There is disrupted functional connectivity (FC) of the default mode network (DMN) and frontoparietal network (FPN) in adults with obstructive sleep apnea (OSA). DMN FC is also particularly sensitive to disruption in Alzheimer's disease (AD). However, there is limited research investigating if OSA affects FC in Down syndrome (DS), despite the prevalence of both OSA and AD pathology within this population. We examined if DMN and FPN FC are also disrupted in older adults with DS and OSA, and whether this is dependent on concurrent cognitive impairment due to AD. Seventy-five participants from the Alzheimer Biomarkers Consortium – Down syndrome (ABC-DS) study (age 49.93+6.6) underwent resting-state functional MRI. For our seed-based connectivity approach, data were harmonized and processed using the CONN Toolbox with the default MNI preprocessing pipeline. FC strength was calculated (1) between regions-of-interest (ROIs) within each network (“within-network FC”) and (2) between ROIs in each network and all other ROIs outside of the network (“between-network FC”). Group differences in FC were assessed based on self-reported OSA and consensus diagnosis of cognitive status – cognitively stable (CS) or cognitively impaired (CI; mild cognitive impairment or dementia). There was a significant interaction between OSA and diagnosis for within- and between-DMN FC ( p -values<0.05). The CS-OSA group had higher FC than the CI-OSA group. There was also a trend showing higher FC in CS-OSA compared to CS-nonOSA. For within- and between-FPN FC, the same groups differences were observed, though the interaction was trending ( p -values<0.10). FC did not differ between CS and CI individuals without OSA, nor between CI groups with and without OSA. We observed higher within- and between-DMN FC in the CS-OSA compared to the CI-OSA group; however, this difference was not observed between the CS-nonOSA and CI-nonOSA groups. This result suggests a unique FC signature for individuals with DS and OSA prior to AD-related cognitive impairment. These findings suggest that there's a unique FC signature for individuals with DS and OSA such that FC is initially elevated prior to AD-related cognitive impairment then is reduced following AD symptom onset.

Adults with Down syndrome (DS) have increased risk for developing Alzheimer’s disease (AD). Several studies have found that the onset of new neuropsychiatric and behavioral symptoms in DS is associated with AD progression. There is evidence in the neurotypical population that AD-related apathy is more severe among males, while females display higher prevalence of depression, psychosis, and delusions. The current study investigates sex differences in AD-related neuropsychiatric symptomology in adults with DS. It is hypothesized that men will have greater frequency or severity of AD-related apathy compared to women while women will display more AD-related depression. A total of 155 adults with DS from the Alzheimer’s Disease in Down Syndrome (ADDS) study (43.3% female, M age = 50.26, SD = 7.20) received cognitive testing. Their care providers completed questionnaires that measured psychiatric and/or behavioral symptoms: the Neuropsychiatric Inventory Questionnaire (NPI-Q), the Reiss Screen for Maladaptive Behavior (RSMB), and the Dementia Questionnaire for People with Learning Disabilities (DLD). AD clinical status was determined through consensus decisions by the research team based on cognitive and functional scores. 113 participants were classified as cognitively stable and 42 had possible/probable AD dementia. Participants with mild cognitive impairment or of uncertain clinical status were excluded. There were no significant main effects for sex on any of the measures examined. However, there was a significant interaction between sex and clinical status on the DLD Activity & Interest scale, adjusting for age, sex, and clinical status (F(4, 154) = 4.055, p = 0.46, η 2 = 0.20). While cognitively stable men and women had similar scores on this scale, men with dementia had significantly greater problems in this area of functioning than women with dementia. AD appears to affect men and women differently after the transition to dementia. Affected males engage in fewer activities and are less interested in their surroundings than females, suggesting greater apathy or withdrawal, despite the lack of sex differences in depressive symptomology during the preclinical and clinical stages of AD. Possible neurobiological reasons will be discussed as well as how individuals with DS and AD may need tailored support based on sex differences in psychiatric and behavioral symptoms.

