INTRODUCTION:Alzheimer's disease (AD) dementia in Down syndrome (DS) occurs at predictable ages. It is unclear whether age can differentiate across AD stages (amyloid positivity, tau positivity, mild cognitive impairment [MCI], dementia). METHODS:Using data from the Alzheimer's Biomarker Consortium-Down Syndrome, we analyzed how well age differentiated stage using receiver operating characteristic curves. We compared areas under the curve (AUC) for age to AUCs for imaging, biofluid, cognitive, motor, and behavioral variables. RESULTS:Sample varied by stage and variable. Up to 148 variables and 461 participants were analyzed. Age effectively differentiated amyloid positivity, tau positivity, and MCI (AUCs > 0.85) but poorly discriminated MCI from dementia (0.588). No variable was better than age in distinguishing stages, except for MCI/dementia. DISCUSSION:Our results show that age alone is effective at staging DS AD. Age is the most reliable correlate of amyloid, tau status, and cognitive impairment in DS and could screen for future clinical trials.

Characterizing the timing and progression of Alzheimer’s disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer’s disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium – Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer’s Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.

Background: The Apolipoprotein E (APOE) ε4 allele increases the risk of Alzheimer's disease (AD), while the APOEε2 allele reduces risk, particularly in females in the neurotypical population. However, the effect of APOE haplotype and sex on AD in Down syndrome (DS) is unclear. Prior work has been limited by sample size, but here we aggregate the two largest APOE-genotyped cohorts of individuals with DS to date. Methods: We examined the impact of APOE genotype on AD biomarkers and cognitive performance in 1,212 individuals with DS. All participants underwent APOE testing and clinical evaluations. Subsets also completed assessments for amyloid (amyloid PET, CSF Aβ42/40, plasma pTau217), neuroinflammation (plasma glial fibrillary acidic protein [GFAP]), neurodegeneration (plasma neurofilament light [NfL] and structural MRI), and cognition (modified Cued Recall Test [mCRT]). Results: APOEε2 was protective, associated with lower amyloid PET uptake and delayed cognitive impairment. In contrast, APOEε4 was associated with lower CSF Aβ42/Aβ40, worse mCRT performance, and earlier cognitive impairment. These effects were more pronounced in females. Conclusion: APOE allele and biological sex interact to influence AD pathology and symptom onset in DS. Clinical trials, especially anti-amyloid therapies, should consider APOE status for intervention timing. Funding: Data collection and sharing for this project was supported by the ABC-DS (U01AG051406, U01AG051412, and U19 AG068054-04), funded by the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. JKW receives support from the NIH (KL2TR002346). Declaration of Interest: JF reports grants from the Fondo de Investigaciones Sanitario, Carlos III Health Institute (INT21/00073, PI20/01473 and PI23/01786 to JF) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1, jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa. This work was also supported by the National Institutes of Health grants (1R01AG056850-01A1; R21AG056974, R01AG061566, 1R01AG081394-01 and 1R61AG066543-01 to JF), the Department de Salut de la Generalitat de Catalunya (SLT006/17/00119 to JF), Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151). It was also supported by Horizon 2020 - Research and Innovation Framework Programme from the European Union (H2020-SC1- BHC-2018-2020 to JF). DA acknowledges support from Institute of Health Carlos III (ISCIII), Spain (PI18/00435, PI22/00611, PI25/00422, INT19/00016, INT23/00048) jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer Europa”, and by the