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: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.

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.

Plasma neurofilament light (NfL) and total tau (t-tau) are emerging as promising biomarkers of Alzheimer’s disease (AD) in adults with Down Syndrome (DS). Sex may influence the levels of these biomarkers however, research on sex differences in these biomarkers is limited. In this study, we examined whether sex influences plasma levels and clinical classification accuracy of NfL and t-tau. We performed a cross-sectional analysis of 275 adults with DS (106 males; 169 females) from a community-based cohort. Levels of plasma NfL and t-tau were measured using the Simoa platform. Based on consensus diagnosis using a battery of direct neuropsychological testing and informant interviews, participants were classified into three clinical dementia groups: cognitively stable (CS), mild-cognitive impairment (MCI-DS) and Alzheimer’s dementia (AD-DS). Two-way analysis of covariance was used to assess group differences in males and females, adjusting for age. Post-hoc pairwise comparisons were adjusted for multiple comparisons using the Bonferroni correction. Receiver operating characteristic analyses were conducted to evaluate the performance of the biomarkers to classify dementia status in males and females, separately. In this study, 27 (16%) and 10 (6%) females while 12 (11%) and 13 (12%) males exhibited MCI-DS and AD-DS, respectively. Females were, on average, 4.5 years younger than males. Age-adjusted levels of plasma t-tau (p interaction = 0.047), but not NfL (p interaction = 0.138), significantly differed by sex. NfL levels were higher in MCI-DS and AD-DS groups than in the CS group in both sexes (all p adjusted < 0.05). T-tau levels were significantly higher in the MCI-DS and AD-DS (both p adjusted < 0.01) groups than in the CS group in females but did not differ across clinical groups in males. NfL showed excellent accuracy in females (range AUC NfL : 0.74-0.97) and males (AUC NfL : 0.71-0.88), while t-tau showed classification utility in females (AUC t-tau :0.69-0.90), but not in males (AUC t-tau : 0.48-0.66). Our findings suggest that levels and accuracy of plasma NfL and t-tau to classify dementia differed by sex in adults with DS. These differences underscore the need to further elucidate sex specific patterns of fluid biomarkers, critical in the development of personalized medicine approaches in AD.

Background: Sex differences in the risk of Alzheimer’s Disease (AD) in adults with Down Syndrome (DS) have not been extensively investigated, and existing studies have found conflicting results. This study examined the effect of sex on the risk of AD in adults with DS, adjusted for covariates. Methods: Adults with DS were assessed longitudinally for the development of AD. Competing risk survival analyses were used to determine the effect of sex alone and after adjustment for APOE-ε4 status, ethnicity, and level of intellectual disability (ID). Results: Sex differences were significant only in adults over 60 years of age, where men with DS were 6.32 (95% CI: 2.11–18.96, p < 0.001) times more likely to develop AD compared with age-matched women with DS. Conclusions: There is an age-associated effect of sex on the risk of AD, with men over 60 years old having six times the risk of AD compared with age-matched women, independent of APOE-ε4 status, ethnicity, and level of ID.

Adults with Down syndrome, the largest population genetically predisposed to high risk for Alzheimer's disease (AD), are ideally suited participants for clinical trials targeting prevention. Critically important considerations for the design of such trials include appropriate selection of participants, outcome measures, and duration of follow‐up.

AbstractBackgroundThe value of plasma neurofilament light (NfL), a marker of neurodegeneration, in Alzheimer’s Disease (AD) has been reported in the general population. However, evidence for NfL as a predictive marker of neurodegeneration in adults with Down Syndrome (DS) is limited. The small number of longitudinal studies have short follow‐up periods. Thus, the value of NfL as a prognostic indicator of AD is still unknown. To date, no study has examined whether levels of NfL predict the trajectories of cognitive decline in adults with DS. In this study, we will examine the association of NfL with incident AD and trajectories of cognitive decline.MethodWe studied 271 adults with DS who were dementia‐free at the baseline and were assessed at 14‐ to 18‐month intervals for up to 5‐cycles. Baseline plasma NfL was measured using the Simoa platform. Neuropsychological tests assessing various cognitive domains were administered at each follow‐up visit and AD status was determined by consensus diagnosis. Cox proportional hazards models were used to assess the association between baseline NfL and incident AD. Linear mixed modeling was used to evaluate the relations between NfL and changes in neuropsychological measures over time. Estimates were adjusted for age at blood collection, sex, presence of APOE ε4 allele, and level of premorbid intellectual functioning.ResultOver the follow‐up period, 54 (21%) individuals developed AD with the mean follow‐up of 4.7 years. Elevated plasma NfL levels were significantly associated with incident dementia (p < 0.001); the risk of AD increases by 34% per 10 pg/mL increase in NfL. Participants who were in the highest quartile of NfL (41‐120 pg/mL) were 8 times (95% CI: 2.5‐25.3) more likely to develop AD, compared to those in the lowest quartile. Moreover, elevated NfL levels were significantly associated with faster declines in various neuropsychological domains (i.e., mental status, episodic memory, visuospatial organization), but not verbal fluency and construction.ConclusionElevated baseline plasma NfL is a prognostic marker of accelerated cognitive decline and subsequent incident dementia in adults with DS. Our findings suggest that NfL may have utility for use in routine disease monitoring and clinical trial screening.