Individuals with Down syndrome (DS) have a 90% lifetime risk for symptomatic Alzheimer's disease. Yet, there is a 20+ year age range in when individuals with DS reach PET amyloid-beta (Aβ) positivity (i.e., centiloid (CL) ≥18). There is a critical need to identify factors associated with resistance (i.e., less than expected Aβ for age) and resilience (i.e., better than expected cognitive function given Aβ) in the DS community. 262 adults with DS (M=43.93, SD=9.29) in the Alzheimer Biomarker Consortium-Down syndrome underwent MRI and amyloid PET scans with [11C] PiB or [18F] florbetapir. A study partner reported on health history. Systolic blood pressure and BMI were obtained. Using multiple regression models, we examined the best fit function for association between: 1) age and Aβ, and 2) Aβ and cognitive performance, adjusted for premorbid intellectual disability level. We than calculated each participant's residual (i.e., difference between observed versus predicted value) to assess resistance to Aβ (defined as less than predicted Aβ for age) and resilience to cognitive impairment (defined as better than predicted cognition for Aβ). The modified Cued Recall Test and Down Syndrome Mental Status Exam were used as cognitive scores. The cardiovascular composite was based on the original and no-lab Framingham Risk Score (BMI ≥ 30, systolic blood pressure ≥ 130, use of statins, and presence of hypertension, hyperlipidemia, and diabetes). In partial correlations adjusted for age, there was a significant positive association between the cardiovascular composite ( r  = .156, p = .016) and resistance score; higher cardiovascular composite was associated with greater than expected Aβ for age. At the item level, hyperlipidemia was associated with a 1.8 x higher likelihood of greater than expected Aβ for age (OR = 1.83, p = .047). There was not a significant correlation between the cardiovascular composite and the resilience scores. Cardiovascular conditions may alter resistance to DSAD, including an earlier age of Aβ accumulation, and be an important target for delaying or preventing DSAD.

90% of adults with Down syndrome (DS) will develop Alzheimer's dementia (AD) in their lifetime, the majority within 3 years of symptom onset. However, clinicians need to be confident that declines are not temporary or due to treatable causes before diagnosing prodromal AD. The present study investigates the medical, psychiatric, and life factors associated with atypical cognitive decline in DS, a population with genetic risk for AD. We aim to identify factors that contribute to temporary or non-progressing cognitive decline over a three-year period. Thirty-eight adults with DS (ages 43 to 62) from the Alzheimer Biomarker Consortium in Down Syndrome (ABC-DS) were classified as having prodromal AD (MCI-DS) at one or more time points. AD clinical status was determined through a consensus process using only clinical and cognitive data. There were three trajectories based upon longitudinal data: (1) progressors (MCI-DS to dementia), (2) reverters (MCI-DS to cognitively stable), or (3) non-progressors (MCI-DS for 3 time points). Comorbidities and life stressors were collected through study partner interviews. Baseline amyloid PET scans and plasma AD biomarkers are used in the present study. Using chi-square and Kruskal-Wallis tests, non-progressors ( n  = 6, M age  = 48.67) were younger ( p  = .032), had lower centiloid values ( p  = .002) and had higher prevalence of seizure disorder ( p  = < .001), hearing impairment ( p  = < .001), and a friend move away ( p  = .027) than progressors ( n  = 26, M age  = 52.88). Reverters ( n  = 6, M age  = 49.17) had a higher incidence of psychotic disorder ( p  = .028) compared to non-progressors and progressors. Both atypical groups had lower incidence of COVID infection ( p  = .046), but still had high amyloid load (M=30.50CL and 48.02CL, respectively). In our sample of adults with DS and MCI-DS, 31.6% did not progress to dementia despite having high levels of amyloid PET. Those whose decline plateaued had more medical conditions and life stressors. Those with temporary decline had more psychiatric problems. Primary care physicians need to understand which reversible or treatable factors are most likely to lead to a misdiagnosis of prodromal AD and address them accordingly.