Department of Health Generalitat de Catalunya PERIS program (SLT006/17/125, SLT042/25/000034). He also received support for Research Groups funding from the Department of Research and Universities from the Generalitat de Catalunya (2021 SGR 00979). AB acknowledges support from Instituto de Salud Carlos III and co-funded by the European Union through the Miguel Servet grant (CP20/00038) and Fondo de Investigaciones Sanitario (PI22/00307), the Alzheimer's Association (AARG-22-923680), and the Ajuntament de Barcelona, in collaboration with Fundació La Caixa (23S06157-001). LDHS acknowledges support from Instituto de Salud Carlos III through the Miguel Servet grant “CP24/00112” co- funded by the European Union, and the the Jérôme Lejeune Foundation (2326 - GRT-2024A). María Carmona-Iragui acknowledges support from Instituto de Salud Carlos III (ISCIII) (PI18/00335, PI22/00758, ICI23/00032); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas CIBERNED Program 1, partly jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, Una Manera de Hacer Europa; Alzheimer's Association (AARG‐22‐973966); the Global Brain Health Institute (GBHI_ALZ‐18‐543740); the Jérôme Lejeune Foundation (#1913 cycle 2019B; #2425 cycle 2024B). MRA was supported by the Alzheimer’s Association Research Fellowship to Promote Diversity (AARF-D) Program (AARFD-21-852492) from 2022 until 2025. LVA is supported by the Sara Borrell postdoctoral fellowship from Institute of Health Carlos III (ISCIII), Spain (CD23/00235). BLH has received research funding from Roche and Autism Speaks; receives royalties from Oxford University Press for book publications; and is the chair of the data safety and monitoring board for the Department of Defense-funded study, “Comparative Effectiveness of EIBI and MABA”. BTC receives research funding from the National Institutes of Health. EH receives research funding from the National Institutes of Health and the BrightFocus Foundation. FL is supported by grants from the National Institute on Aging. HDR has received funding from the National Institutes of Health and is on the scientific advisory committee for the Hereditary Disease Foundation. JHL has received research funding from the National Institutes of Health and the National Institute on Aging. BMA receives research funding from the National Institutes of Health and has a patent (“Markers of Neurotoxicity in CAR T patients”). MSR has received consulting fees from AC Immune and Ionis, Alzheon, Alnylam, Biohaven, Embic, Positrigo and Prescient Imaging. He has received research support from the National Institutes of Health, Eisai and Lilly.. All other authors declare no competing interests. Lucia Maure-Blesa was supported by Instituto de Salud Carlos III through the Río Hortega Fellowship “CM23/00291” and co-funded by the European Union. SG acknowledges support from Institute of Health Carlos III (ISCIII), Spain (PI20/00836) jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, “Una manera de hacer Europa”; the Global Brain Health Institute (GBHI_ALZ-23-971107); the Jérôme Lejeune Foundation (#1801 Cycle 2020), Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151 to JF and SG) ODI reports grants from the Fondo de Investigaciones Sanitario, Carlos III Health Institute (PI21/01395 and PI24/01087 to ODI) jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa, the Jérôme Lejeune Foundation (#202307 to ODI) and the Alzheimer’s Association (AARF-22–924456)" Ethical Approval: Latest Approval dates for ABC-DS: Advarra sponsor #Pro00044843- 4/3/2025 (exp 4/3/2026), Advarra IBR (#Pro00044843) - 4/3/2025 (exp 4/3/2026 - currently submitted for continuing review), Advarra CUIMC (#Pro00044843) - 3/28/2025 (exp 3/28/2026 - currently submitted for continuing review), NKI IRB #8187 - 6/30/25 - reliance agreement approval (exp is Advarra's date 4/3/2026), CUIMC IRB #AAAU0596 - 4/11/2025 (exp 3/28/2026).

