Alzheimer's Disease In Down Syndrome Research Articles

Exploring the complex nexus of Alzheimers disease in down syndrome

In recent years, the life expectancy of individuals with Down Syndrome (DS) has increased significantly thanks to the advancements in healthcare and treatments, giving rise to an older population of people with DS. However, this demographic shift has brought about new concerns: as individuals with DS age, they face a higher incidence of early-onset Alzheimers Disease (EOAD) (i.e. the development of AD before the age of 65). Research has revealed an accelerated progression of symptoms, from onset of dementia to death, in DS patients. Thus, it is essential to identify the factors (both genetic and environmental) that underlie the development of different stages of AD-DS. Concomitantly, there is a pressing need to initiate intervention trials that could slow down or prevent the rapid advancement of AD-DS. This paper underscores the growing importance of addressing AD-DS in an ageing DS population. By elucidating genetic and environmental factors, clinical features, diagnostic challenges, roles of genes in the development of AD-DS, and potential future research directions, the article aims to contribute to a deeper understanding of dementia of the Alzheimer Type (DAT) and facilitate the development of effective treatments that could improve the lives of DS individuals affected by DAT.

Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25–72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). In general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

Age of Alzheimer's disease diagnosis in people with Down syndrome and associated factors: Results from the Horizon 21 European Down syndrome consortium.

People with Down syndrome (DS) have high risk of developing Alzheimer's disease (AD). This study examined mean ages of AD diagnosis and associations with co-occurring conditions among adults with DS from five European countries. Data from 1335 people with DS from the Horizon 21 European DS Consortium were used for the analysis. Mean ages of AD diagnosis ranged between 51.4 (SD 7.0) years (United Kingdom) and 55.6 (SD 6.8) years (France). Sleep-related and mental health problems were associated with earlier age of AD diagnosis. The higher number of co-occurring conditions the more likely the person with DS is diagnosed with AD at an earlier age. Mean age of AD diagnosis in DS was relatively consistent across countries. However, co-occurring conditions varied and impacted on age of diagnosis, suggesting that improvements can be made in diagnosing and managing these conditions to delay onset of AD in DS. Mean age of AD diagnosis was relatively consistent between countries Sleep problems and mental health problems were associated with earlier age of AD diagnosis APOE ε4 carriers were diagnosed with AD at an earlier age compared to non-carriers Number of co-occurring conditions was associated with earlier age of AD diagnosis No differences between level of intellectual disability and mean age of AD diagnosis.

Integrated spatial and single‐cell transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease

AbstractBackgroundThe pathogenesis of Alzheimer’s disease (AD) varies greatly depending on environmental and heritable factors. Neuropathological scores aid in the understanding of disease severity in postmortem tissue, but fail to provide insights into disease onset and progression. Conversely, mouse models of AD like 5XFAD offer predictable timelines of amyloid accumulation due to specific human AD risk signals, but have limitations due to species differences. Studying AD in Down Syndrome (AD in DS) patients provides an opportunity to study the transcriptomics of AD progression due to overexpression of APP, which results in a more predictable disease time course compared to the more stochastic disease progression in the general population.MethodWe present a rigorous transcriptomic analysis of AD using single‐nucleus RNA‐seq (snRNA‐seq) and spatial transcriptomics (ST) in cortical samples from donors with early‐stage AD, late‐stage AD, AD in DS, and cognitively normal controls. We performed ST (10X Genomics Visium) in these groups, and additionally performed snRNA‐seq (Parse Biosciences) in tissue from AD in DS donors and controls. Finally, we profiled 5XFAD and wild type mice at four time points (4, 6, 8, and 12 months) using ST to facilitate cross‐species comparisons. We applied state‐of‐the‐art bioinformatic and statistical approaches to integrate these datasets with published AD snRNA‐seq data and to perform systematic analyses of gene expression and gene networks in these groups.ResultWe found shared and distinct differentially expressed genes (DEGs) between AD and AD in DS in the ST and snRNA‐seq datasets, with greater concordance in neuronal cell types compared to glia. Cell‐cell communication network analysis of integrated snRNA‐seq and ST data revealed vast network remodeling in disease, highlighting an increase in WNT and ANGPTL signaling and a decrease in CD99 signaling among other disrupted pathways. Using geospatial statistical analysis, we identified amyloid plaque proximal DEGs in human and mouse ST data, which were largely species‐specific with little overlap.ConclusionThe primary data generated here will be a valuable resource for the AD community, and our study provides new insights into the transcriptomics of AD and amyloid pathology by performing a holistic analysis considering sporadic and genetic forms of AD.