Abstract Introduction New Alzheimer's disease (AD) treatments have created an urgent need for accurate early diagnosis of high‐risk adults with Down syndrome (DS), distinguishing prodromal DS‐AD symptoms from lifelong cognitive impairments. Often, clinicians will need to evaluate dementia status during a single assessment, and here we describe empirically supported methods effective under such circumstances. Methods Archived data collected between 1987 and 2017 included longitudinal findings for 144 individuals maintaining cognitive stability and 126 developing prodromal DS‐AD. Response operating characteristic analyses compared groups, defined by the presence/absence of prodromal DS‐AD, for a single assessment. Results Groups differed on all measures without adjusting for developmental history, 0.717 < areas under the curve < 0.859, Ps < 0.0001. The balance between sensitivity and specificity improved slightly when developmental histories were considered. Discussion The present study demonstrated that one‐time assessments can inform clinical judgments when diagnosing adults at risk for DS‐AD. Knowledge of developmental history is valuable but non‐essential. Highlights Non‐overlapping distributions were observed for preclinical and prodromal Alzheimer's disease (AD) groups. Receiver operating characteristic area under the curve analyses were in the acceptable to excellent range for all measures. Performance was sensitive to both the severity of intellectual disability and the stage of Down syndrome‐AD progression. Episodic memory tests were sensitive to the transition from preclinical to prodromal AD. Performance results at a single time point can inform dementia status decisions.

INTRODUCTION:Virtually all adults with Down syndrome (DS) will accumulate the neuropathologies associated with Alzheimer's disease (AD) by age 40, with the majority having a clinical dementia diagnosis by their middle 50s. METHODS:This paper complements a 2020 publication describing the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) methodology by highlighting protocol changes since initial funding in 2015. It describes available clinical, neuropsychological, neuroimaging, and biofluid data and bio-specimen repository. Ten years of accomplishments are summarized. RESULTS:Over 500 adults with DS and 59 sibling controls have been enrolled since 2015 with nearly 800 follow-up visits. More than 900 magnetic resonance imaging (MRI), 800 amyloid positron emission tomography (PET), and 600 tau PET scans have been conducted; multiple omics data have been generated using over 1100 blood and 100 cerebrospinal fluid (CSF) samples. DISCUSSION:ABC-DS is the largest U.S.-based, multi-site (including the United Kingdom and Puerto Rico), longitudinal biomarker initiative to target adults with DS at risk for AD. HIGHLIGHTS:The Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) is entering its 10th year. Over 500 adults with Down syndrome (DS) and 59 sibling controls have been enrolled. More than 900 magnetic resonance imaging (MRI), 800 amyloid positron emission tomography (PET), and 600 tau PET scans have been conducted. Multiple omics data have been generated using over 1100 blood and 100 cerebrospinal fluid (CSF) samples. It is positioned to continue to make substantial contributions to the DS field.

There is an increased risk of epilepsy in Down syndrome (DS), especially after the age of 40. The onset of this co-occurring disease is closely associated with Alzheimer’s disease (AD) related cognitive deterioration. Therefore, understanding the impact of late-onset epilepsy on AD biomarkers in people with DS is crucial. Here, we aim to test the difference in tau levels and hippocampal volume in people with late-onset seizures, childhood-onset seizures, and no seizures. We analyzed data from 54 participants (52 +/- 6.5 years, 66% females) with DS enrolled in the Alzheimer’s disease Down syndrome study. A total of 18 participants had a history of seizures: 9 participants had recent onset of seizures in the last 5 years and 9 participants had childhood-onset of seizures. A 2-to-1 match method was used to identify 36 control match participants based on age, sex, and dementia status. Magnetic resonance imaging (MRI) and flortaucipir (FTP) positron emission tomography (PET) were used to assess atrophy and tau accumulation respectively. Plasma ptau181 levels were assessed using the ultra-sensitive single molecule array (Simoa) technology platform HDX imager. ANOVA was used to assess group differences. The results showed significant differences in ptau181 levels between individuals with late-onset seizure disorder, individuals with childhood-onset of seizures, and controls (F(2,51)= 9.649; p <.001). Post-hoc analysis revealed that individuals with late-onset seizure disorder had significantly higher levels of ptau181 compared to individuals with childhood-onset ( p <.001) and controls ( p = 0.002), with no differences between childhood-onset seizures and controls. No differences were observed in the hippocampus volume among the three groups. Differences in the temporal meta-ROI tau SUVR were assessed in a subset of our sample. We observed a trend in individuals with history of seizures showing higher tau SUVR in the temporal meta-ROI compared to controls. Our findings suggest that the levels of ptau181 could be impacted by late-onset seizure disorder. These results shed the light on the importance of assessing the impact of co-occurring disorder on AD related biomarkers. Future research will explore the impact of late-onset seizure disorder on AD-related brain biomarkers longitudinally.