Down syndrome is characterized by triplication of chromosome 21, leading to early-onset Alzheimer disease pathology, with nearly all individuals with Down syndrome developing amyloid and tau pathology. In the new era of amyloid modifying therapies, it is vital to identify early biomarkers for Alzheimer disease (AD) pathology in Down syndrome. Striatal amyloid may begin to accumulate sooner than cortical amyloid in Down syndrome. Tau phosphorylation at specific sites, including 217, can be quantified in plasma and may represent an important mechanistic step in the development of tau pathology. This study had two aims: 1. To compare the relative age at increase of multiple biomarkers (cortical amyloid, striatal amyloid, plasma pTau217 and summary tau pathology) 2. To test whether plasma pTau217 can identify both the current presence and likely future accumulation of amyloid and tau pathology. To identify optimal biomarkers for early intervention, we examined longitudinal cortical and striatal amyloid PET, plasma pTau217, and tau PET in 328 individuals with Down syndrome enrolled in the Alzheimer Biomarker Consortium – Down Syndrome study. To compare the timing of biomarker changes, we modeled longitudinal biomarkers using generalized additive mixed models relative to age. We used receiver operating characteristic curve analysis to identify thresholds for both current and likely future accumulation of amyloid and tau pathology. For all comparisons, we used age as the null model, performing Delong tests to evaluate the performance of age relative to biomarker-based prediction. Imaging biomarkers increased around 40 years old, with plasma pTau217 increasing somewhat later than the three PET biomarkers. Striatal amyloid increased before cortical amyloid in some participants; however, this was not uniform across individuals. If an individual was classified as a reliable accumulator with one biomarker, he or she was likely to be a reliable accumulator in other biomarkers. Age was as sensitive as plasma pTau217 in its ability to both detect preclinical Alzheimer disease pathology and predict near future accumulation of both amyloid and tau. These results suggest that all adults with Down syndrome should be screened for Alzheimer disease pathology starting shortly before age 40 and considered for clinical trials. Age alone was as effective at detecting both current pathology and likely future accumulation as plasma pTau217. Because this disease is so closely concurrent with age in individuals with Down Syndrome, plasma pTau217 may not provide more diagnostic benefits than age.

Abstract Background Life expectancy for individuals with Down syndrome (DS) has significantly increased, primarily due to medical advances. While DS is considered a genetically determined form of Alzheimer’s disease (DS-AD), with neuropathological markers evident by age 40, the onset of clinical dementia varies. Modifiable risk factors are thought to contribute meaningfully to dementia risk in the general population. Advances in intervention studies in the general population suggest cognitive decline can be reduced through multimodal lifestyle interventions, however no large-scale multimodal studies have been conducted in the DS population. Search strategy A comprehensive search was conducted across five electronic databases—Medline, EMBASE, CINAHL, Web of Science, and ASSIA to identify studies that examined the relationship between lifestyle interventions and cognitive outcomes in adults with DS. The search combined database-specific controlled language with keywords related to exercise, diet, social activities, cardiovascular health, and brain stimulation. Studies included were peer-reviewed original research articles focusing on adults with DS and reported on cognitive outcomes or AD-related biomarkers. Results The search yielded 24,774 articles, with 16,868 remaining after duplicates were removed. A total of 44 articles met inclusion criteria across the domains of exercise, diet, cardiovascular health, social connectedness, and cognitive stimulation. Most studies focused on exercise, indicating some cognitive benefits, particularly in executive functions and working memory, though results were inconsistent, and many suggested the necessity of high adherence to intervention protocols. No studies were found that examined the direct impact of diet on cognition in DS. Findings on cognitive stimulation, cardiovascular health and social connectedness suggested potential but inconclusive benefits for cognitive function. Conclusions This review underscores the significant gaps in research regarding non-pharmacological interventions for DS-AD. It highlights the need for tailored, well-structured studies to better understand and leverage potential cognitive benefits of lifestyle interventions in the DS population. Implementing such interventions early in life and before significant disease progression may help maintain quality of life and independence among individuals with DS. Future research should focus on comprehensive, multi-domain interventions to ascertain their efficacy and optimal application.

