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

ABSTRACT: 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 A? 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 ?4 allele. For A?42 levels, the strongest gene-wise association was found for a single nucleotide polymorphism (SNP) on CAHLM1; for A?40 levels, the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the A?42/A?40 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).

SUBMITTER: Schupf N

PROVIDER: S-EPMC4562880 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Schupf Nicole N Lee Annie A Park Naeun N Dang Lam-Ha LH Pang Deborah D Yale Alexander A Oh David Kyung-Taek DK Krinsky-McHale Sharon J SJ Jenkins Edmund C EC Luchsinger José A JA Zigman Warren B WB Silverman Wayne W Tycko Benjamin B Kisselev Sergey S Clark Lorraine L Lee Joseph H JH

Neurobiology of aging 20150619 10

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 Aβ peptides associated with the number of risk alleles, adjusting f ...[more]

PMID: 26166206

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Project description:OBJECTIVE:The objectives of this study were to investigate whether the plasma levels of oligomeric amyloid-β (OAβ) were affected in Alzheimer's disease (AD) and to examine the associations (or possible correlations) between plasma OAβ levels and memory performance. METHOD:Thirty subjects with AD and 28 cognitively normal controls were recruited in the study. The multimer detection system (MDS) was used to measure the levels of OAβ in the plasma. In addition to assessing the general cognitive function with the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), and Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-Cog), the common objects memory test (COMT) was used to examine the episodic memory performance. Pearson's and partial correlation analyses were conducted to explore the associations between cognitive performance and OAβ levels in the plasma. A receiving operating curve (ROC) analysis was used to discriminate between the AD and control groups. RESULTS:The plasma OAβ levels in the AD group were significantly higher than those in the control group [1.88 (0.38) ng/ml vs 1.20 (0.40) ng/ml, p < 0.001]. The elevated levels of plasma OAβ showed a strong correlation with cognitive performance in patients with AD, including an inverse correlation with scores on the MMSE (r = - 0.43, p = 0.02), CASI (r = - 0.56, p < 0.01), and the immediate recall (r = - 0.45, p = 0.01), 5-min delayed recall (r = - 0.56, p < 0.01), and 30-min delayed recall (r = - 0.71, p < 0.001) tests of the COMT, and a positive correlation with the ADAS-Cog scores (r = 0.59, p < 0.001). The EDTA plasma Aβ oligomer optical density (OD) value measured using the MDS could discriminate between the AD and control groups with an area under the curve (AUC) of 0.89. The optimal sensitivity and specificity were 82.1% and 90.0%, respectively. CONCLUSION:The elevated levels of OAβ in the plasma distinguished the AD and control groups and were associated with the severity of symptoms, especially memory performance, in patients with AD. Our results suggested that plasma OAβ could potentially be a simple and non-invasive blood-based biomarker for AD diagnosis. Furthermore, longitudinal studies are warranted to explore the application of plasma OAβ levels as a valid diagnostic biomarker in patients with AD.

Project description:Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.

Dataset Information

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

Publications

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

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