Type 2 diabetes (T2D) is increasingly associated with cognitive impairment and dementia, reflecting the combined impact of metabolic dysregulation, vascular injury, neuroinflammation, and defective brain insulin signaling. While this link is now well recognized, it remains unclear whether cognitive decline in T2D is modifiable. This review focuses on emerging neuroprotective strategies, highlighting both pharmacological and lifestyle-based interventions. Recent evidence indicates that some glucose-lowering agents, notably metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists, may exert pleiotropic effects on brain metabolism, inflammation, and vascular integrity beyond glycemic control. We propose a conceptual shift in T2D management in which cognitive preservation becomes an explicit therapeutic objective, integrating metabolic control with targeted brain-protective approaches.

Aging is the strongest risk factor for Alzheimer's disease (AD). Identifying reliable biomarkers of brain aging helps to predict functional decline and dementia onset. Evaluations of aging-related biomarkers in plasma and neuronal-derived extracellular vesicles (nEVs) from cognitively healthy and AD subjects, alongside post-mortem IPL brain samples from control (Ctr), pre-clinical AD (PCAD), mild cognitive impairment (MCI) and AD cases were performed. Cognitive tests, functional assessments, and MRI data were also included. Biomarkers in nEVs more accurately reflected brain pathology than those measured in plasma and showed stronger associations with cognitive and functional decline. Sex-specific patterns also emerged: GDF-15 was higher in nEVs from females with AD, whereas IL-6, IL-18 and Jag-1 were higher in nEVs from males with AD. A minimal nEV-derived panel including lower GDF-11 and higher GDF-15, Jag-1 and Leptin (after correction for age and sex) discriminated AD from Ctr and was associated with MRI-determined cortical atrophy in regions vulnerable to AD. These markers captured aging-related molecular trajectories that were disrupted in AD, and key associations observed in nEVs were confirmed in post-mortem brain tissue. Our results suggests that nEV-derived biomarkers capture early, brain-specific and sex-modulated aging signatures, providing superior sensitivity compared to plasma. Their convergence with post-mortem findings underscores their biological validity and translational potential. These results highlight the value of nEVs for stratifying individuals at higher risk of AD and support their integration into precision medicine approaches for dementia prevention.

Down syndrome (DS), caused by trisomy of chromosome 21, is characterized by early-onset oxidative stress, impaired neuronal development, and an increased risk of Alzheimer's disease (AD)-like neuropathology. Among chromosome 21 genes, the transcription factor BTB and CNC homology 1 (BACH1) has emerged as a critical regulator of redox homeostasis. Under physiological conditions, the balance between BACH1 and nuclear factor erythroid 2-related factor 2 (NRF2) warrants tight control of antioxidant defenses and heme metabolism. However, in DS, BACH1 overexpression disrupts this balance, impairing the induction of heme oxygenase-1 (HO-1) and of other cytoprotective pathways, thereby contributing to chronic oxidative stress, neuronal vulnerability, and pathological processes. The present review summarizes the molecular mechanisms that regulate the BACH1/HO-1 axis in the central nervous system. We recapitulate data from studies showing how dysregulation of this axis affects antioxidant defenses, iron homeostasis, ferroptosis, neuroinflammation, and mitochondrial function. We further provide evidence from the aging and AD literature, highlighting BACH1 as a convergent molecular node linking genetic and age-related neurodegeneration. Remarkably, we explore BACH1's contribution to the transition of DS to AD-like pathology. Finally, we evaluate emerging therapeutic strategies employing BACH1 inhibitors, NRF2 activators, and upstream signaling pathway modulators, and assess their applicability to the AD-like dementia context, concluding that targeting BACH1-dependent regulation of HO-1 represents a promising and unifying strategy to mitigate neurodegeneration in both DS and AD.