OBJECTIVE:Adults with Down syndrome (DS) often show elevated systemic inflammation, but the association with obesity, aging, and Alzheimer's disease (AD) pathology is not well understood. METHODS:Data were drawn from 188 nondemented adults with DS participating in the Alzheimer Biomarkers Consortium-DS (ABC-DS). Participants completed clinical assessments, blood draws, and neuroimaging. Plasma biomarkers included indicators of general, pro-, and anti-inflammation. Mixed linear models tested associations between BMI, age, PET-measured amyloid burden, and inflammatory biomarkers, adjusting for sex, trisomy type, and collection site. False discovery rate correction was applied. RESULTS:The majority of the participants met criteria for obesity. Higher BMI was significantly associated with elevated levels of CRP, IL-6, TNF-α, B2M, IL-18, and slCAM-1 (p < 0.05). Older age was significantly associated with higher B2M (β = 1.22e + 05, p < 0.001). Amyloid burden was positively associated with IL-6 (β = 0.005, p = 0.037). CONCLUSIONS:Obesity, aging, and amyloid burden relate to systemic inflammation in adults with DS. Obesity showed the strongest and most consistent associations, emphasizing the value of regular monitoring and weight management strategies to help reduce inflammation. Aging and early amyloid accumulation showed more limited links with systemic inflammation; future work should examine whether these processes are more closely related to biomarkers of neuroinflammation as AD progresses.

INTRODUCTION:This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. METHODS:Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. RESULTS:Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. DISCUSSION:These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status.

Alzheimer's disease progresses heterogeneously across diverse cohorts, yet current predictive models fail to capture this complexity while remaining clinically interpretable. Here we present a multi-dimensional attention framework that simultaneously captures both temporal dynamics and biomarker importance to predict disease progression across three fundamentally different populations: the general late-onset population using the Alzheimer's Disease Prediction Of Longitudinal Evolution (TADPOLE) dataset (N=1669), cases with Down Syndrome-associated Alzheimer's disease using the Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS) dataset (N=396), and cases with autosomal dominant Alzheimer's disease using the Dominantly Inherited Alzheimer Network (DIAN) dataset (N=425). Trained on each dataset independently, our framework achieved multi-class Area Under the Receiver Operating Characteristic Curve (mAUC) values of 0.793 (TADPOLE), 0.680 (ABC-DS), and 0.902 (DIAN) when predicting individuals' future diagnostic status (cognitively normal/stable, mild cognitive impairment, or Alzheimer's disease) from their longitudinal biomarker history, outperforming conventional approaches. The model generates individual-specific attention maps revealing distinct biomarker importance over time. Transfer learning from TADPOLE-which included neuroimaging data-improved prediction performance on the imaging-free ABC-DS dataset from 0.680 to 0.771, demonstrating that disease mechanisms transcend both etiological boundaries and data modalities. Ultimately, this framework could enable precision medicine approaches for data-limited cohorts across the Alzheimer's disease spectrum.

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.

INTRODUCTION:It is unknown if neurodegeneration trajectories differ between Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD), both of which are genetic forms of Alzheimer's disease (AD). METHODS:We compared brain volumes in DS, ADAD, and unaffected family members serving as controls. Participants underwent magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET), deriving volumetric and amyloid burden, respectively. Nonlinear associations between regional volumes and estimated years to clinical symptom onset (EYO) were evaluated using generalized additive mixed-models. RESULTS:Longitudinal data from 267 controls, 341 participants with DS, and 358 participants with ADAD were included, totaling 1908 scans. DS volumes were lower than ADAD and controls initially and dropped linearly. ADAD had similar volumes to controls until diverging, beginning at EYO -7. Amyloid was negatively associated with volume, with similar slopes in DS and ADAD. DISCUSSION:ADAD and DS demonstrate distinct patterns of brain volume decline prior to symptom onset despite being similarly affected by amyloid.

