Prodromal Alzheimer's disease can affect activities of daily living for adults with Down syndrome.

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.

Individualized estimated years from onset of Alzheimer's disease- related decline for adults with Down syndrome.

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.

The Association between Sex and Risk of Alzheimer's Disease in Adults with Down Syndrome.

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.

Promising outcome measures of early Alzheimer's dementia in adults with Down syndrome.

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.

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

INTRODUCTION: We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS). METHODS: In a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non-demented and without MCI or AD at baseline and throughout follow-up; n = 103 had incident MCI and n = 81 had incident AD. Proteomics were conducted on banked plasma samples from a previously generated algorithm. RESULTS: The proteomic profile was highly accurate in predicting incident MCI (area under the curve [AUC] = 0.92) and incident AD (AUC = 0.88). For MCI risk, the support vector machine (SVM)-based high/low cut-point yielded an adjusted hazard ratio (HR) = 6.46 (P < .001). For AD risk, the SVM-based high/low cut-point score yielded an adjusted HR = 8.4 (P < .001). DISCUSSION: The current results provide support for our blood-based proteomic profile for predicting risk for MCI and AD among adults with DS.

Proteomic profiles of prevalent mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

INTRODUCTION: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS). METHODS: Plasma samples were obtained from 398 members of a community-based cohort of adults with DS. A total of n = 186 participants were determined to be non-demented and without mild cognitive impairment (MCI) at baseline and throughout follow-up; n = 50 had prevalent MCI; n = 42 had prevalent AD. RESULTS: The proteomic profile yielded an area under the curve (AUC) of 0.92, sensitivity (SN) = 0.80, and specificity (SP) = 0.98 detecting prevalent MCI. For detecting prevalent AD, the proteomic profile yielded an AUC of 0.89, SN = 0.81, and SP = 0.97. The overall profile closely resembled our previously published profile of AD in the general population. DISCUSSION: These data provide evidence of the applicability of our blood-based algorithm for detecting MCI/AD among adults with DS.

Epidemiology of estrogen and dementia in women with Down syndrome.

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.

Candidate gene analysis for Alzheimer's disease 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 ß 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.

Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome.

We examined the contribution of candidates genes for Alzheimer's disease (AD) to individual differences in levels of beta amyloid peptides in adults with Down syndrom, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30-78 years of age. Genomic deoxyribonucleic acid was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aß peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race and/or ethnicity, and the presence of the APOE ε4 allele. For Aß42 levels, the strongest gene-wise association was found for a single nucleotide polymorphism (SNP) on CAHLM1; for Aß40 levels, the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aß42/Aß40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence amyloid precursor protein processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1).

Polymorphisms in HSD17B1: Early Onset and Increased Risk of Alzheimer's Disease in Women with Down Syndrome.

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD. HSD17B1 encodes the enzyme 17ß-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol. Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31-78 years of age, were followed at 14-18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in the HSD17B1 gene region, and their association with incident AD was examined. Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 in COASY (rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1-3.1). Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.

Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with down syndrome.

CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

Estrogen receptor-Beta variants are associated with increased risk of Alzheimer's disease in women with down syndrome.

BACKGROUND/AIMS: Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). We examined the relation of polymorphisms in the gene for the estrogen receptor-beta (ESR2) to the risk of AD in women with Down syndrome. METHODS: Two hundred and forty-nine women with Down syndrome, 31-70 years of age and nondemented at baseline, were followed at 14- to 18-month intervals for 4 years. Women were genotyped for 13 single-nucleotide polymorphisms (SNPs) in the ESR2 gene, and their association with AD incidence was examined. RESULTS: Among postmenopausal women, we found a 2-fold increase in the risk of AD for women carrying 1 or 2 copies of the minor allele at 3 SNPs in introns seven (rs17766755) and six (rs4365213 and rs12435857) and 1 SNP in intron eight (rs4986938) of ESR2. CONCLUSION: These findings support a role for estrogen and its major brain receptors in modulating susceptibility to AD in women.

Altered DNA methylation in leukocytes with trisomy 21.

The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2'deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.

Shorter telomeres may indicate dementia status in older individuals with Down syndrome.

We have recently reported reduced telomere length in T lymphocytes of individuals with Down syndrome (DS) and dementia due to Alzheimer's disease (AD). We have now replicated and extended that study by finding that people with DS and mild cognitive impairment (MCI-DS) also have shorter telomeres than people with DS without MCI-DS. Additional new findings demonstrated that light intensity measurements from chromosome 21 alone, or in concert with chromosomes 1, 2, and 16, exhibited shorter telomeres in adults with DS and with either dementia or MCI-DS compared to aging per se. Chromosome 21 measurements appeared to be especially promising for use as a biomarker because there was no overlap in the distribution of light intensity measurement scores between demented or MCI-DS and non-demented participants. Given that early clinical symptoms of AD can be very difficult to recognize in this population of adults due to their pre-existing cognitive impairments, a valid biomarker would be of great value. Early detection is especially important because it would allow treatments to begin before significant damage to the central nervous system has occurred. Our findings suggest that it may be feasible to use telomere shortening as a biomarker for accurately inferring dementia status.

Increased "absence" of telomeres may indicate Alzheimer's disease/dementia status in older individuals with Down syndrome.