How the brain senses and responds to early metabolic stress, and why this process fails differently across sexes and regions, remains poorly understood. Here we show that biliverdin reductase A (BVRA) sets a tissue- and sex-specific threshold for metabolic resilience, acting as a molecular buffer that couples insulin signalling competence to mitochondrial homeostasis in the brain. Using wild-type and BVRA-deficient mice of both sexes exposed to short-term high-fat diet (HFD) followed by dietary normalization, we show that BVRA loss is sufficient to induce cortical insulin resistance within just one week, phenocopying eight weeks of HFD and preceding detectable oxidative stress or mitochondrial failure. This sequence supports a model in which dysfunctional insulin signalling as the initiating event in a hierarchical cascade of brain metabolic injury. The frontal cortex is the earliest and most vulnerable target; the hippocampus and liver show delayed and milder alterations, reflecting BVRA-dependent buffering capacity. Strikingly, female mice develop cognitive impairments indistinguishable from males despite substantially milder molecular alterations, uncovering a sex-specific differences between molecular severity and functional outcome. After dietary normalization, males show partial recovery of cortical insulin signalling, mitochondrial function, and recognition memory. In contrast, females exhibit progressive BVRA decline, worsening insulin signalling uncoupling, and persistent cognitive deficits that outlast dietary exposure — revealing a metabolic memory encoded at the molecular level. These findings identify BVRA loss as a causal and sex-biased determinant of brain metabolic vulnerability, with implications for understanding the sex-differential risk of insulin resistance-related neurodegeneration.

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.

Dual Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) has been implicated in Alzheimer's disease (AD) pathology. Using Meso Scale Discovery (MSD) technology, we previously demonstrated that individuals with AD, Down syndrome with AD (DS-AD), or tauopathies exhibit reduced plasma DYRK1A levels compared to controls (Delabar et al., 2023). To further evaluate DYRK1A as a potential biomarker, we developed and optimized a homebrew DYRK1A immunoassay using the ultrasensitive Single Molecule Array (Simoa HD-X platform). This assay was applied to measure DYRK1A levels in plasma and brain homogenates from AD mouse models and plasma samples from individuals with DS and DS-AD. To assess the impact of DYRK1A overexpression in the context of AD-related biomarkers, we analyzed DYRK1A levels using Simoa in wild-type controls and AD mouse models (APP23 or P301S), with or without DYRK1A overexpression. Additionally, EDTA plasma from healthy controls and age-matched individuals with DS, with or without AD, was analyzed using the developed immunoassay. The limit of detection (LOD) and limit of quantification (LOQ) for the assay were 0.021 pg/mL and 0.069 pg/mL, respectively. DYRK1A levels in both plasma and brain homogenates from mouse models exhibited a dose-dependent change, with significantly higher levels in DYRK1A-overexpressing mice compared to non-overexpressing counterparts. The assay was also successfully applied to human cohorts, demonstrating its potential clinical utility. Ongoing experiments aim to quantify longitudinal changes in DYRK1A levels in AD mouse models to further evaluate its biomarker potential. This study strengthens the evidence for DYRK1A as a potential biomarker for AD and DS-AD, utilizing ultrasensitive Simoa technology for detection. Future investigations will determine whether longitudinal DYRK1A level changes correlate with AD progression and aging, aiding in early biomarker discovery and potential therapeutic targeting.

Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer’s disease (AD). Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insuffi-ciency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and exces-sive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mi-tophagic flux. The coordinated impairment of the ubiquitin–proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long pro-teostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS.

Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer's disease (AD). Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insufficiency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and excessive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mitophagic flux. The coordinated impairment of the ubiquitin-proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long proteostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS.

INTRODUCTION:Down syndrome (DS) is the leading genetic cause of intellectual disability and Alzheimer's disease (AD), with over 90% of individuals developing AD-related dementia (DSAD). The triplication of the APP gene on chromosome 21 drives early amyloid-β (Aβ) accumulation, but other Hsa21 genes also contribute to pathology. Current DSAD models are limited by species-specific Aβ differences. METHODS:We developed and characterized two novel DSAD mouse models with partial humanization of Aβ. RESULTS:These models exhibit early AD features: cognitive deficits, hyperactivity, altered novelty and risk responses, tau hyperphosphorylation, and endolysosomal dysfunction. Amyloid precursor protein (APP) processing shifts toward β-secretase, increasing CTF-β and altering Aβ dynamics. Aβ humanization modulates behavior, improving specific cognitive tasks but enhancing anxiety traits. Myelinosome formation and impaired autophagic flux further align these models with human AD pathology. DISCUSSION:They offer valuable tools to investigate early DSAD mechanisms and therapeutic strategies, pending development of a fully humanized trisomic model.