INTRODUCTION:Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD), yet identifying the preclinical phase remains challenging. Intraindividual cognitive variability (IICV) may be a sensitive marker of early AD-related changes but remains understudied in DS. METHODS:Adults from the Alzheimer's Biomarker Consortium-DS (ABC-DS) study (N = 460, mean age 43.3 years; 45.7% female) were included. Generalized linear models examined whether baseline IICV predicted incident mild cognitive impairment (MCI)/dementia, cognitive decline, and amyloid and tau positron emission tomography outcomes, adjusting for demographics, intellectual disability, apolipoprotein E ε4, site, assessment interval, and mean cognitive performance, with Bonferroni correction. RESULTS:Greater IICV predicted incident MCI/dementia (odds ratio = 4.63 to 5.13, p < 0.05), greater amyloid burden, early tau accumulation, and higher tau across Braak stages, independent of mean cognition. Exploratory analyses suggested sex-specific interactions with tau outcomes. DISCUSSION:IICV is a sensitive marker of dementia risk and cognitive resilience in DS, with potential utility for secondary prevention and trial enrichment.

INTRODUCTION:Individuals with Down syndrome (DS) face high risk for Alzheimer's disease (AD), yet presymptomatic detection of cognitive decline is hindered by lifelong intellectual disability. METHODS:Using data from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS), blood samples from 246 participants were analyzed, yielding 404 longitudinal observations (45 Converters, 359 Stable) collected at 0, 16, and 32 months were analyzed. A Support Vector Machine was trained on 25 plasma biomarkers spanning neurodegeneration, inflammation, and vascular health, along with demographic factors (age, sex, ethnicity, karyotype, apolipoprotein E [APOE ε4]). Batch-effect correction and feature selection were applied, resulting in 13 key markers. RESULTS:The refined model achieved 92.4% sensitivity, 59.9% specificity, and an area under the curve (AUC) of 77.9%, accurately identifying individuals at risk of cognitive decline up to 16 months before clinical progression. DISCUSSION:This multi-domain, blood-based machine learning approach demonstrates that plasma biomarkers are valuable non-invasive tools for early detection and risk stratification of cognitive decline in DS.

INTRODUCTION:Up to 90% of Down syndrome (DS) patients develop Alzheimer's disease (AD). Sleep disturbance, affecting over 75% of DS patients, is implicated in AD pathogenesis. The thalamus, central to sleep and arousal, shows early vulnerability in DS-related AD. METHODS:Structural 3T MRI scans from 253 DS participants (119 males, mean age 43.0 ± 9.4 years) and 36 controls (30 males, mean age 43.1 ± 12.2 years) from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study were analyzed, alongside neurodegenerative plasma biomarker assays (phosphorylated tau [pTau]181, pTau217, neurofilament light chain [NfL], amyloid beta [Aβ]40, Aβ42). RESULTS:In DS, intracranial volume-adjusted thalamic volume declined with age (t = -2.589, p = 0.00987), approximating 2.5% loss per decade. This was linear, gray matter involution-independent, and heterogeneous across nuclei, correlating negatively with pTau and NfL. Controls exhibited no significant volumetric changes. DISCUSSION:Anteromedial and posterior thalamic shrinkage in DS AD mirrors sporadic AD. Associations with neurodegenerative biomarkers support thalamic atrophy as a sensitive marker of DS-related AD progression.

