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Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome.

ABSTRACT: It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.

SUBMITTER: Mok KY

PROVIDER: S-EPMC3969241 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome.

Mok Kin Y KY Jones Emma L EL Hanney Marisa M Harold Denise D Sims Rebecca R Williams Julie J Ballard Clive C Hardy John J

Neurobiology of aging 20131227 6

It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderlin ...[more]

PMID: 24462566

Similar Datasets

Erratum to "Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome" [Neurobiol. Aging 35 (2014) 1513.e1-1513.e5].

Project description: Not available

| S-EPMC5617740 | biostudies-literature

Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome.

Project description:It is known that individuals with Down syndrome develop Alzheimer's disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer's disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N = 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer's disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer's disease in Down syndrome with PICALM (β = 3.31, p = 0.011) and the APOE loci (β = 3.58, p = 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer's disease in Down syndrome.

| S-EPMC3898582 | biostudies-literature

An Intron 7 Polymorphism in APP Affects the Age of Onset of Dementia in Down Syndrome.

Project description:People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt(5-8), in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt(5-8) and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD.

| S-EPMC3010675 | biostudies-literature

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

Project description: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 17?-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.

| S-EPMC3310186 | biostudies-literature

Alzheimer's disease associated with Down syndrome: a genetic form of dementia.

Project description:Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

| S-EPMC9387748 | biostudies-literature

Monoaminergic impairment in Down syndrome with Alzheimer's disease compared to early-onset Alzheimer's disease.

Project description:IntroductionPeople with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS.MethodsNoradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40).ResultsIn brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus non-DS controls, significantly decreased MHPG levels were noted in various brain regions, though to a lesser extent than for DS+AD versus EOAD. Apart from DOPAC, CSF/plasma concentrations were not altered between groups.DiscussionMonoamine neurotransmitters and metabolites were evidently impacted in DS, DS+AD, and EOAD. DS and DS+AD presented a remarkably similar monoaminergic profile, possibly related to early deposition of amyloid pathology in DS. To confirm whether monoaminergic alterations are indeed due to early amyloid β accumulation, future avenues include positron emission tomography studies of monoaminergic neurotransmission in relation to amyloid deposition, as well as relating monoaminergic concentrations to CSF/plasma levels of amyloid β and tau within individuals.

| S-EPMC5956808 | biostudies-literature

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

Project description:IntroductionAdults 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.MethodsUsing 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.ResultsResults 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.DiscussionSeveral 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.

| S-EPMC7335903 | biostudies-literature

Diagnosis of prodromal and Alzheimer's disease dementia in adults with Down syndrome using neuropsychological tests.

Project description:Introduction:We aimed to define prodromal Alzheimer's disease (AD) and AD dementia using normative neuropsychological data in a large population-based cohort of adults with Down syndrome (DS). Methods:Cross-sectional study. DS participants were classified into asymptomatic, prodromal AD and AD dementia, based on neurologist's judgment blinded to neuropsychological data (Cambridge Cognitive Examination for Older Adults with Down's syndrome [CAMCOG-DS] and modified Cued Recall Test [mCRT]). We compared the cutoffs derived from the normative data in young adults with DS to those from receiver-operating characteristic curve (ROC) analysis. Results:Diagnostic performance of the CAMCOG-DS and modified Cued Recall Test (mCRT) in subjects with mild and moderate levels of intellectual disability (ID) was high, both for diagnosing prodromal AD and AD dementia (area under the curve [AUC] 0.73-0.83 and 0.90-1, respectively). The cutoffs derived from the normative data were similar to those derived from the ROC analyses. Discussion:Diagnosing prodromal AD and AD dementia in DS with mild and moderate ID using population norms for neuropsychological tests is possible with high diagnostic accuracy.

| S-EPMC7322242 | biostudies-literature

Estrogen receptor ? variants affect age at onset of Alzheimer's disease in a multiethnic female cohort.

Project description:BACKGROUND/AIMS:Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer's disease (AD) in women of different ethnicities. We examined the influence of ESR1 polymorphisms on age at onset of AD in a multiethnic cohort of women. METHODS:Among 1,436 women participating in the Washington Heights Inwood Columbia Aging Project, association with age at AD onset was assessed for 41 single-nucleotide polymorphisms (SNPs) on the ESR1 gene using Cox proportional hazard models, adjusting for presence of an APOE ?4 allele, years of education, and body mass index. RESULTS:Six SNPs in self-identified White women were protectively associated with delayed age of AD onset in this self-identified group, including the two restriction fragment length polymorphisms PvuII (rs2234693) and XbaI (rs9340799) (HR range = 0.420-0.483). Two separate SNPs were found to affect age of AD onset in self-identified Black women. CONCLUSIONS:ESR1 polymorphisms affect age of onset of AD in women, and risk alleles vary by ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid environmental or cultural risk factors mediating the SNP effect on risk for AD.

| S-EPMC4141004 | biostudies-literature

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

Project description:Abstract 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.

| S-EPMC10300244 | biostudies-literature

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