BACKGROUND:Individuals with Down syndrome (DS) have a 90% lifetime risk for symptomatic Alzheimer's disease. Yet, there is a 20+ year age range in when individuals with DS reach PET amyloid-beta (Aβ) positivity (i.e., centiloid (CL) ≥18). There is a critical need to identify factors associated with resistance (i.e., less than expected Aβ for age) and resilience (i.e., better than expected cognitive function given Aβ) in the DS community. METHOD:262 adults with DS (M=43.93, SD=9.29) in the Alzheimer Biomarker Consortium-Down syndrome underwent MRI and amyloid PET scans with [11C] PiB or [18F] florbetapir. A study partner reported on health history. Systolic blood pressure and BMI were obtained. Using multiple regression models, we examined the best fit function for association between: 1) age and Aβ, and 2) Aβ and cognitive performance, adjusted for premorbid intellectual disability level. We than calculated each participant's residual (i.e., difference between observed versus predicted value) to assess resistance to Aβ (defined as less than predicted Aβ for age) and resilience to cognitive impairment (defined as better than predicted cognition for Aβ). The modified Cued Recall Test and Down Syndrome Mental Status Exam were used as cognitive scores. The cardiovascular composite was based on the original and no-lab Framingham Risk Score (BMI ≥ 30, systolic blood pressure ≥ 130, use of statins, and presence of hypertension, hyperlipidemia, and diabetes). RESULT:In partial correlations adjusted for age, there was a significant positive association between the cardiovascular composite (r = .156, p = .016) and resistance score; higher cardiovascular composite was associated with greater than expected Aβ for age. At the item level, hyperlipidemia was associated with a 1.8 x higher likelihood of greater than expected Aβ for age (OR = 1.83, p = .047). There was not a significant correlation between the cardiovascular composite and the resilience scores. CONCLUSION:Cardiovascular conditions may alter resistance to DSAD, including an earlier age of Aβ accumulation, and be an important target for delaying or preventing DSAD.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study (n = 195, age = 50.6 +/- 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension. Rizvi et al. found that increased pulse pressure is associated with small vessel cerebrovascular disease in adults with Down syndrome. They also found that pulse pressure was indirectly related to dementia through intermediate markers of white matter hyperintensities and neurodegeneration. Graphical Abstract

BACKGROUND:Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. METHODS:We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. FINDINGS:For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. INTERPRETATION:Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. FUNDING:National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).

INTRODUCTION:Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS:T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS:Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION:The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

INTRODUCTION:Alzheimer's disease (AD) affecting adults with Down syndrome (DS-AD), like late-onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only tasks placing high demands on cognition are expected to be affected during the prodromal stage, with activities of daily living (ADLs) typically being spared. However, cognitive demands of ADLs could be high for adults with DS and may be affected during prodromal DS-AD. METHODS:Cognitively stable cases that subsequently developed prodromal DS-AD were identified within a set of archived data from a previous longitudinal study. Measures of ADLs and multiple cognitive domains were examined over time. RESULTS:Clear declines in ADLs accompanied cognitive declines with prodromal DS-AD while stability in all measures was verified during preclinical DS-AD. DISCUSSION:Operationally defining prodromal DS-AD is essential to disease staging in this high-risk population and for informing treatment options and timing as new disease-modifying drugs become available. Highlights:Cognitive and functional stability were demonstrated prior to the onset of prodromal DS-AD.ADL declines accompanied cognitive declines as adults with DS transitioned to prodromal AD.Declines in ADLs should be a defining feature of prodromal AD for adults with DS.Better characterization of prodromal DS-AD can improve AD diagnosis and disease staging.Improvements in DS-AD diagnosis and staging could also inform the timing of interventions.