INTRODUCTION:Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) and its associated dementia, warranting the development of strategies to improve early detection when prevention is possible.METHODS:Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we evaluated the psychometrics of measures in a large sample of 561 adults with DS. We tracked longitudinal stability or decline in functioning in a subsample of 269 participants over a period of 3 years, all initially without indications of clinically significant aging-related decline.RESULTS:Results identified an array of objective measures that demonstrated sensitivity in distinguishing individuals with incident "mild cognitive impairment" (MCI-DS) as well as subsequent declines occurring with incident dementia.DISCUSSION:Several instruments showed clear promise for use as outcome measures for future clinical trials and for informing diagnosis of individuals suspected of experiencing early signs and symptoms of a progressive dementia process.

Funding information National InstitutesofHealth,Grant/Award Numbers: P01HD035897,U54HD079123, U01AG051412,R01AG014673 Abstract Introduction: Adults with Down syndrome (DS) are at high risk for developing Alzheimer’s disease (AD) and its associated dementia, warranting the development of strategies to improve early detection when prevention is possible. Methods: Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we evaluated the psychometrics of measures in a large sample of 561 adultswithDS.We tracked longitudinal stability or decline in functioning in a subsample of 269 participants over a period of 3 years, all initially without indications of clinically significant aging-related decline. Results: Results identified an array of objective measures that demonstrated sensitivity in distinguishing individuals with incident “mild cognitive impairment” (MCI-DS) as well as subsequent declines occurring with incident dementia. Discussion: Several instruments showed clear promise for use as outcome measures for future clinical trials and for informing diagnosis of individuals suspected of experiencing early signs and symptoms of a progressive dementia process.

Adults with Down syndrome (DS) are at substantially increased risk for developing Alzheimer's disease (AD). Despite significant advancements in the search for biomarkers of AD pathology, the search for blood-based biomarkers that can detect and predict AD risk among adults with DS has received less attention. Here we applied our previously established biomarker profile for detecting AD in the general population to a large cohort of adults with DS. Biobanked plasma samples from adults with DS who have been followed over time were assayed. Proteomics were conducted via electrochemiluminescence from our previously generated algorithm. Support vector machine (SVM) analyses were utilized to create a proteomic risk score taking into account the variable importance of each of the markers specifically for prevalent AD and incident AD. We conducted Cox proportional hazards modeling to examine the relation of the proteomic risk score to onset of dementia in those above the cut point compared with those below the cut point, adjusting for age, sex, level of intellectual disability, race/ethnicity and the presence of an APOE E4 allele. There were 399 participants included in the analysis. Of these 53 were determined to have prevalent dementia, 71 developed dementia and 275 remained nondemented over the 6 year follow-up period. The SVM risk score accurately detected prevalent dementia in DS with an AUC=0.89, sensitivity (SN) = 0.83 and specificity (SP) = 0.98. The SVM risk score was also highly accurate in predicting incident AD. For incident dementia, the SVM risk score yielded an AUC=0.90, SN=0.80 and SP=0.93. When the SVM-based risk scores for incident AD were entered into Cox proportional models, the HR for incident dementia =9.89 (95% CI= 5.8-16.9). Of note, the predictive algorithm was heavily weighted for inflammatory markers (e.g. eotaxin, TARC, I309, IL10, IL5, TNFα). Overall, the current results provide strong support for the use of our blood-based proteomic profile for both detecting and predicting dementia among adults with DS. As we have proposed for AD in the general population, the goal of the blood-based biomarker is to serve as the first-step in a multi-tiered neurodiagnostic approach.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.

COVER FIGURE The cover image, by Edmund C. Jenkins et al., is based on the Research Article Longitudinal telomere shortening and early Alzheimer's disease progression in adults with down syndrome, DOI: 10.1002/ajmg.b.32575.

Abstract Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer’s disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue–green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 – P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.

Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid beta- levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules. (C) 2017 Elsevier Inc. All rights reserved.

Several lines of investigation have shown a protective role for estrogen in Alzheimer's disease through a number of biological actions. This review examines studies of the role of estrogen-related factors in age at onset and risk for Alzheimer's disease in women with Down syndrome, a population at high risk for early onset of dementia. The studies are consistent in showing that early age at menopause and that low levels of endogenous bioavailable estradiol in postmenopausal women with Down syndrome are associated with earlier age at onset and overall risk for dementia. Polymorphisms in genes associated with estrogen receptor activity and in genes for estrogen biosynthesis affecting endogenous estrogen are related to age at onset and cumulative incidence of dementia, and may serve as biomarkers of risk. To date, no clinical trials of estrogen or hormone replacement therapy (ERT/HRT) have been published for women with Down syndrome. While findings from clinical trials of ERT or HRT for dementia have generally been negative among women in the neurotypical population, the short interval between menopause and onset of cognitive decline, together with a more positive balance between potential benefits and risks, suggests an opportunity to evaluate the efficacy of ERT/HRT for delaying or preventing dementia in this high risk population, although questions concerning the optimal formulation and timing of the hormone therapy are not yet resolved.

We hypothesized that irrespective of the differences in antibodies to Aβ40 or Aβ42, analytical platforms or absolute levels of CSF Aβ40 and Aβ42 in ELISA or xMAP, both methods would perform equally well to support the diagnosis of patients with probable AD.