Genome‐wide association meta‐analysis of plasma neurofilament light levels in high‐risk adults with Down Syndrome

AbstractBackgroundOnly a few studies in the general population have investigated genetic contributions to variation in levels of neurofilament light (NfL), which is a general marker of axonal damage and is predictive of Alzheimer’s disease (AD). To our knowledge, no studies have examined this relation in people with Down Syndrome (DS), a population at high risk of developing AD. We performed a genome‐wide search for SNPs associated with plasma NfL levels. We paid special attention to genetic variants identified in the general population to be associated with AD risk and NfL to evaluate whether those variants contributed to AD in DS by altering NfL levels.MethodsWe performed a meta‐analysis using two datasets (N = 455): the omicsADDS and ABC‐DS studies. Levels of plasma NfL were measured using the Simoa platform and genotyping was performed using an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 was performed using the TOPMed Imputation Server. We first assessed the association between SNPs and plasma NfL levels in each dataset using a multivariable linear regression model that included age, sex, dementia status, and genetic ancestry. We then performed meta‐analysis using sample size weighting. We restricted our meta‐analysis to variants that had study‐specific P<5×10−4, to minimize potential false positives.ResultsOur genome‐wide scan, after Bonferroni correction, identified 33 novel SNPs contributing to variation in plasma NfL (28 variants with elevated plasma NfL and 5 variants with decreased plasma NfL). Three AD‐risk variants previously identified in the general population (UNC5CL/rs10947943, USP6NL/rs7912495, FOXF1/rs16941239), were found to be associated with variation in plasma NfL levels at nominal Pmeta < 0.05. Candidate variants associated with NfL in the general population were not replicated in the current meta‐analysis. The novel genes identified have been implicated in tau neuropathology, variation in lipid levels, insulin regulation, and neurotransmitter release.ConclusionThis genome‐wide meta‐analysis revealed multiple novel genetic loci associated with NfL levels in plasma in adults with DS. We additionally found supporting evidence for three known variants. The genes identified here may lead to insight into underlying mechanisms of neurodegeneration and AD in adults with DS.

Association Between Neuroimaging Biomarkers, Plasma NfL, and Memory Performance in Adults With Down Syndrome With and Without Dementia

AbstractBackgroundDown syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex and plasma NfL concentrations were associated with memory performance in adults with DS.MethodWe used 18F‐AV‐1451 (FTP) positron emission tomography (PET) to assess tau accumulation in 44 participants enrolled in the multi‐site Alzheimer’s Disease in Down syndrome (ADDS) study (age 50.72 + 6.21). FTP‐PET scans were partial volume‐corrected, and weighted standardized uptake value ratio (SUVR) were calculated for each of the following regions of interests (ROIs): entorhinal cortex, hippocampus, and the precentral gyrus (control). Participants' plasma NfL concentration (in pg/mL) was measured on a single plex plate using the ultra‐sensitive single molecule array (Simoa) technology platform HD‐X. Memory performance was measured with the modified Cued Recall Test. We evaluated the relationship between FTP SUVRs, NfL, and memory performance using linear regression analysis. Sex and site were used as covariates.ResultIncreased FTP SUVR in the hippocampus and entorhinal cortex were associated with lower scores on free recall (hippocampus: r2 = 0.53, p <0.001; entorhinal: r2 = 0.35, p <0.001) and total recall (hippocampus: r2 = 0.46, p <0.001; entorhinal: r2 = 0.29, p <0.01). As expected, no association between FTP SUVRs and memory performance was found in the precentral gyrus. Additionally, higher plasma NfL concentrations were associated with lower free recall (r2 = 0.35, p <0.001) and total recall (r2 = 0.29, p <0.01). Further, increased levels of plasma NfL were associated with increased FTP SUVRs in the hippocampus (r2 = 0.38, p <0.001), entorhinal cortex (r2 = 0.28, p<0.01), and precentral gyrus (r2 = 0.19, p<0.05).ConclusionIncreased levels of both in‐vivo tau in medial temporal ROIs and NfL in plasma were associated with worse memory performance, consistent with observations in the neurotypical population. Future work will investigate the impact of tau accumulation and NfL concentration on longitudinal cognitive decline in older adults with DS.

Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.

This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. AD polygenic risk scores (PRS) were tested for association with DS-related traits. The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE , p=2.84×10-4 ; PRS excluding APOE, PRSnonAPOE , p=1.60×10-2 ). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

AT(N) biomarker profiles and Alzheimer's disease symptomology in Down syndrome.

Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [11 C]Pittsburgh compound B) and tau (10 mCi of [18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory. Analyses included 162 adults with DS (aged M=38.84 years, standard deviation=8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. Findings add to understanding of AT(N) biomarker profiles in DS. Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS.

Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF.

Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal vacuolar (H+)-adenosine triphosphatase (v-ATPase) and acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr682 phosphorylation restores v-ATPase and lysosome function in DS fibroblasts and in vivo in brains of DS model mice. Notably, lowering APP-βCTF Tyr682 phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr682 phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer previously unknown insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.

Retromer Proteins Reduced in Down Syndrome and the Dp16 Model: Impact of APP Dose and Preclinical Studies of a γ-Secretase Modulator.

The retromer complex plays an essential role in intracellular endosomal sorting. Deficits in the retromer complex are linked to enhanced Aβ production. The levels of the components of the retromer complex are reported to be downregulated in Alzheimer disease (AD). Down syndrome (DS) shares neuropathological features with AD. Recent evidence points to dysregulation of the retromer complex in DS. The mechanisms underlying retromer deficits in DS and AD are poorly understood. We measured the levels of retromer components in the frontal cortex of cases of DS-AD (AD in DS) as well as DS; the frontal cortex of a person partially trisomic (PT-DS) for human chromosome 21 (HSA21), whose genome had only the normal 2 copies of the APP gene, was also examined. We also analyzed these proteins in the Dp16 mouse model of DS. To further explore the molecular mechanism for changes in the retromer complex, we treated Dp16 mice with a γ-secretase modulator (GSM; 776890), a treatment that reduces the levels of Aβ42 and Aβ40. We found VPS26A, VPS26B, and VPS29, but not VPS35, were significantly reduced in both DS and DS-AD, but not in PT-DS. Downregulation of VPS26A, VPS26B, and VPS29 was recapitulated in the brains of old Dp16 mice (at 16 months of age) and required increased App gene dose. Significantly, GSM treatment completely prevented reductions of the retromer complex. Our studies point to increased APP gene dose as a compromising retromer function in DS and suggest a causal role for Aβ42 and Aβ40. ANN NEUROL 2023;94:245-258.

Cross-sectional versus longitudinal cognitive assessments for the diagnosis of symptomatic Alzheimer's disease in adults with Down syndrome.

Down syndrome (DS) is a genetic form of Alzheimer's disease (AD). However, clinical diagnosis is difficult, and experts emphasize the need for detectingintra-individual cognitive decline. To compare the performance of baseline and longitudinal neuropsychological assessments for the diagnosis of symptomatic AD in DS. Longitudinal cohort study of adults with DS. Individuals were classified as asymptomatic, prodromal AD, or AD dementia. We performed receiver operating characteristic curve analyses to compare baseline and longitudinal changes of CAMCOG-DS and mCRT. We included 562 adults with DS. Baseline assessments showed good to excellent diagnostic performance for AD dementia (AUCs between0.82 and 0.99) and prodromal AD, higher than the 1-year intra-individual cognitive decline (area under the ROC curve between0.59 and 0.79for AD dementia, lower for prodromal AD). Longer follow-ups increased the diagnostic performance of the intra-individual cognitive decline. Baseline cognitive assessment outperforms the 1-year intra-individual cognitive decline in adults with DS.

Weight Loss and Alzheimer's Disease in Down Syndrome.

Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (-versus+) and/or decline in memory and mental status were associated with weight loss prior to AD progression. Analyses included 261 adults with DS. PET data were acquired using [11C] PiB for Aβ and [18F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16-20 months was assessed in a subset of participants (n = 77). Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16-20 months. Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS.

Default mode network and medial temporal lobe functional connectivity changes with Alzheimer’s disease severity and cognitive impairment in individuals with Down syndrome

AbstractBackgroundBy age 40, virtually all people with Down syndrome (DS) have sufficient beta‐amyloid and tau pathologies present to meet the criteria for pathological Alzheimer's disease (AD). Determining the timing and location of neurobiological changes caused by AD is critically important for effective intervention within this high‐risk population and more broadly in the general population, but little is known about the brain changes associated with clinical onset of AD in DS. Previous studies in sporadic AD suggest that functional connectivity of the default mode network (DMN) and medial temporal lobe (MTL) is vulnerable to AD pathology‐related impairment.MethodSeventy‐five individuals with DS (mean age 49.9±6.6, 36% women) from a subset of the Alzheimer’s Biomarkers Consortium ‐ Down Syndrome study underwent MRI, including an MPRAGE scan and a resting state functional scan. Participants completed a battery of neuropsychological tests and were assigned a consensus diagnosis for the presence or absence of mild cognitive impairment (MCI‐DS) or AD dementia. Forty‐eight participants were classified as cognitively stable (CS) (mean age 48±6.1, 42% women), 16 participants had MCI‐DS (mean age 50.8±4.2, 19% women), and 11 participants had dementia (mean age 57.2±6.6, 36% women).ResultParticipants with dementia had lower functional connectivity between the posterior DMN and the MTL relative to the CS and MCI‐DS groups. MCI‐DS participants had greater functional connectivity within the MTL relative to the CS group. Functional connectivity differences in these networks tracked with memory performance as well.ConclusionChanges in DMN and MTL functional connectivity are related to the progression of clinical symptoms of AD‐DS and may reflect synaptic changes stemming from AD pathology.

