stratifying the risk of mild cognitive impairment (MCI) progression over a 3 years period. This retrospective, longitudinal study included 349 MCI patients from the SPIN cohort who underwent an extended neuropsychological battery at baseline (2009-2021), enabling the calculation of composite cognitive domain scores; and follow-up clinical visits. A Ridge logistic regression following a data-driven selection of α within an Elastic Net tuning grid was utilized to identify key factors associated with dementia conversion. Over 3 years, 37.8% of patients with MCI converted to dementia, 58.7% remained stable, and 3.4% reverted. At baseline, converters were significantly older, exhibited lower functional status, and demonstrated poorer performance across all cognitive domains compared to the stable and reverter groups. A regularized (Ridge) logistic regression, selected as the optimal model within an Elastic Net tuning grid; was used to identify the most robust predictors, yielding an Area Under the Curve (AUC) of 0.816 [95% CI: 0.769-0.862]. Predictor stability was assessed via 500 bootstrap iterations, which identified older age, male sex, higher education level, and lower baseline scores in MMSE, episodic memory, and executive functions as the most robust contributors to conversion. At the optimal probability threshold of 0.436 (Youden's Index, = 0.536), the model demonstrated robust discriminative power, specifically achieving a good specificity of 83.9% and a moderate sensitivity of 69.7% in forecasting progression to dementia. Findings underscore that baseline performance in episodic memory, and executive functions can effectively assist in screening for MCI progression. While the model shows good discriminatory potential, its clinical utility lies in risk stratification and identifying high-priority patients for monitoring, rather than serving as a definitive individual prognosis. Further research integrating longitudinal biomarkers is needed to refine these predictive frameworks and improve patient outcomes.

Objectives Neuroimaging-based research has revealed varying effects of meditation/mindfulness in sections of the cingulate cortex. However, a formal review of this literature is currently missing. Methods PubMed and APA PsycINFO databases were searched to identify studies based on functional magnetic resonance imaging (fMRI), resting-state fMRI (rs-fMRI), structural MRI (sMRI), and diffusion tensor imaging (DTI) that reported effects (or explicitly stated null effects) of meditation/mindfulness in the cingulate. Results Of the 49 studies published over the last two decades, the majority were cross-sectional in nature (69%) and employed fMRI (61%). Most studies reported significant effects in the anterior cingulate cortex (55%), followed by the posterior cingulate cortex (49%) and the midcingulate cortex (20%). However, the nature of findings was extremely heterogeneous across studies, possibly due to a substantial variability in terms of study designs, sample sizes, demographics, meditation styles, cingulate subdivisions, and nomenclatures, just to name a few. Conclusions Altogether, the outcomes of this review suggest a multifaceted role of the cingulate for processes related to long-term meditation practices, short-term meditation trainings, as well as trait mindfulness.

Following the COVID-19 pandemic, a shift from traditional in-person conferences to virtual and hybrid formats was welcomed for its accessible, cost-effective approach to sharing scientific knowledge and connecting people. Here, we discuss an effective hybrid format that combines in-person and online elements to foster inclusivity by providing a flexible, cost-effective alternative to in-person meetings.

INTRODUCTION In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored. METHODS In 261 DS adults and 131 euploid controls, fluid‐attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume. RESULTS In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo‐parietal GM volumes. DISCUSSION WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks. Highlights White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto‐temporal areas.

Down Syndrome (DS) represents a high-risk group for Alzheimer's disease (AD) due to chromosome 21 triplication, which drives amyloid precursor protein overproduction. While brain atrophy in DS has been widely studied, the underlying brain perfusion changes remain poorly understood. This study leverages MRI pseudo-continuous arterial spin labeling (pCASL) to explore early cerebral blood flow (CBF) alterations along the AD continuum in DS and compares these changes to the perfusion patterns seen in sporadic AD (sAD) METHOD: We performed a cross-sectional analysis including 32 euploid cognitively unimpaired individuals (eCU, age= 56.8yo, 68.7% female), 37 adults with DS (age= 42.64y; females= 37.83%, 40.5% symptomatic including n = 8 prodromal AD and n =  7 dementia) and 24 sAD patients (age 74.2yo, 50% female, 16 MCI and 8 in dementia stage) from the SPIN and DABNI cohorts that underwent 3T-MRI. pCASL images were preprocessed using ASLprep. Analyses explored the effects of demographic variables (age, sex), clinical stages, and AD biomarkers (including cerebrospinal fluid [CSF] Aβ1-42/Aβ1-40 ratio, pTau-181, and hippocampal volume) on global and regional CBF. Age-related decreases in cerebral blood flow (CBF) were observed in prefrontal regions in eCU, parietal structures in DS, and temporal lobes in sAD (Figure 1 A-D). Females had higher perfusion than males in eCU and sAD, but not in DS (Figure 1 E-H). In DS, CBF was reduced in temporal-parietal regions in asymptomatic individuals, extending to frontal areas in symptomatic cases, resembling sAD patterns (Figure 2). Symptomatic DS showed significantly lower CBF in lateral parietal regions than asymptomatic DS. Temporoparietal CBF correlated negatively with CSF-pTau-181 and positively with CSF-Aβ1-42/Aβ1-40 ratio and hippocampal volume, with the strongest association seen with hippocampal volume (Figure 3) CONCLUSION: Brain perfusion is significantly altered in adults with DS along the AD continuum, with changes detectable even before clinical symptoms. Hypoperfusion primarily affects temporoparietal and frontal regions at the symptomatic stage, closely resembling patterns seen in sAD. Notably, perfusion in the parietal areas differentiates asymptomatic from symptomatic DS and correlates strongly with key AD biomarkers. These findings highlight the potential of pCASL to detect early functional changes in this high-risk population.