BACKGROUND:Plasma biomarkers associated with Alzheimer's disease could improve prognostic assessment for people with Down syndrome in both clinical practice and research settings. We aimed to identify the plasma biomarkers that most accurately predict longitudinal changes in Alzheimer's disease-related pathology and cognitive functioning in individuals with Down syndrome. METHODS:This longitudinal cohort study included data from 258 adults (aged ≥25 years) with Down syndrome who were followed up prospectively every 16 months as part of the longitudinal Alzheimer's Biomarker Consortium-Down Syndrome study (recruited from seven university sites in the USA and UK between July 13, 2016, and Jan 15, 2019). Participants had baseline and longitudinal assessments of plasma tau phosphorylated at threonine 217 (p-tau217), glial fibrillary acidic protein (GFAP), amyloid β (Aβ)42/40, neurofilament light (NfL), or total tau (t-tau). Associations of baseline plasma biomarkers and longitudinal changes in plasma biomarkers with changes in global cognitive functioning (Down Syndrome Mental Status Examination [DS-MSE] scores), Aβ-PET, and tau-PET were examined using linear regression models. Plasma biomarker-associated risk of progression to dementia was assessed using Cox regression analysis. FINDINGS:Baseline p-tau217, as well as GFAP, NfL, or t-tau, were individually associated with longitudinal changes in DS-MSE, Aβ-PET, and tau-PET, and with progression to dementia. However, in combined models, only baseline p-tau217 remained associated with changes in DS-MSE (β -0·30 [95% CI -0·45 to -0·15], p=0·0001, n=220), tau-PET (0·42 [0·14 to 0·70], p=0·0039, n=88), and progression to dementia (hazard ratio 3·51 [95% CI 1·76-7·00], p=0·0004, n=194), whereas baseline p-tau217 (0·29 [0·14-0·45], p=0·0003) and GFAP (0·37 [0·18-0·56], p=0·0003) were associated with changes in Aβ-PET (n=106 for both). Similar associations were shown between longitudinal p-tau217 or GFAP and changes in DS-MSE (p-tau217: β -0·33 [95% CI-0·52 to -0·13], p=0·0015, n=133), tau-PET (p-tau217: 0·61 [0·40 to 0·83], p<0·0001, n=87), and Aβ-PET (p-tau217: 0·35 [0·19 to 0·50], p<0·0001; GFAP: 0·49 [0·27 to 0·70], p<0·0001, n=88). INTERPRETATION:Baseline and longitudinal plasma p-tau217 were associated with subsequent decline in global cognition, progression to dementia, and increased tau burden, whereas baseline p-tau217 and GFAP were associated with Aβ accumulation. These findings suggest that plasma p-tau217 and GFAP might be valuable for prognostic assessment of Alzheimer's disease in people with Down syndrome in both clinical and research contexts. The results further support evaluation of these biomarkers for monitoring disease progression in clinical trials of Down syndrome-related Alzheimer's disease. FUNDING:The European Research Council and National Institute on Aging (National Institute of Health).

BACKGROUND:Centiloid provides a standardized process to quantify brain amyloid in which a subject's T1 magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) scans are registered and warped to Montreal Neurological Institute 152 space using prescribed procedures. The method has a high failure rate in Down syndrome (DS) subjects from the Neurodegeneration in Aging Down Syndrome (NiAD) project. We evaluate imaging preprocessing methods (PMs) to improve the DS success rate. METHODS:PMs were constructed from combinations of image origin reset, filtering, MRI bias correction, and MRI skull stripping. Centiloid results were evaluated for adherence to standards using The Global Alzheimer's Association Interactive Network dataset. PMs were also evaluated using the NiAD dataset to judge their suitability for the DS population. DS PM evaluation procedures were developed corresponding to those specified for non-DS populations. RESULTS:Five accepted PMs improved the Centiloid-processing success rate in the DS cohort from 61.3% to 95.6%. DISCUSSION:The identified combinations of preprocessing steps substantially improved the success rate of Centiloid processing in DS. HIGHLIGHTS:Image preprocessing pipeline is proposed for Centiloid analysis of DS. Preprocessing pipelines are evaluated for adherence to Centiloid standards. Pipelines are evaluated for improvement in yield of usable imaging data. Preprocessing of amyloid imaging data resulted in a large yield improvement.