Adults with Down Syndrome (DS) develop Alzheimer disease (AD)-like pathology and dementia as they age. This is attributed to triplication of the amyloid precursor protein gene. Recent work demonstrated that amyloid is elevated in DS and accumulates in a similar topography to autosomal dominant AD (ADAD). Tau accumulation is the second hallmark of AD and may be measured using tau positron emission tomography (PET) imaging. The pattern of tau accumulation remains unknown in DS. In a cross-sectional analysis we evaluated amyloid and tau positron emission tomography (PET) in 124 participants with DS (109 cognitively stable, 8 symptomatic, 7 no consensus), 29 ADAD mutation carriers (26 asymptomatic, 3 symptomatic), and 201 cognitively normal non-mutation carriers (CN). Regional cortical standard uptake value ratios (SUVR) for tau imaging were obtained and compared by cognitive status. Similarly, regional cortical amyloid SUVR were obtained and converted to centiloids. We then compared the magnitude of tau burden as well as spatial spread of tau across groups relative to amyloid burden. Compared to CN, tau PET binding was elevated in participants with (µ DS = 2.12 ± 0.22 SUVR, µ ADAD = 2.52 ± 0.37 SUVR) and without (µ DS = 1.24 ± 0.15 SUVR, µ ADAD = 1.16 ± 0.19 SUVR) cognitive changes. For both groups, tau increased with increasing amyloid (centiloids). In some regions, DS had greater tau burden for a given amyloid level (centiloids) (Figure 1). There was increased spatial distribution of tau throughout the brain for participants with DS compared to CN. In contrast, tau burden was more focal in participants with ADAD with tau primarily elevated in posterior regions (Figure 2). While tau burden was higher with symptomatic disease for both groups, significant differences existed in the overall amount and spatial spread. Tau spread was greatest in participants with DS and more diffuse compared to ADAD. These results indicate a substantial tau burden is present in DS, and suggest not only anti-amyloid but also tau-reducing agents should be considered for treating cognitive decline in adults with DS.

Down 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. We 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. Increased 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). Increased 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.

Only 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. We 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. Our 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 P meta < 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. This 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.

BACKGROUND:Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. METHODS:In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated. FINDINGS:192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p<0·0001) and in people with Down syndrome (n=32; r=-0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. INTERPRETATION:Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. FUNDING:The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Triplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous research has used changes in cortical thickness (CT) as an indicator of neurodegeneration in autosomal-dominant AD 1 , but not DS-related AD. It is unclear when and where cortical thinning occurs along the AD continuum in DS and if these differences are associated with increasing AD pathology. Cross-sectional analysis compared DS participants from the Alzheimer Biomarkers Consortium-Down Syndrome (106 amyloid-/cognitively unimpaired, nonclinical, 20% reserved for receiver-operating characteristic, ROC, analyses; 45 amyloid+/cognitively unimpaired, preclinical; 27 amyloid+/cognitively impaired, clinical) who had amyloid positron emission tomography and magnetic resonance imaging (MRI). Amyloid positivity was defined using standardized uptake value ratio (partial volume corrected) cortical mean values (1.42/1.19 for PIB/AV45 2 ) and impairment was based on consensus diagnosis. CT differences between nonclinical and clinical groups were calculated in FreeSurfer v5.3 for multiple thresholds (p<.05/.01/.005/.001/.0005/.0001) using a cluster-wise false discovery rate of .001, corrected across hemispheres, after controlling for age and sex. CT values were extracted for each threshold and used in ROC analyses (nonclinical reserved participants compared against preclinical and preclinical compared against clinical) to identify key cortical regions that best discriminated amyloid positivity and between unimpaired and impaired. Significant decreases in parietal and inferior temporal CT were observed between nonclinical and clinical (Figures 1 and 2). ROC analyses identified regions in the left (threshold .05) and right (threshold .005) hemispheres that best differentiated nonclinical from preclinical. Observed area under the curves (AUCs) of .772 and .830 exceeded those previously reported for autosomal-dominant AD (.547/.540) 1 . Analyses differentiating preclinical from clinical observed AUCs of .786 for left (threshold .0005) and .770 for right (threshold .0005) hemispheres. CT differences primarily within posterior cortical regions differentiated adults with DS by amyloid status and cognitive impairment. CT differences were more diffuse for amyloid positivity but more focal for impairment. 1. Dincer (2020). NeuroImage: Clinical , 28 , 102491. 2. Su (2019). Alzheimer’s Dement, 11 , 180-190.