A multi-site cohort in Barcelona, Spain - UBRAIN - was used to analyze the impact of neighborhood-level social determinants on aging- and dementia-related outcomes, using Geographic Information Systems (GIS) data. This work focuses on analyzing the representativeness and social disparity-related bias of the cohort to reveal practical challenges of leveraging GIS data from hospital-led research cohorts in the study of social determinants of health. We included 2124 older adults and patients - 16.6% cognitively unimpaired, 47.2% mild cognitive impairment, and 36.2% dementia (62.4% Alzheimer's Disease, 14.8% Frontotemporal dementia, 13.2% Lewy body, other 9.6%) recruited at Clinic and Sant Pau Hospitals in Barcelona (Spain) (Table 1). We compared the cohort's residential distribution to the population distribution data (Barcelona Open Data) using global Moran's I applied to the neighborhood-level sample-to-population ratio. We quantified bias in multiple socioeconomic indicators via standardized mean differences (SMD) between sample-weighted and population-weighted means, with |SMD| ≥ 0.25 denoting strong sampling bias. All analyses were also performed stratifying by sex. We find that our sample's spatial distribution significantly differs from the population distribution in Barcelona (Moran's I=0.451, p <0.001), mostly centering around the recruitment sites (Figure 1 - top). The resulting sample lives in neighborhoods with higher employment rates, lower rates of low educational attainment, and fewer low-skilled workers (Figure 1 - bottom). The magnitude of these SMDs was virtually independent of sex (maximum |ΔSMD| < 0.04). Stratifying by hospital showed a reduced socioeconomic bias in the sample from hospital Clínic. Our analysis of the UBRAIN cohort reveals a significant spatial and socioeconomic bias, with participants disproportionately residing in neighborhoods with few low-skilled workers, high employment rates, and a highly educated population. These differences in representativeness should be taken into account when interpreting results from such cohorts, especially in the context of urban and social determinants of health. Efforts should be made to include participants from neighborhoods with lower socioeconomic status.

Down syndrome (DS) is a form of genetically determined Alzheimer's disease (AD). Understanding the natural history and biomarker specificities in this population can offer insights into AD pathogenesis and potential treatment targets. The Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) is a prospective longitudinal cohort of adults with DS that builds on a population-based health plan screening for neurological conditions (Figure 1). Conducted at the Alzheimer-Down Unit, the study aims to elucidate the natural history of AD in DS through multimodal biomarker investigations and support clinical trials. Participants undergo neurological and neuropsychological evaluations, blood and cerebrospinal fluid collection, structural 3T brain MRI, PET imaging ([18F]FDG-PET, amyloid-PET or tau-PET), as well as electroencephalography and video-polysomnography examinations. The DABNI cohort included 1,135 participants with a mean age of 42.82 years (SD = 11.56), 46.3% of whom are female. At baseline, 673 participants were asymptomatic or cognitively stable, 113 had prodromal AD, 239 had AD dementia, and 110 were uncertain due to non-AD conditions. The cohort's intellectual disability level distribution was 20% mild, 50% moderate, 20% severe, and 7% profound. Over 10,000 visits have demonstrated that AD progression is rare before age 40, but high thereafter (57.5% of individuals over 50 progress within 5 years). Neuropsychological assessments and biomarkers have shown strong diagnostic performance for symptomatic AD, and a prolonged and predictable preclinical phase similar to autosomal dominant AD. The initiative is actively participating in three clinical trials and has yielded a robust body of work, with nearly 100 publications. Table 1 shows the number of clinical visits and biomarker studies in the whole sample and stratified by clinical diagnosis. In 10 years, the DABNI study has become one of the largest multimodal initiatives on AD in adults with DS and has provided critical insights into disease progression and biomarkers, advancing interventions and clinical research.