INTRODUCTION:Individuals with Down syndrome (DS) have a high prevalence of Alzheimer's disease (AD) and reveal an earlier age of amyloid beta (Aβ) onset compared to sporadic AD. Differences in amyloid accumulation rates between DS and sporadic AD populations have not been established. METHODS:Participants with ≥ 3 [C-11]PiB scans (spanning > 6 years) and transitioning to Aβ+ were included, resulting in 20 DS and 23 neurotypical (NT) participants. Amyloid accumulation was compared using global standardized uptake value ratio (SUVR) for Aβ deposition, with individual growth rates (r) estimated using the logistic growth model ( S U V R ( t ) = S U V R B L + K 1 + e - r ( t - t 50 ) $SUVR\ ( t ) = SUV{{R}_{BL}} + \frac{K}{{1 + {{e}^{ - r( {t - {{t}_{50}}} )}}}}$ ). RESULTS:The average growth rate in the DS cohort was 0.28 (0.08)/year versus 0.20 (0.08)/year for NT ( p = . 002 $p = .002$ ), an increase of 40%. DISCUSSION:Using individual longitudinal analyses, accelerated amyloid accumulation in DS is observed, This has important considerations for informing treatment trial design and monitoring beta-amyloid changes in future AD studies involving individuals with DS. HIGHLIGHTS:Aβ accumulation rate was estimated using a logistic growth model. There was no overlap in the age of amyloid positivity between DS and NT cohorts. Participants with DS accumulate amyloid 40% faster than those with sporadic AD.

INTRODUCTION:Individuals with Down syndrome (DS) have elevated risks for Alzheimer's disease (AD) due to amyloid beta (Aβ) precursor protein overexpression, with nearly all developing AD pathology by age 40 at autopsy. This study examined spatial associations between Aβ and tau burden in DS and neurotypical aging. METHODS:Data included 145 DS (25-67 years) and 191 neurotypical aging individuals (63-89 years). Regional Aβ and tau positron emission tomography outcomes were analyzed using multiset canonical correlation analysis to identify joint Aβ/tau spatial patterns, with regression models assessing associations with age and cognition. RESULTS:For a given Aβ burden, cognitively stable DS individuals exhibited relatively higher tau burden than neurotypical aging, while DS mild cognitive impairment/AD individuals exhibited more widespread pathology. Joint Aβ/tau patterns were associated with episodic memory impairment in DS and, as the disease progresses, executive dysfunction. DISCUSSION:DS exhibits overlapping and distinct AD-related neuropathology features, emphasizing the importance of biomarkers for early detection and intervention. HIGHLIGHTS:There are distinct amyloid beta (Aβ) and tau spatial patterns in Down syndrome (DS): For a given level of Aβ burden, individuals with DS exhibited greater and more widespread tau burden compared to neurotypical aging, even before a clinical diagnosis of dementia. Aβ-associated tau burden was linked to episodic memory impairment in DS prior to dementia, with executive dysfunction emerging as the disease progressed, highlighting the sequential impact of pathology on cognition. The unique pattern of early striatal Aβ accumulation in DS supports its use as a potential biomarker for tracking disease progression and guiding clinical trial inclusion criteria for Alzheimer's disease interventions in DS.

Blood-based biomarkers able to detect atypical neuropathology could serve as a cost-effective and noninvasive screening to include participants with Down syndrome (DS) in anti-amyloid clinical trials. Accurately placing these novel biomarkers on the AD pathological cascade as proposed by the AT(N) framework informs relative disease progression of individuals. This work examines associations between plasma pTau217 accumulation, PET amyloid positivity, and cognitive status in adults with Down syndrome. Participants were recruited from the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS) study (Table 1). Amyloid positivity was determined by [ 11 C]PiB or [ 18 F]florbetapir (A+: Centiloids > 18) PET imaging from U01 cycle 1. Participants were classified as cognitively stable, mild cognitive impairment (MCI), or dementia (D). Plasma pTau217 concentration was measured using Lilly’s immunoassay for the Meso Scale Discovery platform. The threshold for ptau217 abnormality was derived using a subsample of amyloid negative participants. Youden’s Index (YI) was optimized to assess ptau217 sensitivity to PET A+ individuals. The time offset between PET amyloid positivity (18 CL) and ptau217 sensitivity was based on amyloid chronicity trajectories (Zammit et al, 2023). A second analysis was performed with respect to varying PET A+ thresholds. Amyloid positive participants showed elevated pTau217 levels compared to amyloid negative participants (A+: 0.82 pg/ml, A-: 0.44 pg/ml, p < 0.05). With a data derived pTau217 threshold of 0.78 pg/ml, optimization of YI identified an optimal cut point of 48.5 CL. In a ROC analysis, AUC increased with increasing PET A+ thresholds (Figure 1). A significant separation of pTau217 with cognitive status was observed (cognitively stable: 0.51 pg/ml, MCI: 0.88 pg/ml, D: 1.50 pg/ml) (Figure 2). Concordance was high between plasma pTau217 using Lilly’s immunoassay and amyloid PET status after reaching elevated amyloid levels of 48.5 CL or ∼6 years PET A+. This work suggests that elevated pTau217 levels follows Aβ neuropathology detected by PET and trends with clinical progression.