Research attitudes in families of individuals with Down syndrome: importance for clinical trials

BackgroundIndividuals with Down syndrome (DS) are increasingly eligible for clinical trial intervention, particularly for the treatment or prevention of Alzheimer disease (AD). Yet, little is known about research attitudes that may contribute to decisions regarding clinical trial enrollment for people with DS, a gap which is addressed in the current study.MethodsThe Research Attitudes Questionnaire (RAQ) is a brief validated instrument that measures cultural and social factors which influence clinical trial enrollment decisions in the general population. Applied herein to a cohort of 1002 families who have an individual with DS, this survey was carried out through a national registry (DS-Connect). In addition to the RAQ, demographic data were collected.ResultsThe response rate to the survey was 49.9%. Respondents were asked to complete demographic information and to respond to the 7 question RAQ. The scores were stratified by a cut point assigned a priori into those more favorable toward research participation vs. those less favorably inclined. Within this sample, nearly 95% self-identified as the primary caretaker for the individual with DS. The RAQ score analyses generally indicated favorable respondent views toward research with particularly high favorability ratings from respondents who had previously participated in research and from those who were older (P = .01 to .001).ConclusionsThis is one of the first formal studies to evaluate research attitudes among relatives of individuals with DS and shows the feasibility of using this approach to answer important questions that will guide trialists developing treatments for AD in DS. Future research will require broadening the racial and ethnic mix of respondents and the role that a standardized assessment of research attitudes will have for clinical trial participation.

Genetic Mapping of APP and Amyloid-β Biology Modulation by Trisomy 21.

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer’s disease (AD), a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer’s disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-β accumulation (AppNL-F) to determine how chromosome 21 genes, other than APP, modulate APP/amyloid-β in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have ADDS, compared to those who have familial AD caused by triplication of APP.

Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer's disease.

Microglia are critical in brain development and Alzheimer's disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide invivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS microglial functions and prevent senescence.

Brain dysmorphologies associated with Alzheimer disease in Down syndrome

Down syndrome (DS) is a genetic disorder occurring in 1 out of every 700 to 1,000 live births caused by trisomy of chromosome 21. The overexpression of the Amyloid Precursor Protein (APP) gene located on this chromosome leads to an early onset and rapid accumulation of ß‐amyloid (Aß) in the brain that invariably results in Alzheimer Disease (AD) in people with DS. Therefore, AD, the most common form of dementia, is currently one of the most relevant medical issues in people with DS. In this study, we assessed brain morphological patterns to quantify dysmorphologies associated with AD in Down syndrome.Brain shape and size analyses were performed using Geometric Morphometrics in a sample of 243 adults, including 153 euploid healthy controls (EU) and 90 individuals with DS at different stages of dementia: asymptomatic DS with no signs of AD‐related cognitive impairment (N=58), individuals with DS and prodromal AD (N=21) and individuals diagnosed with AD dementia (N=11). A set of 38 3D brain landmarks representing the overall shape of the brain and internal brain structures (ventricles, corpus callosum, cerebellum and pons) were located on magnetic resonance images of the head.Results showed a significant separation between EU and DS populations based on both global and local brain shape and size analyses. Individuals with DS displayed a smaller cerebellum, a protruding posterior midbody in the corpus callosum, a frontally projected brain and expanded ventricles. Significant brain shape differences were detected in individuals diagnosed with AD, which mainly affected the shape of enlarged brain ventricles. Remarkably, individuals at advanced stages of the disease displayed more severe dysmorphologies as compared to those individuals at prodromal stages and individuals with no signs of dementia, confirming a phenotypic continuum associated with the severity of dementia that highlights the impact of this neurodegenerative disorder in brain morphology.

Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n=36, mean age ± SD=53±6.2) and as being cognitively stable (n=78, mean age=49±6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals.The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.