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer's disease. Thus, this noncanonical BVRA-NRF2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings position BVRA as a dual-function integrator of antioxidant defense across both lipophilic and hydrophilic compartments, bridging these two distinct modes of redox protection in the brain.

BACKGROUND AND PURPOSE:Understanding of the insulin-mediated effects on signalling and metabolism is important not only for fundamental knowledge of insulin's action in the brain but also for elucidating the mechanism of therapeutic potential in neurodegenerative disorders with underlying brain metabolic dysfunction. One of the main goals of this research is to clarify and explore the time-dependent regular insulin distribution and activity in the rat brain following intranasal administration. EXPERIMENTAL APPROACH:Male Wistar rats were given insulin (2 IU) intranasally and were killed 3, 7.5, 15, 30, 60 and 120 min after administration. Control animals were killed without intranasal administration. Insulin, C-peptide and glucose concentrations were measured in plasma and cerebrospinal fluid (CSF), while levels and activity of the insulin signal transduction network were measured in brain and epithelia. KEY RESULTS:Insulin immediately distributed to all brain regions after intranasal administration and was rapidly utilized and/or metabolized. Intranasal insulin positively influences insulin secretion seen as increment of C-peptide and insulin in the periphery and in distinctive brain regions. Secondary activation of AMP-activated protein kinase and calcium/calmodulin-dependent protein kinase occurred, perhaps due to brain region-dependent negative-feedback mechanisms on the overstimulated insulin signalling pathway. CONCLUSION AND IMPLICATIONS:The insulin dose was likely too high and caused its transport back to epithelia through unknown mechanisms (most likely by transporter), which could be of relevance for human dose reduction. Possible beneficial insulin action could be due to overstimulation of the insulin-signalling pathway with subsequent inactivation through insulin receptor substrate phosphorylation at Ser307.

Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.

Disturbances of protein O-GlcNAcylation have pointed out as a possible link between altered brain metabolism and cognitive decline. We previously demonstrated the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and we confirmed the relevance of O-GlcNAcylation in the appearance of Alzheimer disease hallmarks in the brain of a murine model of Down syndrome (DS). Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition (Thiamet G). The primary objective of this study is to provide evidence for the neuroprotective effects of brain-targeted OGA inhibition (Thiamet G) by analyzing mice cognition and molecular pathways associated with Alzheimer-like neurodegenenration. The neuroprotective effects of Thiamet G was evaluated in DS mice by analyzing mice performances in the novel object recognition and Y maze tests. Furthermore we analyzed by immunochemical methods APP and tau modification, and by proteomic approach using ESI-MS/MS technique , we identified brain proteins whose O-GlcNAcylation levels resulted significantly modulated by the treatment. Data supported the beneficial effect Thiamet G in DS mice hippocampus. The rescue of OGA activity was able to restore protein O-GlcNAcylation, rescue cognitive impairments and reduce AD-related hallmarks. In particular, the recovery of O-GlcNAcylation was associated with the modulation of protein specific O-GlcNAc levels occurring to several components of neuronal architecture, stress response mechanisms and energy production. Our work emphasizes the central role of altered protein O-GlcNAcylation in DS neuropathology and lays the foundations to consider the rescue of protein O-GlcNAcylation as a valuable therapeutic strategy to reduce the alterations of brain metabolism and the development of AD-hallmarks.

The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer's disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer's disease and accelerated aging. Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer's disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagon-like peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative distress and neuroinflammation. This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative distress regulation, as these are pivotal in both Alzheimer's disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders.

Insulin resistance is a risk factor for Alzheimer's disease (AD). Chen et al.1 show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.