Introduction:Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) and vary in their age of transition from AD preclinical to prodromal or more advanced clinical stages. An empirically based method is needed to determine individual "estimated years from symptom onset (EYO)," the same construct used in studies of autosomal dominant AD . Methods:Archived data from a previous study of > 600 adults with DS were examined using survival analysis methods. Age-specific prevalence of prodromal AD or dementia, cumulative risk, and EYOs were determined. Results:Individualized EYOs for adults with DS ranging in age from 30 to 70+ were determined, dependent upon chronological age and clinical status. Discussion:EYOs can be a useful tool for studies focused on biomarker changes during AD progression in this and other populations at risk, studies that should contribute to improved methods for diagnosis, prediction of risk, and identification of promising treatment targets. HIGHLIGHTS:Years from Alzheimer's disease (AD) onset (EYO) was estimated for adults with Down syndrome (DS).EYOs were informed by AD clinical status and age, ranging from 30 to > 70 years.Influences of biological sex and apolipoprotein E genotype on EYOs were examined.EYOs have advantages for predicting risk of AD-related dementia compared to age.EYOs can be extremely informative in studies of preclinical AD progression.

BACKGROUND:Obesity in adults without Down syndrome is associated with an adverse metabolic profile including high prevalence of pre-diabetes and diabetes, high levels of insulin, non-high-density lipoprotein (HDL) cholesterol, leptin and high-sensitivity C-reactive protein (hsCRP) and low levels of HDL and adiponectin. We examined whether obesity in middle-aged adults with Down syndrome is also related to an adverse metabolic profile. METHODS:This cross-sectional study included 143 adults with Down syndrome, with a mean age of 55.7 ± 5.7 years and 52.5% women. Body mass index (BMI) was classified as underweight (BMI < 18.5 kg/m2 ), normal (BMI 18.5-24.9 kg/m2 ), overweight (BMI 25-29.9 kg/m2 ) and obese (BMI ≥ 30 kg/m2 ). Diabetes was ascertained by history or by haemoglobin A1c (HbA1c) as normal glucose tolerance (HbA1c < 5.7%), pre-diabetes (HbA1c 5.7-6.4%) and diabetes (HbA1c ≥ 6.5%). We measured non-fasting lipids, hsCRP, insulin, adiponectin and leptin. RESULTS:The majority of the sample had an overweight (46.9%) or obesity (27.3%) status. However, there was a relatively low prevalence of pre-diabetes (9.8%) and diabetes (6.9%). Overweight and obesity status were not associated with lower HDL and adiponectin and higher insulin, non-HDL cholesterol and hsCRP as expected in adults without Down syndrome. However, overweight and obesity were strongly associated with higher leptin (P < 0.001). CONCLUSIONS:The only metabolic correlate of obesity in middle-aged adults with Down syndrome was high leptin levels. Our findings are limited by non-fasting laboratory tests but suggest that middle-aged adults with Down syndrome do not have the adverse metabolic profile related to obesity found in adults without Down syndrome.