We have reported previously that telomeres (ends of chromosomes consisting of highly conserved TTAGGG repeats) were shorter in metaphase and interphase preparations in T lymphocytes from short-term whole blood cultures of women with Down syndrome (DS) and dementia compared to age-matched women with DS but without dementia [E.C. Jenkins, M.T. Velinov, L. Ye, H. Gu, S. Li, E.C. Jenkins Jr., S.S. Brooks, D. Pang, D.A. Devenny, W.B. Zigman, N. Schupf, W.P. Silverman, Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia, Neurobiol. Aging 27 (2006) 41-45]. Our previous study was carried out by measuring changes in fluorescence intensity [using an FITC-labeled peptide nucleic acid (PNA) probe (Applied Biosystems; DAKO) and Applied Imaging software], and we now report on a substantially simpler metric, counts of signals at the ends of chromosomes. Nine adults with DS and dementia plus four who are exhibiting declines in cognition analogous to mild cognitive impairment in the general population (MCI-DS) were compared to their pair-matched peers with DS but without dementia or MCI-DS. Results indicated that the number of chromosome ends that failed to exhibit fluorescent signal from the PNA telomere probe was higher for people with dementia or mild cognitive impairment (MCI-DS). Thus, a simple count of chromosome ends for the "presence/absence" of fluorescence may provide a valid biomarker of dementia status. If this is the case, then after additional research for validation to assure high specificity and sensitivity, the test may be used to identify and ultimately guide treatment for people at increased risk for developing mild cognitive impairment and/or dementia.

Estrogen receptor-alpha variants increase risk of Alzheimer's disease in women with Down syndrome.

BACKGROUND: Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). Two tightly linked polymorphisms (PvuII and XbaI) in the first intron of estrogen receptor 1 (ESR1), the gene for ER-alpha, have been reported to influence estrogen receptor expression and may influence the risk of AD. METHODS: We examined the relation of polymorphisms in ESR1 to the risk of AD in women with Down syndrome. The subjects (181 women with DS, 41-78 years of age) were followed at 14- to 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record reviews and neurological examinations was used to classify dementia. Genomic DNA was genotyped for 5 single-nucleotide polymorphisms in the upstream region and the first exon/intron of the ESR1 gene. Their association with dementia risk was evaluated, adjusting for covariates. RESULTS: Women with at least 1 copy of the C allele at rs2234693 (PvuII) and those homozygous for the C allele at rs2077647 had an almost 3-fold increase in the risk of AD, compared with women without the C allele. The increased risks were independent of the apolipoprotein E genotype. CONCLUSION: These findings support a role for estrogen receptor activity in the development of AD in women with Down syndrome.

Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome.

Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African-American and Isreali-Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of beta amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45-70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR=0.26, 95% CI: 0.08-0.86; and HR=0.40, 95% CI: 0.16-0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.

Elevated plasma beta-amyloid peptide Abeta(42) levels, incident dementia, and mortality in Down syndrome.

BACKGROUND: Deposition of the beta-amyloid peptide Abeta(42) is thought to be an important initial step in the pathogenesis of Alzheimer disease (AD). Individuals with Down syndrome have increased levels of beta-amyloid peptides and an increased risk for AD. OBJECTIVE: To examine the relation of plasma levels of Abeta(42) and Abeta(40) to the risk of dementia in nondemented participants and all-cause mortality in adults with Down syndrome. DESIGN: Prospective, community-based longitudinal cohort study. SETTING: State and voluntary service providers in New York State. PARTICIPANTS: Adults with Down syndrome (N = 204). MAIN OUTCOME MEASURE: Plasma Abeta(42) and Abeta(40) levels were measured at initial examination. Participants were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health and vital status at 14- to 18-month intervals for 4 cycles of data collection. RESULTS: Among participants who were nondemented at baseline, those in the middle and highest tertiles of plasma Abeta(42) levels were more than 2 times as likely to develop AD as those in the lowest tertile. Compared with participants without AD, participants with prevalent AD had higher levels of plasma Abeta(42) but not Abeta(40). Among all participants, those in the highest tertile of plasma Abeta(42) level at baseline were more than twice as likely to die during the study period as those in the lowest tertile, whereas there was no difference in risk of death between those in the middle and lowest tertiles of plasma Abeta(42) level. CONCLUSION: Elevations in plasma Abeta(42) peptide levels are associated with earlier onset of AD and increased risk of death.

Bioavailable estradiol and age at onset of Alzheimer's disease in postmenopausal women with Down syndrome.

Several lines of evidence suggest that loss of estrogen after menopause may play a role in the cognitive declines associated with Alzheimer's disease (AD). Women with Down syndrome (DS) experience early onset of both menopause and AD. This timing provides a model to examine the influence of endogenous estrogen deficiency on risk of AD. We hypothesized that low serum levels of bioavailable estradiol (E2) would be associated with increased risk of AD. One hundred and nineteen postmenopausal women with DS, 42-59 years of age, were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Women with DS who developed AD had lower levels of bioavailable E2, lower levels of total estradiol, higher levels of sex-hormone binding globulin, and lower levels of dehydroepiandrosterone sulfate at baseline than women who remained dementia free over the course of follow-up. Women who had low levels of bioavailable E2 at baseline were four times as likely to develop AD (HR=4.1, 95% CI: 1.2-13.9) and developed AD, on average, 3 years earlier, than those with high levels of bioavailable E2, after adjustment for age, level of mental retardation, ethnicity, body mass index, history of hypothyroidism or depression and the presence of the apolipoprotein varepsilon4 allele. Our findings support the hypothesis that reductions in estrogen following menopause can contribute to the cascade of pathological processes leading to AD.

Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia.

Telomere shortening has been recently correlated with Alzheimer's disease status. Therefore, we hypothesized that a possible association might exist for adults with Down syndrome (DS). Using blind, quantitative telomere protein nucleic acid FISH analyses of metaphase and interphase preparations from 18 age-matched trisomy 21 female study participants with and without dementia, we have observed increased telomere shortening in adults with DS and dementia (p < .01). From this initial study, we conclude that telomere shortening is associated with dementia in this high-risk population and suggest that additional research may show that telomere shortening may be a biological marker of dementia status.