The landscape of Down syndrome-associated Alzheimer's disease (DSAD) research reflects decades of scientific endeavor and collaborative effort, charting a remarkable journey from initial observations to the elucidation of complex genetic and molecular mechanisms. This perspective article chronicles key milestones and breakthroughs, paying homage to the pioneering scientists and advancements that have shaped the field. A thorough review of historical and contemporary literature offers a comprehensive narrative, highlighting the evolution of knowledge surrounding DSAD, from early recognition to the characterization of clinical presentation and natural history. The unique challenges and ethical considerations associated with DSAD populations are also examined, underscoring the importance of tailoring research and clinical approaches. By reflecting on the field's trajectory, this work celebrates past achievements while emphasizing the critical need for sustained research efforts. As part of a special issue, this article provides a foundation for appreciating the challenges and opportunities that lie ahead in advancing DSAD understanding and care. HIGHLIGHTS: This article provides a comprehensive overview of Down syndrome-associated Alzheimer's disease (DSAD) history, from early descriptions to its recognition as a genetic form of AD. It reflects on historical challenges faced by individuals with intellectual disabilities in achieving inclusion in scientific research. This historical perspective highlights the critical contributions of individuals with DS in advancing understanding of AD natural history. It explores pivotal milestones and efforts that have driven progress in DSAD research. Finally, it provides context to understand challenges and opportunities in DSAD research and its future directions.

Background: Down syndrome (DS) is the most common genetic cause of intellectual disability. Ocular manifestations occur frequently in people with DS (pwDS) but to date, there is no systematic review or meta-analysis of these conditions across the lifespan. Methods: PubMed, Medline, Embase, Web of Science and Scopus were searched for observational studies reporting ocular manifestations in pwDS, without limiting publication date. The proportion of pwDS with specific ocular manifestations were meta-analysed to obtain a pooled incidence using a random effects model. Sources of heterogeneity were assessed using a meta-regression analysis. For manifestations reported, but without sufficient prevalence data available, a narrative approach was adopted. Results: The search identified 1208 papers. Reviewers independently screened the abstracts, and 54 studies were found to fit the criteria. The age range of the individuals was birth to 88.7 years. Ocular manifestations from highest to lowest prevalence included refractive errors (69.97%, 95% CI 59.95%-79.13%), strabismus (31.41%, 95% CI 24.66%-38.57%), lens opacities (13.79%, 95% CI 8.61%-19.86%), nystagmus (12.72%, 95% CI 9.02%-16.92%) and keratoconus (9.34%, 95% CI 2.47%-19.26%). Alterations of lens and corneal morphology, posterior segment anomalies (including glaucoma) and Brushfield spots were also identified. Conclusions: The ocular manifestations of pwDS are common but varied. Age and/or ethnicity may influence the prevalence of certain ocular manifestations. The level of intellectual disability may also affect the prevalence of ocular manifestations as the prevalence of ocular disorders is known to increase with the severity of intellectual disability in pwDS.